Clinical Features of Infection and Pathology

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PrV is able to infect most mammals productively, with the exception of humans and other higher primates. However, primate and human cells are infectable in cell culture, and the reason for the natural resistance is not clear. Equids and goats are also rather resistant but may be infected experimentally. In addition, pseudorabies has been reported in many species of wild mammals, including wild boar, feral pigs, coyotes, raccoons, rats, mice, rabbits, deer, badgers, and coatimundi. It is so far not known whether these animals play a role in farm-to-farm transmission of PrV. In susceptible species other than porcines, infection is fatal and animals die from severe neuronal disorders.

After infection of the natural host, the clinical picture varies depending on the age of the animal, the virulence of the virus, and the route of infection. In nature, infection occurs predominantly oronasally, although genital transmission may also take place, especially in feral pigs. After replication in epithelial cells the virus gains access to neurons innervating the facial and oropharyngeal area, in particular the olfactory, trigemi-nal, and glossopharyngeal nerves. The virus spreads centripetally by fast axonal retrograde transport and reaches the cell bodies of infected neurons where either lytic or latent infection ensues (see below). PrV is disseminated viremically to many organs, where it replicates in epithelia, vascular endothelium, lymphocytes, and macrophages. In nonporcines, PrV is rather strictly neurotropic.

Neonates become prostrate and die quickly, often without nervous signs. In slightly older piglets, severe central nervous system (CNS) disorders are characterized by incoordination, twitching, paddling, tremors, ataxia, convulsions, and/or paralysis, whereas itching is only rarely present (Figure 4). Mortality in piglets up to 2-3 weeks of age may be as high as 100%, resulting in severe losses. Piglets at 3-6 weeks of age may still exhibit neurological signs and high morbidity, but mortality is usually reduced. Infection in older pigs induces primarily respiratory symptoms, such as coughing, sneezing, and heavy breathing, resulting from viral replication in, and destruction of, pulmonary epithelium. Despite the absence of overt nervous signs, virus gains access to neurons and remains latently established in the olfactory bulb, trigeminal ganglia, and brain stem or, after venereal transmission, in the sacral ganglia. PrV infection of pregnant sows may result in abortion or delivery of stillborn or mummified fetuses due to endo-metritis and necrotizing placentitis with infection of trophoblasts. In susceptible species other than swine, PrV infection is invariably fatal, sometimes after a rapid, peracute course without preceding overt clinical signs. Pruritus is a lead symptom of PrV infection in these species which, particularly in rabbits and rodents, may result in violent itching and automutilation. The death of mice, rats, cats, or dogs on farms is often a telltale sign of the presence of PrV prior to the appearance of symptoms in pigs.

Transmission occurs via virus-containing body fluids such as nasal and genital secretions, which gain access to epithelial surfaces within the respiratory or genital tract. Airborne transmission is efficient at short range, but long-range transmission covering several kilometers may also occur. Carnivores become infected by ingesting contaminated meat. After primary replication in epithelial cells, the virus enters the endings of sympathetic, parasympathetic or sensory and motor neurons innervating the area of primary replication. Infection probably occurs by the same mechanism as outlined above for cultured cells. Virus is transported in retrograde fashion to the neuronal cell body, where DNA replication and formation of progeny virions ensues. It is not clear whether complete virions or viral subassemblies are then transported to the synapse, or how transsynaptic transfer occurs. Depending on the virulence of the virus and the age and immune status of the host, infection may not proceed beyond the first neuronal level (i.e., ganglia directly innervating the affected peripheral site). However, virus may also spread to the brain resulting in ganglioneuritis and encephalitis. Lymphocytes can also become infected by PrV and this may help viral spread within the body, playing an important role in infection of the fetus. However, the percentage of infected cells in the blood is rather low, even during acute infection, and difficult to detect. A major target organ for latency in swine is the tonsils, and tonsil biopsies allow reliable detection of virus by molecular biological techniques or virus isolation.

There are no pathognomonic, gross lesions of AD. In piglets, there may be necrotizing tonsillitis, rhinotra-cheitis, or proximal esophagitis. Other lesions commonly seen include pulmonary edema, necrotizing enteritis, and multifocal necrosis of the spleen, lung, liver, lymph nodes, and adrenal glands. Histologically, PrV causes a nonsuppurative meningoencephalitis and paravertebral ganglioneuritis. The gray matter is especially affected, and infected neurons or astrocytes may present acido-philic intranuclear inclusions. The presence of viral antigen can be visualized by immunostaining and viral genomes can be detected by in situ hybridization. PrV infected cells usually show more or less extensive degeneration and necrosis due to lytic viral replication. Whether apoptosis induced by PrV infection also plays a role in vivo is unclear. A predominantly T-cell-mediated reaction of the immune system induces ganglioneuritis, polio- or panencephalitis with foci of gliosis contributing to the loss of neuronal function. The described extraneural lesions in pigs and acute myocarditis in carnivores might provide additional explanations for the fatal outcome of infections in which virus cannot be recovered from the brain.

Figure 5 The principle of DIVA or marker vaccination. Whereas antibodies are produced against all immunogenic viral proteins after wild-type infection, antibodies against the missing gene product (circled) will not be formed after vaccination with a gene-deleted virus. The presence or absence of these antibodies is used to differentiate between infected and vaccinated animals. Reprinted with permission from Mettenleiter TC (2005) Veterinary viruses. Nova Acta Leopoldina NF92 344: 221-230.

Figure 5 The principle of DIVA or marker vaccination. Whereas antibodies are produced against all immunogenic viral proteins after wild-type infection, antibodies against the missing gene product (circled) will not be formed after vaccination with a gene-deleted virus. The presence or absence of these antibodies is used to differentiate between infected and vaccinated animals. Reprinted with permission from Mettenleiter TC (2005) Veterinary viruses. Nova Acta Leopoldina NF92 344: 221-230.

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