Genetic Diversity in the Collaborative Cross Model Recapitulates Human West Nile Virus Disease Outcomes

Abstract

West Nile virus (WNV) is an emerging neuroinvasive flavivirus that now causes significant morbidity and mortality worldwide. The innate and adaptive immune responses to WNV infection have been well studied in C57BL/6J inbred mice, but this model lacks the variations in susceptibility, immunity, and outcome to WNV infection that are observed in humans, thus limiting its usefulness to understand the mechanisms of WNV infection and immunity dynamics. To build a model of WNV infection that captures human infection outcomes, we have used the Collaborative Cross (CC) mouse model. We show that this model, which recapitulates the genetic diversity of the human population, demonstrates diversity in susceptibility and outcomes of WNV infection observed in humans. Using multiple F1 crosses of CC mice, we identified a wide range of susceptibilities to infection, as demonstrated through differences in survival, clinical disease score, viral titer, and innate and adaptive immune responses in both peripheral tissues and the central nervous system. Additionally, we examined the Oas1b alleles in the CC mice and confirmed the previous finding that Oas1b plays a role in susceptibility to WNV; however, even within a given Oas1b allele status, we identified a wide range of strain-specific WNV-associated phenotypes. These results confirmed that the CC model is effective for identifying a repertoire of host genes involved in WNV resistance and susceptibility. The CC effectively models a wide range of WNV clinical, virologic, and immune phenotypes, thus overcoming the limitations of the traditional C57BL/6J model, allowing genetic and mechanistic studies of WNV infection and immunity in differently susceptible populations.

A Mouse Model of Chronic West Nile Virus Disease

“…Notably, however, half of the mice surviving past d13 p.i. displayed sustained weight loss that was distinct from B6 mice (Fig 1A), as well as from the 100+ RIX lines screened [17]. Due to this novel and unique sustained weight loss following infection, we examined the viral burden within the CNS to determine if virus also persisted.…”

“…We have previously demonstrated that the CC can be used as a resource to model WNV infection in humans such that infection and comparison of CC mouse lines improves upon inbred mouse models to better capture the diversity of WNV infection outcomes observed across the genetically diverse human population [17]. Here, we further characterize the RIX line CC032/GeniUnc crossed to CC013/GeniUnc (hereafter CC(032x013)F1)), which serves as a mouse model of chronic WNV infection.…”

Identifying protective host gene expression signatures within the spleen during West Nile virus infection in the collaborative cross model

“…West Nile virus TX-2002-HC (WN-TX) was propagated using previously described methods [4]. Viral stocks were generated using supernatants collected from infected vero cell lines and stored at 80 °C.…”

End-point disease investigation for virus strains of intermediate virulence as illustrated by flavivirus infections

“…Variability in disease outcomes has been reported regularly for WNV infections in humans and certain mouse strains (Graham et al, 2015;Petersen et al, 2013). Particularly relevant in an Australian context, variable end-point disease outcomes have been reported for other Australian WNV strains of intermediate virulence in the Swiss white mouse model (Bingham et al, 2014).…”