Pandemic Survival Guide

Swine Influenza

Swine Influenza

SWINE INFLUENZA frightening you? CONCERNED about the health implications? Coughs and Sneezes Spread Diseases! Stop The Swine Flu from Spreading. Follow the advice to keep your family and friends safe from this virus and not become another victim. These simple cost free guidelines will help you to protect yourself from the swine flu.

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Pandemic Survival

This eBook shows you what it takes to survive the next pandemic. There is no doubt that in the future, the world will be hit with a huge pandemic, either from natural causes or from a terrorist attack. As you look through history, you will be hard-pressed to find any pandemic in history that has killed less than 1 million people. You do not want you or your family to be among those millions. And with the help of the information in this eBook, you have a way to survive the global pandemic that will come. Wishing it won't happen doesn't do anything Preparing for it gives you the tools to survive AND thrive. This book contains the two-pronged approach of John Hartman's years of research in figuring out how pandemics work and living through a dangerous flu outbreak. This gives you the methods to both avoid getting a virus in the first place, and how to strengthen your immune system should you come down with a virus. You don't have to lay down and die. You can fight the next pandemic.

Pandemic Survival Overview


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Avian Influenza H5N1 Virus An Emerging Global Pandemic

The specter of avian influenza emerging from Asia and spreading all over the globe is causing deeper concern by the day. As we witness the H5N1 virus evolving and becoming increasingly dangerous, a major pandemic may be unavoidable. The bird flu virus has already claimed more than 140 lives worldwide as of August 2006. Should bird flu spark a global pandemic, several hundred million people could die within a matter of weeks, which is many times the number of deaths due to AIDS so far. This pathogen is completely different from seasonal influenza virus, which kills between 1 and 2 million people worldwide in a typical year. In the worst previous pandemic of 1918, more than 20 million humans died of the Spanish flu. The current bird flu virus has emerged from a pool of animals that have previously never infected humans implying that humans do not have antibodies to combat the infection. This virus also causes severe disease and high fatality within a short time span. The only remaining...

Gathering Positive Neutral and Negative SARs During HTS

In this regard, it becomes important to briefly review some aspects of SARs that would be worthwhile to include within the database assemblies that are currently being drawn up to handle the mountains of data already arriving from today's HTS programs. One can predict that once ADMET profiling by HTS is validated in the future, it will become extremely valuable for a knowledge-generating paradigm to be able to discern not just the most active compounds within an efficacy database and to be able to compare their structural patterns to those in another database, but to also be able to flag the regions on compounds that can be altered with little effect on the desired biological activity as well as those areas that are intolerant toward structural modification. The neutral areas, in particular, represent ideal points for seamless merging of one set of a database's hits with that of another regardless of the degree of pattern overlap, or for further chemical manipulation of a hit so as to...

Ebola Virus History

Ebola virus (EBOV) was first discovered during near-simultaneous outbreaks in the former Zaire and Sudan. These outbreaks were due to serologically distinct viral species that would be designated ZEBOV and SEBOV, respectively. The CF was 88 in the initial ZEBOV outbreak and 53 in the SEBOV outbreak. The source ofthese outbreaks was never determined. These outbreaks were followed by several smaller outbreaks in the late 1970s. After an almost 20-year absence, a new EBOV outbreak was reported in 1989 in a colony of cynomolgus monkeys (Macaca fascicularis), imported from the Philippines to a holding facility in Reston (VA, USA). Although the Reston species appeared to be highly lethal in nonhuman primates (NHPs), no disease was reported in any of the documented human exposures. Although there have been a number of subsequent outbreaks of REBOV in NHP facilities both in and outside of the US, to date there have been no cases of human infections reported. Investigations traced the source...

Satellite DNAs and Associated Proteins

The class III satellite consists mostly of a 359-bp AT-rich repeat (73) located almost entirely on the X chromosome (approx 11 Mb 46). Dimers and trimers of this satellite behave as efficient scaffold-associated attached regions (SARs) (79 for a review, see ref. 80), defined as DNA restriction fragments that bind strongly to histone-depleted chromosomal scaffolds extracted from nuclei. SARs (also referred to as matrix-associated regions MARs ) are typically AT-rich sequences of several hundred basepairs and are cooperatively bound by DNA topoisomerase II (79). SARs have been found flanking a number of Drosophila genes, in some cases comapping with transcription enhancerlike sequences (81), and are postulated to define the sites where chromatin loops attach to an underlying scaffold or nuclear matrix (80). The observed cleavage of a 359-bp satellite by topoisomerase II may be important for satellite III condensation (79).

Exotic Viruses and Unmet Needs

At present there are no approved therapies for several types of 'exotic' viruses, those which are rare in the USA and Europe. However, several recent examples of emerging and life-threatening diseases due to Ebola viruses and hantaviruses have made it clear that, with world travel requiring less time than many virus disease incubation periods, disease might spring up at any locale, and geographic containment alone is not realistic. There have been 15 outbreaks of Ebola virus infections reported since 1967, and the horrors of these infections have received considerable publicity. Hantaviruses have long been known to cause Korean hemorrhagic fever (KHF). More recently hantavirus pulmonary syndrome (HPS), with rapid disease course and mortality as high as 50 in less than a week, has occurred in regions of the USA. These examples have been part of the stimulus for investigations of immunotherapy, extended evaluation of available antiviral drugs, and new drug discovery to define effective...

Regional Epidemiology

Following the earliest 'first colonization' descriptions of CMD epidemics in the 1920s and 1930s, a few reports were made of rapid area-wide spread of severe CMD at other times during the twentieth century, some of the most notable of which were epidemics in Cape Verde and southeastern Nigeria in the 1990s. Of much greater importance, however, has been the African CMD pandemic that was first reported from the northern-central part of Uganda in the late 1980s. CMD associated with the epidemic was unusually severe and was being rapidly spread by superabundant populations of B. tabaci. During the 1990s it became apparent that the zone affected by this severe CMD was expanding southwards at a rate of 20 30 km per year, and in 1997 molecular studies revealed that the severe disease phenotype was associated with the occurrence and spread of an 'invasive' recombinant CMG, EACMV-UG, commonly in mixed infection with the locally occurring, but now synergized ACMV. Regular monitoring surveys...

Host Plant Resistance

CMG-resistant varieties have been widely disseminated throughout the cassava-growing areas of sub-Saharan Africa. However, their adoption by farming communities has been most widespread in CMD pandemic-affected countries, where they have provided the only effective means of restoring cassava production to pre-pandemic levels.

Future Perspectives

Simian hemorrhagic fever virus (SHFV) was first isolated in 1964 during outbreaks of a fatal hemorrhagic fever in macaque colonies in the United States, Russia and Europe. A number of additional SHFV outbreaks in macaque colonies have occurred since the 1960s. The most 'famous' of these was the one in Reston, Virginia, which occurred in conjunction with a Reston Ebola virus outbreak. SHFV causes asymptomatic acute or persistent infections in several genera of African monkeys that are thought to be the natural hosts for this virus.

Factors That Impact Developability

Medicinal chemistry is always the starting point and driver of drug discovery programs. In a large pharmaceutical R& D organization, early discovery of bioactive compounds (hits) can be carried out either by random, high-throughput screening of compound libraries, by rational design, or both. Medicinal chemists will then use the structural information of the pharmacophore thus identified to optimize the structures. Chemical tractability needs to be examined carefully at the very beginning when a new chemical series is identified. Functional modifications around the core structure are carefully analysed. After the examination of a small number of compounds, the initial exploratory structure-activity relationship (SAR) or quantitative SAR (QSAR) should be developed. Blackie et al.16 described how the establishment of exploratory SAR helped the discovery of a potent oral bioavailable phospholipase A2 inhibitor. In this example, numerous substructural changes were made, leading to the...

Brief History of Hivaids

Although the first cases of acquired immune deficiency syndrome (AIDS) were recognized in the United States in 1981, phylogenetic analysis of human immunodeficiency virus (HIV) sequences suggest that HIV may have been initially transmitted to humans around 1930. By 1985, HIV had been identified in every region of the world and an estimated 1.5 million people were infected globally. Since then, unprecedented scientific advances have been made in the epidemiology, basic science, and treatment of this newly identified virus. Despite these advances, the global HIV pandemic has expanded rapidly. By 2007, an estimated 33.2 million people were living with HIV and greater than 20 million people had died of AIDS. AIDS is now the leading cause of death among people 15 59 years old and the world's most urgent public health challenge. The implementation of effective prevention strategies has proven challenging but there have been notable successes. In the US and Western Europe, extensive...

Fear of the Microorganisms and Response

Combination with product developers responded with new germ-fighting strategies and brilliant products such as hand sanitizers and disinfectants. As shown in Table 1.1, new diseases have been reported (emerged during the past 25 years) such as the Ebola virus or Creutzfeldt-Jakob diseases, which can significantly affect health in a short period. As per the WHO's report, there is a common misconception that frequent new drug discoveries are made to replace ineffective drugs 5 . In reality, while new versions of older drugs continue to be developed, there is a dearth of new classes of antibacterials 5 . With a period of 10-20 years taken for developing new anti-infective drugs and for the approval process, the emergence of new drugs or vaccines from the research and development pipeline is diminishing. Imagine the disaster if the eradication of smallpox in 1980 happened after few years delay the unforeseen emergence of HIV (in the developing nations mostly) might have undermined safe...

