Chapter 39 : Immunogenetics of Virus Pathogenesis

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Identification of the genetic component of infectious disease susceptibility is an area of intense investigation, which, as presented in this chapter, can provide clues to fundamental questions about virus pathogenesis and the diversity, redundancy, and specialization of host mechanisms against infection. The chapter addresses some methodological approaches of the identification of susceptibility genes to virus infection. It talks about genetic control of virus entry into the host cell. Infection with mouse coronavirus has served as a model to understand the viral and immunological determinants of coronavirus disease, including severe acute respiratory syndrome. Parvovirus B19, a significant human pathogen that causes fetal loss and severe disease in immunocompro-mised patients, is classified as an erythrovirus due to its ability to infect red blood cell precursors of the bone marrow. Noroviruses or Norwalk-like viruses are the leading cause of viral acute gastroenteritis in humans. The chapter deals with genetic control of interferon (IFN)-mediated immunity in viral infection. An important consequence of type I IFN secretion is the activation of natural killer (NK) cells, a central component of the innate response against virus infection. It also discusses major histocompatibility complex (MHC) I alleles and TCR repertoire which can influence CD81 t responses and outcomes after viral infection. Pathogens are considered one of the most powerful forces shaping the evolution of the human genome. Numerous studies have shown that genes or loci involved in host defense against infection present signs of positive or negative selection.

Citation: Wiltshire S, Watkins D, Skamene E, Vidal S. 2011. Immunogenetics of Virus Pathogenesis, p 491-508. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch39

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Severe Acute Respiratory Syndrome
MHC Class I
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Image of FIGURE 1

Human resistance or susceptibility to noroviruses. Phylogenetic analysis has shown that the most variable domain of norovirus nucleocapsid corresponds to the carbohydrate ligand-binding domain, named the P2 site. Variation in norovirus strains is depicted by different shading of the P2 site in the nucleocapsid. Noroviruses bind to carbohydrates (represented by geometric shapes) regulated by the and loci, which are polymorphic in the population. The cell receptor for Norwalk virus is a 1,2 linked-fucose (grey circle) controlled by the gene. Therefore, individuals homozygous for nonfunctional alleles are fully protected against Norwalk virus infection. However, these individuals are susceptible to norovirus strains that bind fucose residues (white circles) controlled by the gene, or N-acetylgalactosamine or galactose residues (white triangles) depending upon gene polymorphisms (adapted from ).

Citation: Wiltshire S, Watkins D, Skamene E, Vidal S. 2011. Immunogenetics of Virus Pathogenesis, p 491-508. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch39
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Image of FIGURE 2

Genetically nonredundant molecular pathways in the type I IFN response to viral infections. (a) Upon viral infection, viral nucleic acid is initially detected by two classes of receptors (in black). The TLR class of receptors are located in the endosomal compartment and require UNC93B for maturation. TLRs 3, 7, and 9 bind pathogen-associated molecular patterns (PAMPs) such as double-stranded RNA, viral ssRNA, and viral dsDNA. The cytosolic helicases RIG-I and MDA5 perform similar functions in the cytoplasm. (b) Upon binding a PAMP, a signal is relayed through an adaptor molecule (light grey, black border) such as MYD88, TRIF, or IPS-1 to a series of kinases (dark grey, light border), and ultimately to transcription factors (dotted border) such as IRF3, IRF7, or NF-κB, which induce the expression of type I IFN (white). (c) IFN signals to self and neighboring cells through the IFN receptor, which initiates a signaling cascade involving JAK and TYK2, these induce formation of the ISGF3 transcription factor from STAT1, STAT2, and IRF9. The ISGF3 transcription factor leads to the production hundreds of genes including antiviral effector molecules such as Mx, PKR, and OAS1b. (d) Genetically determined nonredundant genes in whole pathways are shown in bold and underlined.

