West Nile Virus, Susceptibility To

A number sign (#) is used with this entry because variation in the CCR5 gene (601373) is associated with susceptibility to West Nile virus (WNV).

Description

WNV is an enveloped, neurotropic, single-stranded sense RNA flavivirus that is naturally maintained in a zoonotic cycle between avian hosts and mosquito vectors. The virus was first isolated from a Ugandan woman in 1937 and subsequently emerged in Europe and, in 1999, in New York, with eventual spread throughout North America. WNV causes a spectrum of disease ranging from acute fever to lethal encephalitis. Susceptibility to WNV is increased in the elderly and in immunocompromised individuals (summary by Diamond and Klein (2006) and Glass et al. (2005)).

Clinical Features

Clinical manifestations of WNV infection are variable. About 80% of infections remain subclinical, whereas 20% progress to a febrile illness associated with joint pain, muscle aches, headache, and fatigue. Nearly a third of patients with fever in the U.S. progress to paralysis, meningitis, and/or encephalitis. Approximately 4% of cases in the U.S. are fatal (Diamond and Klein, 2006; Glass et al., 2005).

Pathogenesis

Using flow cytometric analysis to identify regulatory T-cell (Treg) frequencies in 32 blood donors with acute WNV infection, Lanteri et al. (2009) demonstrated that CD4 (186940)-positive/FOXP3 (300292)-positive Treg frequencies increased in all individuals in the 3 months after the index donation that revealed WNV RNA in plasma. However, symptomatic donors exhibited lower Treg frequencies up to 1 year after index donation without showing systemic T-cell or generalized inflammatory responses. Studies in WNV-infected mice showed that symptomatic mice displayed lower Treg frequencies than asymptomatic mice. Moreover, mice lacking Foxp3-positive Tregs experienced increased lethality following WNV infection compared with controls. Lanteri et al. (2009) concluded that higher levels of peripheral Tregs after infection protect against severe WNV disease in immunocompetent animals and humans.

Molecular Genetics

Glass et al. (2006) analyzed the distribution of CCR5 delta-32 (601373.0001), a defective CCR5 allele found predominantly in Caucasians, in independent cohorts of WNV-seropositive individuals. They observed a strong deviation from Hardy-Weinberg equilibrium due to an increased frequency of delta-32 homozygotes. The delta-32 homozygotes also had increased risk of fatal WNV infection. Glass et al. (2006) concluded that CCR5 delta-32 is a risk factor for symptomatic WNV infection.

Bigham et al. (2011) tested 360 common haplotype-tagging and/or functional SNPs in 86 genes encoding immune function regulators in 422 individuals with symptomatic WNV infections and 331 WNV-infected individuals without symptoms. After correcting for multiple tests, they found that SNPs in IRF3 (603734) and MX1 (147150) were associated with symptomatic WNV infection and that a single SNP in OAS1 (164350) was associated with increased risk of WNV encephalitis and paralysis. Bigham et al. (2011) concluded that genetic variation in the interferon response pathway is associated with risk for symptomatic WNV infection and WNV disease progression.

By genotyping 501 WNV-infected Caucasians, Lim et al. (2009) showed that the frequency of the hypofunctional A allele of SNP rs10774671 (164350.0001) of OAS1 was increased in both symptomatic and asymptomatic WNV seroconverters. Highest WNV accumulation occurred in tonsil tissue from donors homozygous for the hypofunctional A allele. Lim et al. (2009) concluded that OAS1 activity may influence the probability of initial WNV infection, but not the severity or symptomatic nature of the infection after WNV exposure.

Animal Model

Mehlhop and Diamond (2006) dissected the contributions of individual complement activation pathways to protection from WNV disease in mice. Mice lacking C1q (C1QA; 120550) in the classical pathway, C4 (C4A; 120810) in the classical and mannose-binding lectin (MBL; 154545) pathways, or factor B (CFB; 138470) or factor D (CFD; 134350) in the alternative pathway had increased mortality, suggesting all pathways function to limit WNV spread. However, mice deficient in C5ar (113995) had survival rates comparable to wildtype mice. Alternative pathway deficiencies were associated with earlier dissemination to the central nervous system and reduced Cd8 (see 186910)-positive T-cell responses, but anti-WNV antibody profiles were near normal. Mice lacking classical or MBL pathways had deficits in both B- and T-cell responses to WNV. Mehlhop and Diamond (2006) proposed that all 3 complement pathways are required to fully prime adaptive immune responses and control WNV infection.