Molecular Epidemiology

HIV is an extremely genetically diverse virus. There are three phylogenetically distinct groups of HIV-1 based on genomic sequencing, groups M(main), O (outlier), and N (non-M, non-O). Each group has likely evolved from independent cross-species transmission events of chimpanzee simian immunodeficiency virus (SIVcpz) to humans. HIV-1 group M has spread to every region of the world and caused the global AIDS pandemic. Group O infections are uncommon and limited to people living

Infectious Disease Challenges

Despite predictions of healthcare workers and various organizations working toward public health, various microbial diseases have not been eliminated in total. The emerging pathogens have been broken down into the following categories (1) emerging old infections due to antimicrobial resistance (2) earlier unrecognized infections such as Lyme disease (3) known infections such as West Nile encephalitis spreading to new geographic areas or populations and (4) new infections due to change or evolution of existing organisms such as SARS 13 . Emergence of newly recognized diseases, reemergence of diseases thought to be controlled or eradicated, and the development of new drug-resistant organisms continue The need for basic and applied research leading to practical solutions, training of healthcare professionals, caregivers, and informing the public is ever present. The recent outbreaks of bird flu in Asian countries reinforced the need for an effective control of infectious diseases. SARS...

HIV1 Evolves to Create Global and Intra Patient Antigenic Variation

HIV-1, a member of the genus Lentivirus of the subfamily Orthoretrovirinae of the family Retroviridae, is one of the most rapidly evolving pathogens ever studied. Through a combination of rapid production of highly genetically diverse progeny and the extreme plasticity of many of its viral proteins, HIV-1 has managed to elude efforts aimed at control through drug treatment or vaccination. The most recent common ancestor of the HIV-1 pandemic subtypes came into the human population less than a century ago. Over the course of that relatively short interval, the virus has become not only one of the most significant human pathogens, but also one of the most diverse. The pandemic HIV-1 can be segregated into subtypes A K (minus E, I, and K) (Figure 4). Most subtypes co-circulate in West-Central Africa pointing to this region, where the geographical habitat of chimpanzees and humans overlap, as a nexus for the phylogenetically inferred initial transmission events into humans. Circulating...

Expansion into Therapies for Other Viruses

Once the structure of influenza virus neuraminidase was known, new inhibitors of influenza viruses were discovered. Recent advances with replication systems for hepatitis C virus (HCV) have allowed the discovery of anti-HCV compounds. Currently, the threat of bio-terrorism has prompted the successful search for drugs active against poxviruses and, with the prospect of the next influenza pandemic looming, there is renewed research effort directed to anti-influenza drugs. There are at least 25 (Table 1) widely used licensed antiviral agents and that number looks set to increase rapidly in the coming years.

Asiatic Cholera Mole Hills and Mountains

Abstract The disease cholera has persisted in Asia since time immemorial. Almost all the pandemic phases of cholera had its origin from the Indian subcontinent. Historically, waves of cholera have wiped many million lives in this region mainly due to the general insanitary conditions and poor management of the disease. All the three cholera causing vibrios namely classical, El Tor, and the O139 have emerged from Asia at different times and one was replaced by the other by overcoming the acquired immunity. Antimicrobial resistance was not a big problem in the early 1960s as its use was very limited. With the use of third-generation drugs, Vibrio cholerae has acquired many resistance mechanisms over the passage of time and also due to prevailing antibiotic pressure. With its biotypes serotypes there are considerable variations at the genetic level and many clones of V. cholerae have been detected. Recently, the hybrid strain of El Tor has spread in many Asian countries causing several...

Regulatory Viral RNAs and RNABinding Proteins

B2 protein of the betanodavirus flock house virus (FHV) is an important determinant of virulence that acts by sequestering double-strand RNA and preventing its recognition by the host. RNA-binding proteins encoded by both RNA viruses (influenza, Ebola virus, and reovirus) and DNA viruses (vaccinia, CMV, and HSV) have also been implicated in modulating cellular strategies for controlling RNA levels.

Pathogenicity and Clinical Features of Infection

Isolates of SHFV that induce persistent, asymptomatic infections and ones that cause acute, asymptomatic infections of patas monkeys have been reported. All SHFV isolates cause fatal hemorrhagic fever in macaque monkeys. Infected macaques develop fever and mild edema followed by anorexia, dehydration, adipsia, proteinuria, cynosis, skin petechia, bloody diarrhea, nose bleeds, and occasional hemorrhages in the skin. The pathological lesions consist of capillary-venous hemorrhages in the intestine, lung, nasal mucosa, dermis, spleen, perirenal and lumbar sub-peritoneum, adrenal glands, liver, and periocular connective tissues. These signs and symptoms are not unique to SHFV-infected animals, since they are also observed after infection of macaques with other types of hemorrhagic fever viruses such as Ebola virus. Although the SHFV-induced lesions are widespread in infected animals, the level of tissue damage is not severe. Even so, mortality in macaques infected with SHFV approaches 100...

The Fourth Epidemiological Transition

The second epidemiological transition happened when science and technology gave humankind the upper hand in the struggle with infectious diseases. The second transition witnessed the dawn of the ''golden age'' of scientific and technological advances against microbial threats. The third epidemiological transition reveals humanity confronted by ''a disheartening set of changes that in many ways have reversed the effects of the second transition and coincide with the shift to globalism'' ( 3 , p. 27). Powerful evidence of the third transition was found in the global crisis of emerging and reemerging infectious diseases detected in the 1990s 4 . Symbolic of the third transition was the relentless march of HIV AIDS across the planet and the devastation this pandemic caused in developing nations, especially in sub-Saharan Africa.

The Emergence of New Viral Diseases is Inevitable yet Unpredictable

Ebola* and Marbur f viruses (natural reservoirs unknown, the cause of the most lethal hemorrhagic fevers known) Guanarito vims' (rodent-borne the cause of Venezuelan hemorrhagic fever) Influenza viruses (the cause of thousands of deaths every winter in the elderly the cause of the single most deadly epidemic ever recorded - the worldwide epidemic of 1918, in which 25-40 million people died)

Epidemiologic Considerations in the Emergence of Viral Diseases

Continuing evolution of a virus which is already present in a population can cause what appears to be re-emergence of epidemic disease. For example, the evolution of influenza viruses is accompanied by variances in virulence, with some variants being responsible for greatly increased mortality. The greatest example of this phenomenon is the global influenza pandemic of 1918, in which 25 40 million people died.

The Axis of Illness Emerging and Reemerging Infectious Diseases

The axis of illness. (From Fidler, D.P., SARS, Governance, and the Globalization of Disease, Palgrave Macmillan, Basingstoke, United Kingdom, 2004.) perhaps best illustrates the challenge microbial resilience presents 18 . Human mobility underscores how international trade, travel, and migration play critical roles in infectious disease emergence and spread. This factor includes the contributions that technology and industry make to the increased speed, scope, and impact of human mobility on pathogenic threats. The emergence and global spread of severe acute respiratory syndrome (SARS) in 2003 provides an example of the dangers human mobility presents in the context of a new transmissible pathogen. Globalization focuses on many factors that speed up economic, technological, industrial, and cultural interconnectedness in ways that de-territorialize human behavior and the environment in which people and pathogens interact. The spread of HIV AIDS, SARS, avian influenza, and resistant...

Prominence in Perspective The Axes of Evil and Illness in a Dangerous World

The world after 9 11 is a far more dangerous place than the first phase of the post-cold war era. Infectious diseases contribute to this danger, as the potential for avian influenza's spread to trigger pandemic human influenza suggests. But public health does not make the world go round, and the worsening of other problems, such as the crisis in Iraq, the emerging oil crisis, the nuclear standoff between Iran and the United States, and the ongoing war on global terrorism, can easily divert political capital and resources from public health to other policy and governance objectives. Other global problems are experiencing political and governance deterioration, creating the potential for public health to fall again into the ''low politics'' of foreign policy and international relations.

Assessment of Disease Occurrence and Outcome

An infectious disease is characterized as endemic when there are multiple or continuous chains of transmission resulting in continuous occurrence of disease in a population over a period of time. Epidemics are peaks in disease incidence that exceed the endemic baseline or expected rate of disease. The size of the peak required to constitute an epidemic is arbitrary and is related to the background endemic rate and the anxiety that the disease arouses (e.g. a few cases of rabies is regarded as an epidemic, whereas a few cases of influenza is not). A pandemic is a worldwide epidemic.

Expanding the Scope of the IHRs Governance Strategy

In terms of the scope of disease application, the IHR 2005 increase disease coverage in three ways. First, the IHR 2005 replace the static and closed disease-specific approach of the classical regime with an approach built on the broadly defined terms ''disease,'' ''event,'' ''public health risk,'' and ''public health emergency of international concern.'' This approach allows the IHR 2005 to catch not only already identified disease risks but also new, unexpected threats. The old IHR did not apply to the SARS outbreak because SARS was not on the list of diseases subject to the regulations. The IHR 2005 do, however, apply to unknown or unforeseen disease threats, which makes the IHR 2005 far more flexible, dynamic, and forward looking than any manifestation of the classical regime. The changes made in the IHR 2005 embody an attempt to design a governance regime to handle the myriad challenges presented by the axis of illness in a context of intensifying globalization. The IHR 2005 also...