Citation: Wiltshire S, Watkins D, Skamene E, Vidal S. 2011. Immunogenetics of Virus Pathogenesis, p 491-508. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch39
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The human and mouse major histocompatibility complex (MHC) and natural killer complex (NKC). (a) The MHC is a genomic region central to the immune response found in most vertebrates, including on the short arm of human chromosome 6 and proximal mouse chromosome 17. The MHC encodes proteins that help to distinguish between self and nonself protein components. MHC class I molecules (human HLA-A, HLA-B, and HLA-C; mouse H2-D, H2-K, H2-L) present endogenous antigens to CD8 T cells and class II molecules (human HLA-DP, HLA-DQ, HLA-DR; mouse H2-P, H2-A, H2-E) present exogenous antigens to CD4 T cells. A number of other proteins that support these two pathways also map to the MHC, such as the class III complement (C) proteins and inflammatory cytokine genes (TNF), and the antigen processing proteins (TAPBP, TAP/LMP). MHC class I proteins also serve as ligands to MHC class I NK cell receptors, as a set of molecules that modulate NK cell activity. (b) Two distinct structural families of NK receptors that bind to MHC class I ligands have been identified: the human killer immunoglobulin-like receptors (KIRs) encoded on chromosome 19, and the mouse killer cell lectin-like receptors (KLRs or Ly49s) on chromosome 6. Both families contain activating and inhibitory members that perform similar functions. The presence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic tail of the receptor inhibits NK lysis. In contrast, activation requires the recruitment of an adaptor molecule (DAP12) through a charged amino acid in the transmembrane domain. DAP12 contains an immunoreceptor tyrosine-based activation motif (ITAM), which triggers NK cell activating pathways. Inhibitory receptor genes (human KIR3DL3, KIR3DP1, KIR2DL4, KIR3DL2; mouse Ly49q, Ly49e, Ly49i, Ly49g, Ly49c, Ly49a) are generally conserved. In contrast the number of activating receptor genes (in brackets) is highly variable among individuals.

Citation: Wiltshire S, Watkins D, Skamene E, Vidal S. 2011. Immunogenetics of Virus Pathogenesis, p 491-508. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch39
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Image of FIGURE 4

Models of NK cell receptormediated response in mice (top). In mice, a diverse array of MHC class I NK cell receptors of the Ly49 family are critical for the host response against MCMV. (A) The mouse strain 129/J is susceptible to MCMV infection. This strain possesses the ITIM-containing inhibitory receptor Ly49I, which binds the virus MHC class I-like protein, m157. In this case, Ly49I-mediated inhibitory signals prevent NK cell activation. (B) MCMV-resistance in C57BL/6 mice is mediated by the DAP12-associated Ly49H receptor, which also binds to m157. Upon m157 recognition, Ly49H triggers NK cell-mediated cytotoxicity via perforin and granzyme (black circles), cytokine secretion mainly through IFN-γ (white circles), and cell proliferation leading to clearance of MCMV-infection. (C) MCMV-resistance in MA/My strains is mediated by a different activating receptor, the DAP12-associated Ly49P receptor. Ly49P recognition of the infected cell requires the presence of both a host MHC class I molecule, H2Dk, and an MCMV-encoded protein, m04. Arrows in the NK cell diagram indicate activating signals emanating from stimulatory receptors. Human NK cell receptors in virus infection (bottom). In humans, a diverse array of MHC class I NK cell receptors of the KIR family, in concert with their MHC class I ligands, determine the host response against viruses. The outcome of infection depends on the strengh of signals elicited by receptor/ligand pairs. (D) A patient with a genotype for the high-affinity interaction between inhibitory KIR2DL1 and HLA-C2 presents severe and recurrent herpes infections (HCMV, VZV, EBV) associated with NK cell impaired cell-mediated cytotoxicity and cytokine production against cognate target cells. (E) HCV-infected drug users with a genotype for the low-affinity interaction between inhibitory KIR3DL3 and HLA-C1 are relatively protected against chronic HCV infection. The weak inhibitory signals are thought to lower the threshold for NK cell activation. (F) HIV patients encoding the compound genotype for the activating KIR3DS1 receptor and its cognate ligand, HLA-Bw4, have delayed progression to AIDS. Upon challenge with HIV-infected cognate cells, KIR3DS1 NK cells from these patients proliferate and elicit secretion of cytokines (white circles), and cytotoxic granules (black circles). Arrows in the NK cell diagram indicate activating signals emanating from stimulatory receptors.

Citation: Wiltshire S, Watkins D, Skamene E, Vidal S. 2011. Immunogenetics of Virus Pathogenesis, p 491-508. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch39
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Image of FIGURE 5

Factors affecting development of elite control (EC) or rapid progression (RP) in HIV and SIV infection (top). Effective function of cytotoxic (CD8) T cells has been shown to depend on allele of MHC, characteristic peptides presented to T cells by MHC, a broadly specific CD8 response to pathogen and a more rapidly expanding response. Rapid progression of HIV to AIDS has been correlated with allele of MHC, as well as an immunodominant response and delayed expansion of CD8 T cells (bottom).

Citation: Wiltshire S, Watkins D, Skamene E, Vidal S. 2011. Immunogenetics of Virus Pathogenesis, p 491-508. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch39
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Susceptibility loci with function

Citation: Wiltshire S, Watkins D, Skamene E, Vidal S. 2011. Immunogenetics of Virus Pathogenesis, p 491-508. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch39

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