Arjona et al. (2007) showed that patients with acute WNV infection had increased levels of MIF (153620) in plasma and cerebrospinal fluid. They found that blocking Mif action in mice either by antibody, small molecule antagonist, or gene deletion increased resistance to WNV lethality. PCR and confocal microscopy showed that mice lacking Mif had lower viral load and brain inflammation, as well as lower circulating Tnf (191160), than wildtype mice. Injection of Evans blue dye demonstrated that the blood-brain barrier remained intact in Mif -/- mice, but not in wildtype mice, after WNV challenge. Arjona et al. (2007) concluded that MIF is involved in WNV pathogenesis and that pharmacotherapeutic approaches targeting MIF may be useful in treating WNV encephalitis.

Using mice less than 6 months of age (i.e., adult) and greater than 18 months of age (i.e., old), Brien et al. (2009) observed reduced survival of the old mice after subcutaneous or intraperitoneal challenge with West Nile virus. Susceptibility correlated with significantly higher viral titers in brain, but not blood. Mice lacking Ifnar (107450) were more susceptible than old mice, whereas Rag1 (179615) -/- mice were as susceptible as old mice in terms of survival time, suggesting that old mice are not deficient in innate immunity. Adoptive transfer of adult and old mouse spleen or T cells conferred protection to Rag1 -/- mice, but the protection was greater with adult cells. Functional analysis showed that old cells made weaker Cd8-positive antigen-specific responses, produced reduced amounts of Ifng (147570), Tnf (191160), and Gzmb (123910), and mediated weaker cytotoxic T-cell responses. Survival of Rag -/- mice provided with Ifng -/- or Gzmb -/- Cd4 (186940) or Cd8 cells or with old Cd4 or Cd8 cells was equally poor. Immunofluorescence microscopy demonstrated reduced numbers of effector T cells in the brains of old mice after West Nile virus challenge. Brien et al. (2009) proposed that some of the identified defects in old animals could be targets for immunomodulation in elderly humans, who are also more susceptible to West Nile virus than younger adults.

Town et al. (2009) found that mice lacking Tlr7 (300365) or Myd88 (602170), but not those lacking Tlr9 (605474), had increased WNV viremia and susceptibility to lethal WNV infection. Although tissue concentrations of most innate cytokines were increased, Cd45 (PTPRC; 151460)-positive leukocytes and Cd11b (ITGAM; 120980)-positive macrophages failed to home to WNV-infected cells in Tlr7 -/- mice. This failure was associated with reduced Il12p40 (IL12B; 161561) and Il23a (605580) expression in Tlr7 -/- mice and Tlr7 -/- macrophages. Mice lacking Il12b or Il23a, but not those lacking Il12a (161560), were more susceptible to lethal WNV infection, similar to Tlr7 -/- mice. Town et al. (2009) concluded that TLR7- and IL23-dependent responses are vital to host defense by affecting immune cell homing to WNV-infected target cells.

Lim et al. (2011) found that Ccr2 (601267) -/- mice exhibited a markedly increased susceptibility to WNV encephalitis that was associated with a selective reduction of a monocyte subset in brain. In contrast, wildtype mice, but not Ccr2 -/- mice, experienced a selective monocytosis in peripheral blood. Intravenous administration of a mixture of Ccr2 +/+ and Ccr2 -/- monocytes into WNV-infected Ccr2 -/- mice resulted in accumulation of equal amounts of the 2 types of monocytes in the central nervous system. Lim et al. (2011) concluded that CCR2 mediates highly selective peripheral blood monocytosis during WNV infection and that this is critical for monocyte accumulation in brain.

Using a mouse model of WNV neuroinvasive disease, Vasek et al. (2016) showed that viral infection of adult hippocampal neurons induced complement-mediated elimination of presynaptic terminals. In contrast with models using virulent WNV strains, infection of mice with a WNV strain with a mutation in nonstructural protein-5 (NS5) resulted in survival rates and cognitive dysfunction similar to those observed in human WNV neuroinvasive disease. Recovered mice displayed impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from recovered mice with poor spatial learning showed increased expression of genes that drive synaptic remodeling by microglia via complement. During WNV neuroinvasive disease, C1qa was upregulated and localized to microglia. Mice with fewer microglia, i.e. Il34 (612081) -/- mice, or with deficiency of C3 (120700) or C3ar (605246) were protected from WNV-induced synaptic terminal loss. Vasek et al. (2016) proposed that C3 and C3ar mediate presynaptic terminal loss in hippocampi of mice exhibiting spatial learning defects during recovery from WNV neuroinvasive disease.