Granting WHO Increased Authority and Power

If the WHO Director-General declares that a public health emergency of international concern exists, the IHR 2005 authorize the Director-General to issue temporary recommendations on how states parties and non-state actors should respond to the threat. Although these recommendations are not legally binding, the ability to issue them accords the WHO Director-General tremendous power vis-a-vis states parties. The political and economic pain created for states by the travel advisories WHO issued during SARS demonstrates that the authority to issue temporary recommendations involves the exercise of real power. Examples of intergovernmental organizations wielding this kind of material power independently of states are virtually unheard of in international relations.

Integrating Human Rights Principles

The global health governance pincer. (Fidler, D.P., SARS, Governance, and the Globalization of Disease, Palgrave Macmillan, Basingstoke, United Kingdom, 2004.) The global health governance pincer. (Fidler, D.P., SARS, Governance, and the Globalization of Disease, Palgrave Macmillan, Basingstoke, United Kingdom, 2004.)

The Singapore Contribution in the Battle against the Severe Acute Respiratory Syndrome

Severe acute respiratory syndrome (SARS) emerged in November 2002 in Guangdong Province, China. The disease finally spread to more than 30 countries, with more than 8,000 people infected worldwide. Under the coordination of the World Health Organization, laboratories from all over the world, including Singapore, worked together to identify and characterize the causative agent. SARS first reached Singapore in mid-March 2003 and by the end of the outbreak more than 230 probable cases of SARS were recorded in the small island-nation. Subsequently, the contribution of research from Singapore to understanding this potentially lethal infection and its causative agent has been significant. This review aims to record the contribution made by researchers in Singapore to the current understanding of SARS, including the epidemiology in the Singapore setting. Also the development of diagnostic tests such as antibody detection and polymerase chain reaction will be discussed. Finally, a summary of...

Beyond Unstructured Plurality Whither Global Health Governance

The increased calls for better governance architecture for global health suggests that the governance transition that will characterize the fourth epidemiological transition remains incomplete. Although groundbreaking and significant in so many ways, the IHR 2005 do not provide the overarching architecture experts perceive is necessary. In fact, many of the concerns arising from the development of unstructured plurality in global health involve infectious disease problems for which the IHR 2005 provide little, if any assistance. At the same time that the WHO Executive Board calls for voluntary accelerated implementation of the IHR 2005 with respect to potential pandemic influenza 30 , most experts do not believe the IHR 2005 add much to the ongoing struggles with the three main infectious disease killers HIV AIDS, malaria, and tuberculosis. Each of these plagues is, depressingly, showing signs of becoming more deeply entrenched, and thus more difficult as a governance challenge.

Origin and Geographic Distribution

In the 1990s HIV-1 infection has become pandemic, rapidly developing in new regions such as India, South-East Asia and South America. In Africa, the infection has spread to the East (Uganda, Kenya, Tanzania, Rwanda, Burundi) and to the North (Ivory Coast). Concerning HIV-2, its spread has been more limited from the areas where it was first detected Guinea-Bissau, Cap Verde Islands, Senegal. HIV-2 is also present in other countries of the Western part of Africa (Ivory Coast, Burkina Faso, Cameroon, Liberia etc.) and Portuguese-speaking countries (Angola, Mozambique). An outbreak of HIV-2 infection has been detected in prostitutes of the Bombay area, India, suggesting that the virus has also reached Asia.

Abnormal Microbial Infection

Indeed, within the past millennia, microbial disease has proven to be a formidable adversary, one that has the potential to decimate the human population if left unchecked. During the Middle Ages and extending into the nineteenth century, diseases such as bubonic plague, cholera, and typhoid swept through Europe, causing massive mortality. The influenza pandemic at the end of World War I, for example, killed more people than the war itself.

Host Range and Virus Propagation

The only known reservoir of Lassa virus in West Africa is Mastomys natalensis, one of the most commonly occurring rodents in Africa. At least two species of Mastomys (diploid types with 32 and 38 chromosomes) inhabit West Africa, and both have been found to harbor the virus. All species are equally susceptible to silent persistent infection, as seen when LCMV infects mice. This presumably occurs as in LCM infection, from a selective deletion of the thymic T cell response to the virus. All of the arenaviruses pathogenic for humans will also infect and produce illness in a wide range of primates. However, it is not known whether such infections occur in nature, as is known for Ebola virus for example. In addition human infection plays no biological role in the life cycle and ecology of the arenaviruses.

Hantavirus Pulmonary Syndrome

Hantavirus pulmonary syndrome (HPS) was first noticed in the southwestern United States in 1993 by physicians treating victims with symptoms frightfully similar to those of Ebola (Section 12.7.9). Patients were suffering from an initial fever followed by the abrupt onset of acute pulmonary edema and shock. This outbreak involved 53 infections, with 32 fatalities. A rapid, systematic epidemiological study eventually determined that the responsible agent was a hantavirus, with the deer mouse as the principal reservoir. Infection usually stems from inhalation of aerosolized dried mouse feces or urine.

Taxonomy and Classification

Filoviruses are classified in the order Mononegavir-ales, a large group of viruses that have nonsegmented negative-stranded RNA as their genomes. The family Filoviridae, genus Filovirus, was created on the basis of unique morphologic, physicochemical, genetic and biological features of its members. Filoviruses are separated into two distinct species, Marburg and Ebola. The Marburg species consists of a single subtype Marburg including five strains. The Ebola

Properties of the Virion

By electron microscopy, filovirus particles are pleomorphic, appearing as long filamentous sometimes branched forms, or as 'U'-shaped, '6'-shaped or circular forms. The particles vary greatly in length (up to 14 000nm), but have a uniform diameter of about 80 nm. Virions purified by ratezonal gradient centrifugation are bacilliform in outline and show an average length associated with peak infectivity of approximately 665 nm for Marburg and 805 nm for Ebola virus. Except for the difference in length, filoviruses seem to be very similar in morphology. Virions contain a nucleocapsid consisting of a dark, central space (20 nm in diameter) surrounded by a helical capsid (50 nm in diameter) bearing cross-striations with a periodicity of approximately 5 nm. Within the nucleocapsid is an axial channel of 10-15 nm (Fig. 1). The nucleocapsid is composed of the genomic RNA and the large (L) protein, nucleopro-tein and virion proteins 35 and 30. It is surrounded by a lipoprotein unit membrane...

Properties of the Genome

The sedimentation coefficient is 46S (0.15moll-1 NaCl, pH 7.4). Filovirus genomes are approximately 19 kb in length and very rich in adenosine and uridine residues. Genomes show a linear gene arrangement in the order 3' leader - nucleoprotein (NP) - viral structural protein (VP) 35 - VP40 - glycoprotein (GP) - VP30 - VP24 - polymerase (L) - 5' trailer. All genes are flanked at their 3' and 5' ends by highly conserved transcriptional start (3'-CUnCnUnUAAUU-5') and termination (3'-UaAUUCUUUUU-5') signal sequences, respectively, which almost all contain the pentamer 3'-UAAUU-5'. Most genes are separated by intergenic sequences variable in length and nucleotide composition, but some genes overlap by the conserved pentanucleotide sequence. Subtype Zaire Ebola viruses show three overlaps that alternate with intergenic sequences (VP35 VP40, GP VP30, VP24

Properties of Viral Proteins

Virions contain at least seven proteins with presumed identical functions for the different viruses. The electrophoretic mobility patterns of the structural proteins are characteristic for Marburg strains on the one hand and Ebola strains on the other. Four proteins are associated with the viral ribonucleo-protein complex (NP, L, VP30 and VP35), the single glycoprotein (GP) is inserted in the envelope, and the location of two proteins (VP40 and VP24) has not been determined exactly, but they seem to be membrane associated. The L protein is the largest protein and, like other L proteins of nonsegmented negative-stranded RNA viruses, represents the virion-associated RNA-dependent RNA polymerase. Its size, as calculated from the deduced amino acid sequence of the Marburg virus (Musoke strain) L gene, is 267 kDa. GP (Marburg virus 170 kDa Ebola virus 160 kDa) is a type I transmembrane protein and inserted in the lipid membrane as a homotrimer, as shown directly for Marburg virus. It is...

Geographic Distribution

Filoviruses, with the exception of subtype Reston of Ebola viruses, appear to be indigenous to the tropical rain forest regions of Central Africa, as indicated by the geographic locations of known outbreaks and seroepidemiological studies. This is also suggested by the fact that almost all filovirus isolates from human patients are of African origin. This includes the European isolates of Marburg viruses that could be traced back to foci in Uganda, from where vervet monkeys were imported to Germany and the former Yugoslavia. The Ebola-Reston outbreak suggested for the first time the presence of a filovirus in Asia. Studies among captive macaques in the Philippines indicated that the source of Ebola-Reston virus might be wild nonhuman primates thus, it appears that filoviruses are not confined to Africa.

Host Range and Virus Distribution

Experimental hosts include monkeys, for which infection with Marburg and Ebola-Zaire virus are usually lethal, whereas some animals survive infections with Ebola-Sudan and Ebola-Reston viruses. Guinea pigs show febrile responses 4-10 days after inoculation with Marburg and Ebola viruses. However, none of these viruses kills guinea pigs consistently on primary inoculation. Ebola-Zaire virus is usually pathogenic for newborn mice after intracerebral and intraperitoneal inoculation. For growth in cell culture, primary monkey kidney cells and monkey kidney cell lines, usually Vero cells, are used. Filoviruses also grow in human endothelia maintained as primary cell cultures or as organ cultures.

