Host Genetic Resistance

David G Brownstein, Yale University School of Medicine, New Haven, Connecticut, USA

Copyright © 1999 Academic Press


Genetic diversity is maintained among individuals of any noninbred species in order to provide the raw material to adapt to evolutionary forces. Although the species as a whole benefits from this diversity, individuals may not. Individuals may inherit certain genes or gene combinations that make them unusually susceptible to specific infectious or noninfectious diseases. In genetic terms, alleles, or alternative forms of the same gene, are the basis of variations in genetic resistance to diseases whether these variations are controlled by single or multiple loci. Developments in many fields but especially molecular genetics have facilitated the characterization of genes with multiple alleles that regulate disease resistance. Those polymorphous genes that regulate resistance to viral diseases are the subject of this entry.

In 1933, Webster was the first to observe that resistance to a disease caused by a virus could be inherited. The virus was yellow fever and the host was the laboratory mouse. He crossed strains of mice that were resistant and susceptible to the lethal effects of yellow fever virus and showed that segregant progeny expressed resistance according to predictions of Mendelian genetics. Other examples of genetic resistance in mice to what were then termed arboviruses were soon to follow. Today, polymorphous genes that regulate resistance to 11 genera of viruses have been reported.

Experimental results using laboratory mice needed corroboration in a natural population of another

species. This came in the 1950s when the highly virulent myxoma virus was introduced into wild European rabbits in Australia to control burgeoning lagomorph populations. Although numerous factors conspired to attenuate initially high mortality rates, selection for resistant host genes was clearly an important factor. In humans, attempts to associate the severity of smallpox, poliomyelitis, congenital rubella and hepatitis B with various blood group and major histocompatibility antigens met with limited success. An impetus for this line of inquiry in humans came with Allison's discovery in 1964 of the relationship between resistance to falciparum malaria and heterozygosity of the sickle cell gene. Although this work did not deal with a viral infection, it established that genetic polymorphisms in humans regulate resistance to at least one microbial disease.

To date, the most systematic approach to the study of relationships between the severity of viral diseases and specific host genes remains comparisons of highly inbred strains of mice that vary in their susceptibility to a particular disease. Derivatives of resistant and susceptible strains such as bilineal congenic and recombinant inbred strains have been especially valuable in these studies. What has emerged from them is confirmation that polymorphous host genes are important regulators of the severity of many if not most viral infections, that single or multiple loci are involved, and that each locus appears to specify resistance to a particular genus of virus, or even a specific strain of virus within a genus. These studies have also shown that polymorphisms within the major histocompatibility complex (MHC) may influence the course of viral infections, but that loci outside of the MHC are often more important.

During the past several years a number of viral disease resistance genes have been identified. In some cases their protein products or their mechanisms of action are known. In other cases their protein products and their functions are unknown but as they become more precisely mapped and eventually cloned 'reverse genetics' can be used to delineate their functions. Substantial homology between the murine and human genomes makes it possible to identify similar genetic resistance elements in humans. This has already been done for the Mxl locus on mouse chromosome 16 and human chromosome 21 which regulates susceptibility to influenza A and B viruses. The resistance loci that have been provisionally or definitively mapped are discussed here since this represents the most substantial progress in recent years (Table 1).

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