A Mouse Model of Chronic West Nile Virus Disease

Abstract

Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.

West Nile Virus spread and differential chemokine response in the central nervous system of mice: Role in pathogenic mechanisms of encephalitis

“…These studies demonstrated that chronic disease in mice infected subcutaneously was associated with altered innate immunity and increased regulatory T‐cell frequency. Chronically infected mice showed lower expression of genes associated with cytolysis (Graham et al, ).…”

Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches

“…More recently, incipient CC lines were used to identify variants in Trim55 associated with vascular cuffing after infection with a mouse adapted SARS-CoV strain (Gralinski et al, 2015) and QTLs for survival to Klebsiella pneumoniae infection (Vered et al, 2014). Importantly, CC mice have been used to create improved models of EBOV (Ebola virus) and WNV (West Nile virus) infection (Graham et al, 2016;Graham et al, 2015;Rasmussen et al, 2014) and mouse populations showing diverse susceptibility to M. tuberculosis and Pseudomonas aeruginosa (Lore et al, 2015;Smith et al, 2016). These models await genome-wide scans to unveil the genetic determinants of infection susceptibility and severity.…”

Giving the Genes a Shuffle: Using Natural Variation to Understand Host Genetic Contributions to Viral Infections

“…Highlighting another powerful characteristic of the CC, completely new mouse models for spontaneous colitis [41], Ebola-associated hemorrhagic fever [42], novel neurological responses to Theiler's murine encephalomyelitis virus (TMEV) [43], and persistent West Nile virus (WNV) infection in the brain [44] were discovered, a harbinger of new model systems that may emerge over time.…”

“…Sample collection should anticipate that the CC model is likely to identify CC strains that progress to different stages in disease severity, replicating phenotypes seen in human populations and allowing the identification of susceptibility alleles that regulate disease progression from mild to severe to chronic infections in vivo. This is important as it has been shown that novel disease phenotypes might be discovered in the CC (severe neuroinvasive disease and chronic WNV infection [44]). New models for diseases that are completely unrelated (spontaneous colitis [41], human leukocyte adhesion and recruitment deficiencies [55]) or related to the study design (SARS-CoV [40], Ebola [42]) will generate a panel of variable disease-state mouse models that capture the different phases of disease seen in human populations.…”