Serologic Relationships

Comparison of the two species of filoviruses, Marburg and Ebola, showed similarities between amino acid sequences of the structural proteins. This finding indicates that the structural proteins have maintained similar structures and functions. Despite this amino acid similarity, there is no indication that there is any significant serological (antigenic) crossreactivity between Ebola and Marburg viruses, but the different subtypes of the Ebola species share common epitopes. Neutralization tests for Marburg and Ebola viruses have not yet been shown sufficiently reliable to enable determination of taxonomic relationships.

Transmission and Tissue Tropism

The mode of primary infection with Marburg and Ebola viruses in any natural setting is not known. The physical contact route of infection is undoubtedly the most common means of transmission from humans to humans. Especially activities such as nursing and preparing bodies for burials are associated with an increased risk of becoming infected. One Marburg case was acquired by sexual contact more than 60 days after the original infection. Neonatal transmission has been reported for the 1976 outbreak in Zaire. Transmission by droplets and small-particle aerosols has been observed among experimentally infected and quarantined imported monkeys (Ebola-Reston virus, 1989-1990). This is confirmed by identification of filovirus particles in alveoli of naturally and experimentally infected monkeys. However, the contribution of aerosol transmission to the course of human outbreaks is still unknown.

Clinical Features of Infection

Clinical symptoms are similar with Marburg and Ebola virus infections. Following incubation periods of 4 16 days, onset is sudden, marked by fever, chills, headache, anorexia and myalgia. These signs are soon followed by nausea, vomiting, sore throat, abdominal pain and diarrhea. When first examined, patients are usually overtly ill, dehydrated, apathetic and disoriented. Pharyngeal and conjunctival injections are usual. Most of the patients develop severe hemorrhagic manifestations, usually between days 5 and 7. Bleeding is often from multiple sites, with the gastrointestinal tract, lungs and gingiva the most commonly involved. Bleeding and oropharyngeal lesions usually herald a fatal outcome. Death occurs between days 7 and 16, usually from shock with or without severe blood loss.

Pathology Histopathology and Pathogenesis

Marburg and Ebola viruses cause similar pathological changes in humans. The most striking lesions are found in liver, spleen and kidney. These lesions are characterized by focal hepatic necrosis with little inflammatory response and by follicular necrosis of lymph nodes and spleen. In late stages of the disease, hemorrhage occurs in the gastrointestinal tract, pleural, pericardial and peritoneal spaces, and into the renal tubules with deposition of fibrin. Abnormalities in coagulation parameters include fibrin split products and prolonged prothrombin and partial thromboplastin times, suggesting that disseminated intravascular coagulation is a terminal event. There is usually also profound leukopenia in association with secondary bacteremia. Ebola-Reston virus causes similar pathological changes in monkeys, as described for human infections with Marburg and other subtype Ebola viruses. In Reston-infected animals it was clearly demonstrated that virus replication was extensive in fixed...

Prevention and Control

Although neutralizing antibody titers in human convalescent sera can, if at all, only barely be detected in laboratory tests, there are anecdotal case reports suggesting the potential benefit of passive immunization against Ebola virus infection. Furthermore, recent reports from the 1995 outbreak in Zaire about effective treatment of acutely ill patients with whole blood transfusions from convalescent donors suggest that quantities of antibodies, predicted to be marginally effective in laboratory tests, may still be protective. There is experimental evidence that active immunization employing killed virus, recombinant expressed glycoprotein, and recombinant gene 4 (GP)-DNA (DNA vaccination) is partially successful in animals, suggesting that these may be feasible strategies to elicit protective immunity. At present, however, vaccines for human application are not available. A specific chemotherapeutic treatment is not available to date, but knowledge of the expected clinical course...

Diseases and Host Range

Replicate at virtually every epithelial surface in the host. Some coronaviruses have their most profound effect in the alimentary tract (e.g., porcine TGEV causes > 90 mortality in neonatal pigs). Human coronaviruses are known to be associated with enteric and respiratory diseases (e.g., diarrhea), in addition to respiratory disease. SARS-CoV was also associated with diarrhea in humans, in addition to serious lung disease. Other coronaviruses, for example, MHV and porcine HEV, spread to cells of the central nervous system, producing disease, for example, acute or chronic demyelination in the case of MHV. Coronavirus replication and disease are not necessarily restricted to a single host species. Canine enteric CoV and feline CoV can replicate and cause disease in pigs these two viruses have proteins with very high amino acid identity to those of porcine TGEV. Canine respiratory CoV has proteins, including the S protein (which is the attachment protein and a determinant of host...

Molecular Features of CoVs

CoV virions (Figure 1(a)) are composed of a large RNA genome, which combines with the viral nucleocapsid protein (N) to form a helical nucleocapsid, and a host cell-derived lipid envelope which is studded with virus-specific proteins including the membrane (M) glycoprotein, the envelope (E) protein, and the spike (S) glycoprotein. CoV particles vary somewhat in size, but average about 100 nm in diameter. The genomic RNA (gRNA) inside the virion, which ranges in size from 27 to 32 kb for different CoVs, is the largest viral RNA identified to date. CoV gRNAs have a broadly conserved structure which is illustrated by the SARS-CoV genome shown in Figure 1(b). The gRNA is Figure 1 CoV virion and the genome of SARS-CoV. (a) Schematic diagram of a CoV virion with the minimal set of four structural proteins required for efficient assembly of the infectious virus particles S, spike glycoprotein M, membrane glycoprotein E, envelope protein and N, nucleocapsid phosphoprotein which encapsidates...

CoV Accessory Proteins

SARS-CoV Bat-SARS-CoV name implies, these accessory proteins are not required for CoV replication in tissue culture cell lines, but they may play important roles in tropism and pathogenesis in vivo. How were these additional genes acquired. Current evidence indicates that these additional sequences may have been acquired by RNA recombination events between co-infecting viruses. For example, the hemagglutinin-esterase (HE) glycoprotein present in four different CoVs (MHV, BCoV, HCoV-OC43, and HCoV-HKU-1) was likely acquired by recombination of an ancestral CoV with the HE glycoprotein gene of influenza C. Interestingly, the expression of the HE gene has no effect on replication of the virus in cultured cell lines, but has been shown to enhance virulence in infected animals. Other CoV accessory genes may have been acquired through recombination with host cell mRNA or other viral mRNAs. The specific role of the accessory proteins in CoV replication and pathogenesis is under...

Vaccines and Antiviral Drug Development

Because of the economic importance of CoV infection to livestock and domestic animals, a variety of live-attenuated and killed CoV vaccines have been tested in animals. Vaccines have been developed against IBV, TGEV, CCoV, and FIPV. However, these vaccines do not seem to provide complete protection from wild-type virus infection. In some cases, the wild-type CoV rapidly evolves to escape neutralization by vaccine-induced antibodies. In studies of vaccinated chickens, a live-attenuated IBV vaccine has been shown to undergo RNA recombination with wildtype virus to generate vaccine escape mutants. Killed virus vaccines may also be problematic for some CoV infections. Vaccination of cats with a killed FIPV vaccine has been shown to exacerbate disease when cats are challenged with wild-type virus. Therefore, extensive studies will be required to carefully evaluate candidate vaccines for SARS-CoV. A variety of approaches are currently under investigation for developing a SARS-CoV vaccine,...

Endemic and Epidemic Cholera in Africa

Abstract Cholera had entered the African continent during the late 1880s mainly through trade and travel from the Asian region. The 7th cholera pandemic had started from the early 1970s and is rampant till to-date claiming many lives. Though the endemicity of cholera is common in many African and Asian countries, the morbidity and mortality are relatively high in Africa. This has been attributed mainly due to lack of health and hygiene of the population, scarcity of water, prevailing multidrug-resistant strains of Vibrio cholerae O1, and to a lesser extent the management of cholera in the early 1990s. Molecular epidemiological studies revealed that there is a propensity of the pathogen to change its clonality that has been attributed to the recurrent infection and waves of cholera epidemics in many African countries. One of the mysteries is why the spread of V cholerae O139 serogroup is restricted only to Asian countries despite the geographical proximity and common mode of...

Viruses Affecting the Pancreas

Nevertheless, studies on children with disseminated fatal viral infections showed that pancreatic lesions, often with islet cell destruction, were present in patients with coxsackie B, CMV, varicella-zoster and congenitally acquired rubella. In addition, pancreatitis has been observed following mumps and, less commonly, following Epstein-Barr virus (EBV) infection and hepatitis B virus infections. The finding that hepatitis B surface and core antigens have been detected in the acinar cells of patients with hepatitis B antigenemia suggests that this virus may replicate in pancreatic tissue. Although such filoviruses as Marburg and Ebola induce generalized infections with severe hepatic involvement, some patients develop clinical features of acute pancreatitis, and postmortem studies have demonstrated areas of focal pancreatic necrosis.

