Maneuvering for advantage: the genetics of mouse susceptibility to virus infection

Abstract

Genetic studies of host susceptibility to infection contribute to our understanding of an organism's response to pathogens at the immunological, cellular, and molecular levels. In this review we describe how the study of host genetics in mouse models has helped our understanding of host defense mechanisms against viral infection, and how this knowledge can be extended to human infections. We focus especially on the innate mechanisms that function as the host's first line of defense against infection. We also discuss the main issues that confront this field, as well as its future.

Fig. 1

A typical virus life cycle. Despite the diversity of genomic organization and mechanisms of replication found among virus families, most viruses pass through several common stages during the infection process. Host resistance factors that determine the outcome of virus infection exist at each of the following stages: 1, viral attachment and entry into the host cell; 2, virus multiplication inside the host cell; 3, recognition and lysis of virus-infected cells. Mouse genes affecting susceptibility are shown in yellow boxes, human genes are shown in green boxes.

Fig. 2

Direct recognition of virus-infected cells by natural killer (NK)-cell receptors. (a) NK-cell recognition and killing of mouse cytomegalovirus (MCMV)-infected cells in mice. The recognition of the m157 protein by the activating Ly49H receptor provides the first example of direct recognition of a virally encoded molecule by an NK-cell receptor. Ly49H associates with the adaptor molecule DAP12 through a charged arginine residue in its transmembrane domain. DAP12 possesses an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain that serves as a docking site for Syk and Zap70 protein tyrosine kinases. Upon Ly49H binding to m157, a cascade of tyrosine phosphorylation is initiated leading to cellular activation and perforin-mediated killing of the virus-infected cell. (b) Proposed NK-cell recognition and killing of HIV-infected cells in humans. Human killer-cell immunoglobulin-type receptor (KIR) is considered to be a functional homolog of mouse Ly49. An epistatic interaction between KIR3DS1 and HLA-B delays progression to AIDS, suggesting that HLA-B behaves as a ligand for KIR3DS1 . The peptide presented on HLA-B that is responsible for this interaction remains to be identified. Because KIR3DS1 receptor is also associated with the adaptor molecule DAP12, the intracellular signaling cascade leading to cellular activation and killing of virus-infected cells seems to be similar to that triggered by mouse Ly49H.

Fig. 3

Roles of the major histocompatibility complex (MHC) in combating virus infections. (a) Mouse susceptibility loci in the MHC are shown. Studies using congenic mice having intra-MHC recombination identified the contribution of specific MHC alleles to virus infection. Mostly, MHC class I genes play a crucial role against virus infection of mice. Only a small number of genes in the MHC and their relative positions on chromosome 17 are shown. (b) Genetic associations of the human MHC with susceptibility to virus infection. Only a small number of genes in the MHC, with their relative positions on chromosome 6, are shown. The genes encoding class I are depicted in red, class II in yellow and class III in green. TNF is the gene encoding tumor necrosis factor. C2 and C4 are complement genes.