Epidemics and Outbreaks

Cholera is a major health burden in many developing countries and its endemicity is mostly confined to Africa and Asia. A treatment facility-based cholera surveillance showed that annual incidence of the disease is low in Jakarta (Indonesia, 0.5 1,000 population), moderate in Kolkata (India, 1.6 1,000), and high in Beira (Africa, 4 1,000) 1 . Historical evidence showed that the 6th pandemic of cholera had reached East Africa and the mode of spread was seemingly associated with caravans and trade ships. Between 1881 and 1893, the epidemic had spread in East (Zanzibar), Central, North (Sudan), and Western parts of Africa 2-4 . The 7th El Tor pandemic had gained its entry into West Africa (Guinea) during August 1970, maybe from asymptomatic travelers from the Asian continent 4, 5 . Within a year, 25 African countries were affected by cholera with a high mortality of 16 6 . In the following years (1972-1991), cholera was rampant in most of the African countries with case fatality ranging...

Microarray Design for Viral Detection

Maximize the probability of detecting any viral species from a known family, it is often desirable to choose sequences that are the most conserved among a group of viruses. For example, while there exists a large range of sequence diversity among human rhinoviruses, sequences in the 5' UTR are highly conserved, even among more distant picornaviruses. These sequences may thus serve as a type of universal 'hook' to capture both existing and new variants of these RNA viruses. In case of novel pathogens, such as the SARS coronavirus, the use of conserved sequences was a key determinant for successful detection by microarray. Clearly, unique species-specific or even genotype-specific oligonucleotides can further augment the discrimination of the microarray. A logical extension of this strategy takes into account features of viral taxonomy. Rather than choosing all conserved, or all unique sequences, one may attempt to cover, by design, each level of the taxonomic tree for each family....

Real World Applications Research and Clinical

In addition to the detection of previously known pathogens, DNA microarrays have also been effective for the detection of novel viral species. In the case of SARS, total nucleic acid from a supernatant from an infected vero cell culture revealed a coronavirus signature consisting of oligonucleotides originating from avian infectious bronchitis, human and bovine coronaviruses, and, interestingly, several astroviruses. At first glance, the hybridization signal from astrovirus-derived oligonu-cleotides would seem to be aberrant. In fact, this is expected, since several astroviruses and coronaviruses share conserved sequences at the 3' end of their genomes. These particular sequences were represented on the microarray since the panviral design algorithm purposely selected conserved sequences within and among viral families.

SIV Infections as Animal Models of AIDS

The HIV-1 pandemic continues unabated and developing effective vaccines and therapies is the greatest current public health need. Samples from HIV-infected individuals have provided key insights into AIDS pathogenesis. However, direct experimental testing of specific hypothesis arising from these studies cannot be undertaken in humans for ethical reasons and HIV-1 infection of chimpanzees does not produce AIDS. Thus, SIV infection of Asian macaques is the most widely accepted animal model of HIV pathogenesis. The biology of the macaque immune system, and the key organ systems (gut, lym-phoid tissue, and reproductive tract) involved in AIDS pathogenesis and HIV transmission are very similar to humans, and SIV and HIV are closely related phylogen-etically. Thus, SIV infection of macaques closely mimics the pathogenesis, virology, immunology, and pathology of HIV infection in the human. The model has been used to show that infection with a molecular clone of SIV is sufficient to cause...

Emerging and reemerging viral diseases

While this book was in preparation, there was a sharp reminder of the ever-present threat of emerging viral diseases, in the form of a new viral disease called severe acute respiratory syndrome (SARS). The outbreak of this disease began in Guangdong province in southern China in November 2002. The Chinese authorities were heavily criticised for not reporting the extent of the outbreak until some 3 months later, by which time cases were appearing in many parts of the world, illustrating the role of increased intercontinental travel in the spread of such a disease. At its peak in April 2003, over 1000 new cases of SARS were being reported per week. The cause of SARS was quickly identified as a member of the Coronaviridae (single-stranded RNA viruses). Transmitted by droplets from coughs and sneezes, it produces flu-like symptoms, but has a mortality rate of around 4 percent. Strict public health measures were brought into force, including restrictions in flights to and from affected...

The Supply Crisis in Transplantation

One of the most promising, and controversial, sources for new organs for humans are xenotransplants from other species, particularly baboons and pigs. Many individuals are very strongly opposed to raising animals for the sole purpose of harvesting their organs for humans, viewing it as inhumane. Another area of controversy, particularly concerning baboon donors, is the possibility of spreading unknown diseases into the human population. There are already established precedents for viral diseases jumping from primates to humans, such as the AIDS virus (HIV), Ebola virus, and the hantavirus. Consequently, there is a fear that xenotransplantaion could unleash a new plague upon humans. More and more xenotransplant research is moving toward the use of pigs, since it is very much less likely that a pig virus could

Evaluation of Surveillance

They should also be sufficiently flexible, so that 'new' or emerging infections can be included in an emergency or when the need arises. The successful implementation of international surveillance for SARS was instrumental in controlling it. Emergency surveillance was also essential following the tsunami of 2004, and is also necessary for the successful management of other disasters following earthquakes, hurricanes, and floods.

Global and International Surveillance

Veterinarians, managers, and planners - in many different countries so that information can be exchanged, and attempts made on a global basis, to prevent the next pandemic. Only recently, a new variant of chikungunya virus jumped from Kenya, where it seems to have started, to islands in the Indian Ocean and hence to India. It has now, in 2007, even reached Italy. In Reunion alone, it affected 265 000 people, an astoundingly high incidence of 34 , and an estimated case-fatality rate of 1 1000. In India 1.3 million persons are thought to have been affected (so far, to February 2007).Two species of mosquito have been involved, Aedes aegypti and A. albopictus. Epidemics of dengue and West Nile virus have also spread widely recently. AIDS HIV was destined to become a global problem almost from the time of its first discovery. On a more positive note, SARS was contained through the use of international surveillance and surveillance was the backbone of the smallpox eradication program.

Clinical Features

Shock, the final event in severe lethal cases, is caused by three processes, which influence each other systemic viral replication and immune evasion, increase in vascular permeability, and coagulopathy. Infection of primary target cells such as monocytes macrophages and DCs results in systemic spread of the virus and differential activation. Monocytes macrophages are activated to produce pro-inflammatory cytokines and tissue factor (TF), while DC activation is impaired, leading to poor protective immune responses. Type I interferon responses are also inhibited by virus-encoded inhibitors (VP35 and VP24). Despite no infection of T- and natural killer (NK) cells, there is extensive apoptosis in those cell types. ECs are activated by pro-inflammatory cytokines and virus, which leads to increased permeability. TF expression induces coagulopathy, which is also able to increase inflammation. Figure 3 Ebola virus pathogenesis. Shock, the final event in...

Classification And Identification

Yersinia enterocolitica and Yersinia pseudotuberculosis are included in the genus Yersinia. These species were formerly included in the genus Pasteurella and later placed into the genus Yersinia, named in honor of the French bacteriologist A. J. E. Yersin, a discoverer of the plague bacillus (1). Y. pseudotuberculosis was the first species identified in this genus (2). This organism was described in 1889 as a disease in guinea pigs. However, Y. pseudotuberculosis has shown to be the ancestor of Y. pestis, which was the cause of pandemic plague already during 541-767 AD (3). The Y. enterocolitica was identified in 1939 and named by Frederiksen in 1964 (4). The genus Yersinia is presently composed of 11 species, three of which can cause disease in humans and animals Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis (5-8).

Picornalike Viruses of Hymenopterans Wasps and Bees

Kashmir bee virus (KBV) was initially isolated from A. cerana in Kashmir and India. Several strains of KBV were subsequently isolated from the European honeybee in Australia and New Zealand as well as from the wasp V. germanica and has since been shown to be pandemic in A. mellifera populations. Initially it was thought to cause extensive mortality in hives. Later studies showed that KBV normally exists in a latent state but that infections with other bee pathogens such as the microsporidian Nosema apis and the foul brood bacterium Melisococcus pluton can trigger virus replication leading to death. Some data suggest that KBV has a serological relationship to ABPV. However, this may be a nonspecific reaction similar to the serological crossreactivity detected between CrPV and the mammalian picornavirus EMCV or an example of convergent evolution since they can both be transmitted through the salivary glands. Molecular studies on the genome of KBV and ABPV will likely resolve these...

Human Demographics and Behavior

The ability of such new infections to spread in the population has been greatly enhanced by population growth and ease of movement as a result of rapid air travel. A dramatic recent example of this was the appearance of the coronavirus causing severe acute respiratory syndrome (SARS) in late 2002 which spread by air travel from a single infected Chinese physician who infected 12 persons in a Hong Kong hotel. These infected persons then traveled by air and spread the infection to more than 8000 individuals worldwide, 10 of whom died. The virus then apparently receded from the human population in July 2003. Only recently was it discovered that the SARS coronavirus has a natural reservoir in Chinese horseshoe bats (Rhinolophus sinicus). Some other species such as Himalayan palm civets and raccoon dogs from which the virus has been isolated may serve as amplification hosts. Following the recognition of the human coronavirus SARS, research on coronaviruses intensified, and this led to the...

Epidemiologic Studies

Viruses can offer the same kind of geographic information of virus movement as has proved so useful in polio control and eradication programs, but because of political sensitivities in some countries a robust international reference laboratory system has not been established that could provide the same kind of practical disease control information as has been the case with polio. Thus, with many human and animal viruses molecular epidemiologic studies are flourishing, but more such studies should lead to international reference laboratory systems to guide prevention and control actions. Such studies are developing rapidly today to deal with the threat of a human pandemic of avian influenza, but there are many more viral diseases, especially animal diseases, in need of this kind of development.

Never Ending Adaptation

Not all RNA virus populations show this dynamic of a continual change or even the diversity expected from quasispecies. Even in influenza virus A, avian isolates from natural host (waterfowl) can be genetically stable. Some RNA (and retro) viruses with high error rates can nevertheless maintain stable populations in specific hosts. For example, measles virus shows much less antigenic drift in human infections compared to influenza virus A. Hepatitis G virus (a human prevalent and distant relative of HCV) shows little variation in even isolated human populations. The filoviruses (Ebola virus and

Never Ending Emergence

A remaining concern of virus evolution is to understand the emergence of new viral pathogens. The unpredictable and stochastic nature of such virulent adaptations makes predictions difficult, as the link between virulence and evolution is vague. For example, the genetic changes that made the SARS virus (persisting in bats) into an acute human pathogen are still not predictable. Viral fitness and selection, and how they change from persistent states with acute species jumps, are not yet defined. However, some variables contribute to the likelihood of viral emergence, such as virus ecology. The population density and dynamics of the new host and the ecological interactions-between new and stable viral host are often crucial. In addition, virus-virus interactions can be important, allowing for recombination and or reassortments or lowering immunological selective barriers via immunosup-pression. The emergence of HIV-1 from different, persistent SIVs of African monkeys through chimpanzees...

ESIMS for Linking Lowaffinity Ligands

The low hit rates for RNA targets in traditional HTS assay formats can be traced to difficulties in detecting and accurately measuring low-affinity interactions between small molecules and the RNA. We have developed a high-throughput MS-based assay that directly measures ligand affinities of 0.01-1000.0 M for RNA targets. In contrast to traditional HTS assays, the MS-based assay accurately quantifies binding affinity, stoichiometry, and specificity over a wide range of ligand KD values. This highly quantitative information allows a pattern of SARs to emerge, even among relatively weak binders, and guides elaboration to higher-affinity compounds.

Thymidylate Synthase Proof of Principle

Screens with chemically similar fragments showed that, although substitutions around the aromatic moiety and in the stereochemistry of the proline residue preserved the fragments conjugation strength, the proline residue itself was essential. Crystallography of N-tosyl-d-proline covalently linked to TS explained these SARs the proline residue sits snugly within a hydrophobic pocket and one of the sulfonamide oxygen atoms makes a hydrogen bond to Asn 177 on the enzyme, but the phenyl ring is in a relatively open area (Fig. 14.3).

Severe Acute Respiratory Syndrome

SARS is a newly recognized acute viral respiratory syndrome caused by a novel SARS coronavirus (SARS-CoV) 108 . The first case was retrospectively recognized as having occurred in Guandong province, China, in November 2002. By July 2003, the international spread of SARS-CoV resulted in 8098 SARS cases in 26 countries, with 774 deaths 109 . The disturbing characteristic of this illness was the apparent ease of transmission in healthcare facilities. The novel coronavirus can be found in sputum, tears, blood, urine, and feces of an infected person. It can be shed in the feces for 30 days and has been shown to survive on hard surfaces for more than 24 h. This raises the possibility of transmission by fomites and the amplification of its communicability within hospital settings, becoming an almost ''perfect pathogen'' 110 . The primary mechanism by which SARS-CoV appears to spread is through droplets and through contact either directly (person-to-person) or via contaminated environmental...

Introduction Concepts in RNA Virus Evolution

Foot-and-mouth disease virus (FMDV) is one of the prototypes of anti-genically variable virus, reflected in seven serotypes (A, O, C, Asia 1, SAT1, SAT2, SAT3), and many subtypes and variants, too numerous to be amenable to any reasonable cataloguing at present. The diversity of antigenic types creates difficulties for prevention of FMD by vaccination because there is no predictable, reproducible and effective protection that can be afforded by a limited number of vaccine antigens against multiple variants cocirculating in different world areas, and sometimes even within the same geographical area (Doel 2003 Sutmoller et al. 2003). Traditionally, vaccine manufacturers have known that it is necessary to tailor vaccine composition to match the antigenic properties of the circulating FMDV in much the same way as the influenza vaccines must be periodically updated. Chemically defined vaccines would be desirable, but they will often fail to provide protection against the diverse and...

Epidemiology Of Cholera

V. cholerae is the causative agent of cholera, an acute dehydrating diarrhea that occurs in epidemic and pandemic forms. 2,3 Cholera has been recognized as one of the ''emerging and reemerging infections, threatening many developing countries.'' Several recent events that mark the epidemiological importance of the disease include the reemergence of cholera in Latin America in 1991, the explosive outbreak of cholera in Rwandan refugees in Goma and Zaire, 3 and the emergence of V. cholerae in the Indian subcontinent during 1992. 6,7 All pandemics, except for the seventh pandemic, which originated in Indonesia, arose from the Indian subconti

Viral Hemorrhagic Fevers

The term ''viral hemorrhagic fever'' (VHF) describes a variety of viral diseases which are characterized by fever and bleeding in humans. This syndrome is caused by RNA viruses belonging to the families Filoviridae (Ebola virus and Marburg virus), Arenaviridae (Lassa virus, Junin virus, Machupo virus, Guanarito virus, and Sabia virus), Bunyaviridae CCHF virus, Rift Valley fever (RVF) virus, and Hantaviruses , and Flaviviridae (yellow fever virus and dengue virus). After transmission from their reservoir host or vector to humans, these viruses cause an acute infection and there is no evidence of chronic courses. The clinical symptoms in the early phase of a VHF are very similar irrespective of the causative virus and resemble a flu-like illness or a common enteritis. Headache, myalgia, gastrointestinal symptoms, and symptoms of the upper respiratory tract dominate the clinical picture. Hepatitis is also common. Therefore, especially in the early phase, virological testing is of utmost...

Viruses Occurring in Africa Rift Valley fever virus

Marburg and Ebola viruses The reappearance of epidemic Ebola disease in Kikwit, Democratic Republic of the Congo (formerly Zaire) in 1995 and Makokou, Gabon in 1996 again focused international attention on this hemorrhagic disease. Marburg and Ebola viruses have sporadically caused severe hemorrhagic fever in humans. Marburg virus, although of African origin, first appeared in laboratory workers in Germany who had handled cell cultures originating from African primates. Later, epidemics of severe hemorrhagic fever occurred in the Sudan and in Zaire, and Ebola virus was isolated. These viruses produce hemorrhagic shock syndrome and visceral organ necrosis, and have the highest case fatality rate (30-90 ) of the hemorrhagic fevers. These viruses, with their bizarre filamentous, pleomorphic morphology, belong to the Filoviridae family. They are presumed to be zoonotic, but their hosts in nature and mechanisms of transmission in the field have not been determined. Most of the Makokou,...

Emerging and Reemerging Zoonoses Ecological change

Human activity alters animal populations, contact between wild and domestic animals, and human-animal interactions, changing the occurrence of zoonotic diseases and the risk of infection to humans. For example, emergence of new influenza strains is related to the interaction of populations of people, pigs and aquatic birds. It is hypothesized that the emergence of the new H5N1 influenza strain in Hong Kong in 1997 was the result of a chain of events resulting in transmission from migrating shorebirds to ducks, to chickens, and finally to humans. Fortunately, this pathogenic strain was not easily transmitted from human to human, or a serious pandemic could have resulted. cephalitis viruses and related viruses causing hemorrhagic disease Tick-borne encephalitis and Wesselsbron viruses Hantaviruses (Bunyaviridae) Lassa, Junin, Machupo and Guanarito viruses (Arenaviridae) Rhabdoviruses (Rhabdo-viridae) Plant rhabdoviruses Ungrouped mammalian, bird and fish rhabdoviruses Emerging and...

Geographical Distribution

Image Indian Cassava Mosaic Virus

The cassava geminivirus pandemic in Africa started in the early 1990s and is still going on today. It started in Uganda in 1994, invaded several countries in East Africa around Lake Victoria, before crossing the mountains in Rwanda-Burundi, to infect the entire Congo Basin and invade up to Gabon and the south of Cameroon (Figure 3). Cassava plants were already infected with African cassava mosaic ACMV and EACMV-UG are both members of the genus Begomovirus, in the family Geminiviridae, similarly to TYLCV above. These viruses however are bipartite viruses, with a second DNA molecule coding for two movement proteins. Furthermore, EACMV-UG is a recombinant between ACMV and EACMV, with a fragment of 550 nt from the core part of the coat protein of ACMV integrated into the EACMV genome. Although there is no direct proof that this recombinant has any specific advantage over the nonrecombinant EACMV, it is a fact that the EACMV-UG strain is present in all the plants that show severe symptoms...

Innate Immune Responses

During virus replication' the innate immune response is activated' resulting in the production of several hundred antiviral proteins converting the intracellular environment into a suboptimal context for replication.60 In response to this selective environment, evidence suggests that a number of viral proteases have adapted a ubiquitin-removal specificity as a mechanism to disable the host immune system and optimize the intracellular environment for efficient virus replication and release.10 For example, the nonstructural protein of severe acute respiratory syndrome (SARS) corona virus, nsp3, known to be involved in the processing of replicase polyproteins, has recently been shown to carry a conserved deubiquitinase (DUB) motifwithin its papain-like protease (PLpro) domain.61,62 This protein efficiently inhibits IRF3 ubiquitination in a protease dependent mechanism.63 IRF3 is a critical transcription factor for the activation of antiviral IFN and requires ubiquitination to translocate...

Enterovirus type 70 EV70 History

Similar epidemics of conjunctivitis involved major cities in the Indian subcontinent, southeast Asian countries and Japan, and small localized outbreaks occurred in London, Holland and Moscow in 1970-1971. The extent of the involvement of EV70 as compared with CA24v during the 1969-1972 AHC pandemic cannot be ascertained because most reports were based on clinical findings. Furthermore, the agent responsible for the African 1969-1970 epidemics has not been available for comparative investigations. It is clear that EV70 played a prominent role in the 1980-1982 AHC pandemic, during which not only Africa, southeast Asian countries, India and the Middle East were affected but the western hemisphere also became involved for the first time. A small localized outbreak in Oakland, California occurred in July 1980 and extensive epidemics which originated in Brazil spread rapidly through South and Central America, Oceania and Islands of the Western Pacific Ocean from mid-1981 to the beginning...

Antigenic Variation in Influenza Viruses

Antigenic drift is a less dramatic form of antigenic variation but is responsible for annual epidemics of influenza. The term refers to a gradual change in serological cross-reactivity when compared to the original pandemic virus. Drift has been continuous in H3 HA since 1968, in N2 NA since 1957, and in H1 and N1 since 1977. Drift is detected using ferret antiserum, which discriminates better than antisera of other species, raised against a particular H3N2 strain. There is some degree of cross-reactivity to viruses isolated before and after the appearance of that strain, typically over a period of about 10 years, but for better protection, the vaccine strain is changed as soon as cross-reactivity is decreased.

CTXyPreCTXq NonO1 NonO139 Strains

Recently a type III secretion system (TTSS) that is related to the TTSS2 gene cluster found in a pandemic clone of Vibrio parahaemolyticus was identified in the genomes of certain non-O1, non-O139 strains including isolates from patients with severe watery diarrhea. The genes for this V cholerae TTSS system appear to be present in many non-O1, non-O139 strains, both clinical and environmental 119, 120 . The TTSS genes were localized in a 48 kb gene vcs cluster on chromosome I 119 and were predicted to encode the structural components of the TTSS membrane-associated pore-forming complex (vcsCJRTQVU) and an ATPase that provides energy to drive secretion by means of the apparatus (VcsN) 120 . Moskvitina EA. Current trends in the evolution of the seventh cholera pandemics. Problemy OOI. 2008 1 22-6 (in Russian). Narkevich MI, Onischenko GG, Lomov YuM, Moskvitina EA, Podosinnikova LS, Medynsky GM. The seventh pandemic of cholera in the USSR, 1961-1989. WHO Bulletin OMS. 1993 71 189-96....

PTX3 in Pathogen Recognition and Inflammation

Similarly, upon binding to influenza virus (H3N2), PTX3 inhibits virus-induced hemagglutination and viral neuramidase activity, neutralizes virus infectivity in vitro and reduces mortality and viral load in vivo in mice (Reading et al. 2008). However, it has been recently reported that both seasonal and pandemic H1N1 influenza A viruses were resistant to the antiviral activity of PTX3 (Job et al. 2010).

Examples Involving Site Directed Mutagenesis

While the drug discovery process has been influenced by biotechnology in numerous ways (e.g., Tables 2.4 and 2.5), one development deserves to be especially noted as this brief account of medicinal chemistry's history and present status is brought to a close. This development is already having a major impact directly on the process of uncovering SARs relevant to small-molecule drug design.45 The method involves site-directed mutagenesis (SDM). SDM applies to systematic point mutations directed toward specific sites on genes that translate to proteins associated with enzyme-active sites or drug receptor systems such that the targeted changes can be used to study SARs while holding one or more active site receptor ligands constant during the assessment (Fig. 2.3). Numerous investigators are now utilizing this reverse SAR approach to explore both enzyme and receptor ligand interactions. Three examples are provided below wherein the site-directed mutagenesis studies have been further...

Prions And Prion Diseases

Can we give any scientific rationale for this hope What is the nature of the barrier The best answer, in our present state of knowledge, has to do with PrP diversity. We have already noted that there are at least twenty different mutations in the PRNP gene associated with human prion diseases (CJD, GSS, FFI). This genetic diversity is greatly increased by post-translational processing, especially glycosylation. If the mechanism of prion propagation is as sketched above (Figure 21.1) then PrPSc from evolutionarily distant species may be too different in molecular structure to react with human PrPC to initiate the pathological cascade. There is nowadays a great deal of evidence from transgenic mice expressing differently mutated prion genes to support this hypothesis. Nevertheless, as is now well known, well over a hundred humans (all teenagers or young adults) have suffered from incurable vCJD derived from the 1990s BSE pandemic in UK cattle and that appalling number may grow in the...

Other Control Methods

Although ACMV and EACMV-like CMGs interact syn-ergistically, there is evidence that EACMV-like CMGs may hinder infection by other EACMV-like viruses and interfere with their replication. Studies in Uganda showed that plants initially infected by mild strains of EACMV-UG were much less likely to become severely diseased when exposed in the field than plants initially CMG-free. This cross-protective effect seems to be an important cause of symptom amelioration in post-CMD pandemic areas of East and Central Africa. A thorough understanding ofthe molecular mechanisms underlying this phenomenon will be required, however, before an assessment can be made of the potential utility of cross protection for CMG management. Biological control and whitefly resistance are being investigated for their potential to reduce the impact of B. tabaci that comes from its transmission of CMGs as well as the physical damage it causes to cassava plants. The latter is a particularly important feature of the...

General Features

Viruses and hantaviruses have made it clear that, with world travel requiring less time than many virus disease incubation periods, disease might spring up at any locale, and geographic containment alone is not realistic. There have been 15 outbreaks of Ebola virus infections reported since 1967, and the horrors of these infections have received considerable publicity. Hantaviruses have long been known to cause Korean hemorrhagic fever (KHF). More recently hantavirus pulmonary syndrome (HPS), with rapid disease course and mortality as high as 50 in less than a week, has occurred in regions of the USA. These examples have been part of the stimulus for investigations of immunotherapy, extended evaluation of available antiviral drugs, and new drug discovery to define effective strategies to treat and contain exotic virus outbreaks. Hyperimmune polyclonal equine antibody and MAb are being developed and tested to prevent acute Ebola disease and death in non-human primates. Furthermore,...

Economic Importance

The relatively moderate losses attributable to ACMV infection, coupled with moderate to low incidences, have been the reasons for the apparent lack of concern through large parts of cassava-growing Africa about the impact of CMGs and CMD. This outlook has changed markedly, however, following the emergence and regional spread of the CMD pandemic. Extensive surveys of CMD incidence, CMD severity, and the occurrence of the causal viruses have made it possible to make continent-wide yield loss estimates for CMD. The most recent of these (2006) provides estimates for losses in pandemic-recovered (16 loss), pandemic-affected (47 ), and as yet unaffected (18 ) countries in sub-Saharan Africa, leading to an overall loss figure of 34 million tons per year, roughly a third of total African production of fresh cassava roots. Significantly, as the pandemic-affected area

Cultural Methods

A range of cultural methods has been proposed for the control of CMGs. The methods most widely recommended have been the removal of infected plants (roguing) or the selection of disease-free planting material for the establishment of a new crop (selection). Crop isolation, adjusting crop disposition in relation to the prevailing wind, varying planting date, varietal mixtures, and intercropping cassava with other 'putative' protective crops have all been suggested at various times as potentially useful control options for CMGs. No convincing experimental evidence has yet been presented to confirm the value of any of these methods, however, and current field practice is restricted to selection and occasional roguing. Roguing is considered to be of value within the framework of institutional programs for the multiplication of CMD-resistant germ-plasm, in view of the requirement for the production of high-quality planting material. Experiments conducted in 'post-epidemic' areas of East...


Yersinia pestis microevolution and origin Alexandre Yersin is credited with isolating the causative agent for plague (his namesake, Yersinia pestis) in 1894 (Perry and Fetherston 1997). As the announcement of the discovery was being made, the third pandemic of plague, this time originating in China and spreading along shipping routes that intersected Hong Kong, was underway (Achtman et al. 1999). The death toll from plague, at least during recorded history, has been estimated at approx. 200 million (Perry and Fetherston 1997). A large proportion of these fatalities occurred during the three pandemics that swept through different portions of the known world (i) the Justinian plague from 541 to 544 ad in the Mediterranean basin, Mediterranean Europe, and the Middle East (ii) the European Black Death from 1347 to 1351 ad (followed by epidemic cycles until the nineteenth century) and (iii) the pandemic begun in the Yunnan province of China around 1855 that subsequently spread via...

Global Response

The world was initially slow to recognize the severity of the HIV pandemic but global efforts have increased dramatically in recent years. Between 1996 and 2005, annual funding for AIDS in low- and middle-income countries increased from 300 million to 8.3 billion. This acceleration of the world's response was prompted by increased human rights advocacy from people living with HIV and a concern that AIDS could destabilize global economic systems and threaten global security. Although these increases in funding are impressive, an effective global response will depend on sustained growth in annual funding of effective prevention and treatment programs until the epidemic can be stopped.


As a further aid to molecular epidemiology of FMDV, Samuel and Knowles have established topotypes of various FMDV serotypes, so, for example, FMDV type O can be divided into eight topotypes, each containing viruses which differ in VP1 sequence by at least 15 and are also geographically distinct (Samuel and Knowles 2001). With these techniques it has been possible to track the recent type O pandemic strain from Asia and into Africa and Europe.

General Introduction

In V cholerae, more than 200 serogroups have been identified and of these, only O1 and O139 are known to cause epidemics pandemic cholera. Diversity in the somatic (O) antigen is due to the composition of monosaccharide components and biosynthesis mechanisms. Information on the genetic basis of O-polysaccharide (OPS) capsule structures is developing steadily. Sequencing of specific genomic regions allowed examining genetic diversity in many V cholerae strains. Chapter 8 summarizes the biochemical composition and structure of O-polysaccharides, genes involved in their biosynthesis, and the role of horizontal gene transfer in creating this diversity. The concept of horizontal gene transfer has been widely accepted for the evolution of new variants and acquisition of new genes in bacteria. Integrating


Plague outbreaks occurred prior to the current era (i.e., 2000 years ago), but the numbers affected and the societal impact of the events remain unrecorded. During the current era, however, there have been three well-documented plague pandemics. The first, the plague of Justinian, arrived in 542 and raged intermittently until 750. It came to the Mediterranean region from an original focus in northeastern India or central Africa and was spread by infected rats hitchhiking on ships. It is estimated that a million people died. In Constantinople, the capital of the Roman Empire in the east, plague contributed to Justinian's failure to restore imperial unity because of a diminution in resources, which in turn prevented Roman and Persian forces from offering more than token resistance to the Muslim armies that swarmed out of Arabia in 634. In the year 1346, the second pandemic began, and by the time it disappeared in 1352 the population of Europe and the Middle East had been reduced from...


Although generally perceived by the public to be a recurring, endemic, non-life-threatening problem, viral influenza ranks high on the list of diseases with epidemic potential. During years with high levels of influenza incidence, tens of thousands of fatalities may be experienced in the United States. During the World War I pandemic of 1918, it has been estimated that 40 to 50 million victims died worldwide, more than died directly from the war itself


Because Marburg and Ebola viruses are highly virulent, special precautions need to be taken when samples are handled, and for some procedures biocontainment (BSL4) is necessary. For acute diagnosis polymerase chain reaction (PCR) and antigen-ELISA are suitable. For confirmation virus isolation Feldmann H and Klenk H-D (1996) Filoviruses Marburg and Ebola. Adv. Virus Res. 47 1. Pattyn SR (ed.) (1978) Ebola Virus Hemorrhagic Fever. Amsterdam Elsevier North-Holland. Peters CJ, Sanchez A, Rollin PE, Ksiazek TG and Murphy FA (1996) Filoviridae Marburg and Ebola viruses. In Fields BN, Knipe DM, Howley PM et al (eds) Fields Virology 3rd edn, p. 1161. Philadelphia Lippincott-Raven.

Cholera Toxin

Cholera is a profuse watery diarrhea produced by infection with Vibrio cholerae and caused mainly by the action of cholera enterotoxin (CT) on the intestinal epithelium. V. cholerae is a Gram-negative, motile, rod-shaped bacterium that is classified into over 140 serogroups based on O antigens. Only V. cholerae serogroups Ol and 0139 cause epidemic cholera. V. cholerae Ol consists of two biotypes, classical and El Tor, that are differentiated by biochemical properties, polymyxin B resistance and bacteriophage sensitivity. The biotypes of strains that caused the first four recorded cholera pandemics (1817 through 1879) are unknown. Classical Ol strains caused the fifth and sixth cholera pandemics (1881 through 1923), and the Ol El Tor biotype has predominated in the seventh pandemic (1961 to present). V. cholerae 0139, believed to have arisen from an El Tor strain by acquisition of novel O antigen determinants, was first identified as a cause of epidemic cholera in 1993.


Incompleteness is an almost universal drawback of most notification systems. They should never be dismissed for this reason alone. Statutory notification systems can be essential for surveillance and control. For common infections completeness may not be worth striving for, because notifications (assuming consistency in reporting) will generally provide information on trends, as well as fairly accurate information on age, sex and seasonal distributions, and possibly on place. The effect of mass vaccination programs can also be monitored fairly closely with statutory notification systems, as with measles (Figure 1) and acute paralytic poliomyelitis (Figure 2) in the UK. When a mass vaccination or other universal control program reduces the incidence of an infection to low levels, completeness becomes much more essential. For serious infections also, such as SARS or Lassa fever, for which contact tracing or other control measure is necessary, completeness is essential.


Analysis by age and sex is another basic analysis in surveillance. It can identify those most affected, and vulnerable groups. Changes in age distributions may provide important clues about a changing viral infection, and the effect of mass interventions on the age distribution of an infection can be monitored. Changes in the age distribution of measles in 1994 in the UK signified that an epidemic in older children was imminent, and the vaccine schedule was changed to include an extra booster injection (MR) to children aged 5-16 years. This averted the outbreak and the booster dose became a permanent feature of the routine immunization schedule in the UK. Indeed the changes in age distribution following mass vaccination could be considered an epidemiological side effect ofmass vaccination. Requests for occupational groups and travel histories should be selective. For poliomyelitis, SARS, dengue, and the viral hemorrhagic fevers, travel histories are required. Occupational group may be...


Note Investigation of an ongoing hemorrhagic fever outbreak in southwestern Uganda revealed what appears to be an additional distinct species of Ebola virus associated with this outbreak. Preliminary genome sequence analysis suggests the most closely related Ebola virus species would be the Cote d'lvoire ebolavirus. Initial outbreak investigations suggest that infection with this newly discovered virus is associated with a lower case fatality than infections with Zaire ebolavirus (60-90 ) or Sudan ebolavirus (50-60 ) (T. G. Ksiazek, Centers for Disease Control and Prevention, Atlanta, GA, United States, personal communication).


The emergence of new viruses is likely to continue as viruses evolve and find new ecological niches in the human and animal population. It is noticeable that most newly recognized viruses have been RNA viruses, perhaps since RNA evolves at a faster rate than DNA, for which host cells have developed efficient proofreading enzymes. It will be important in the future to detect new viruses before they can emerge to cause disease in the population. The SARS epidemic provides an excellent example. Before the epidemic, only two human coronaviruses were known, human coronaviruses 229E and OC43. Despite the fact that serious coronavirus diseases were well known in other vertebrates, such as feline infectious peritonitis and avian infectious bronchitis virus, it was not until the SARS epidemic that research on human corona-viruses led to the discovery of three new human coronaviruses - SARS, HKU1, and NL63 New Haven. Finally, one of the most important viruses that continue to emerge in...


Each gene (element II), and a conserved element located at the beginning of each subsequent gene (element III). The SYNV 'gene junctions' are very similar to the intergenic region following the N gene of the nucleorhabdovirus, RYSV. LNYV also has some similarity to other rhabdoviruses in element I, but elements II and III diverge substantially. Element 1 (AUUCUUUUU) of SYNV is also nearly identical to the analogous regions (AUUCUUUUUU) of Ebola virus, suggesting that some conservation of regulatory regions may extend to the Filoviridae. Sequence similarities in this region are also found in paramyxoviruses and in borna disease virus. Thus, intergenic regions of the genome that play an important role in regulating mRNA transcription and replication appear to have been stringently conserved. However, the leader and trailer genes and the genes encoding the proteins appear to 'have undergone extensive evolution to accommodate diverse host requirements.

Avian Influenza

During 2003, the public has become keenly aware of the global spread of SARS. At the same time, in southeast Asia, highly pathogenic strains of avian influenza virus including the H5N1 again crossed from birds to humans and caused fatal disease. Since 2003, avian H5N1 influenza virus has infected 217 persons and killed 123, in 10 countries all over the world 120 . Normally, avian influenza viruses do not infect humans because of host barrier and direct avian-to-human influenza transmission was unknown before 1997. Direct transmission of H5N1 viruses of purely avian origin from birds to humans was first described during an outbreak among poultry in Hong Kong in 1997. In this outbreak, 6 of 18 confirmed human H5N1 patients died 121 . And serologic evidence was found for asymptomatic infection in humans after exposure to infected poultry 122 . To date, the risk of human-to-human transmission of influenza H5N1 has been suggested in several household clusters 123 , and in one case of


Figure 2.8 Random walk taken by an oral drug on route to its point of efficacious contact within a human target cell. This continuum of interactions between a drug and various biological surfaces within the human biological realm is typically divided into categories associated with ADMET and efficacy. Biological milieu marked with an asterisk represent compartments having particularly high metabolic capabilities. Blood is notably high in esterase capability. In the future, medicinal chemists will utilize knowledge about ADMET-related SARs to more effectively identify the best drug leads and to further enhance the therapeutic profiles of selected compounds. (The phrase random walk is taken from ref. 217.) Figure 2.8 Random walk taken by an oral drug on route to its point of efficacious contact within a human target cell. This continuum of interactions between a drug and various biological surfaces within the human biological realm is typically divided into categories associated with...