Genetic diversity of collaborative cross mice enables identification of novel rift valley fever virus encephalitis model

Abstract

Rift Valley fever (RVF) is an arboviral disease of humans and livestock responsible for severe economic and human health impacts. In humans, RVF spans a variety of clinical manifestations, ranging from an acute flu-like illness to severe forms of disease, including late-onset encephalitis. The large variations in human RVF disease are inadequately represented by current murine models, which overwhelmingly die of early-onset hepatitis. Existing mouse models of RVF encephalitis are either immunosuppressed, display an inconsistent phenotype, or develop encephalitis only when challenged via intranasal or aerosol exposure. In this study, the genetically defined recombinant inbred mouse resource known as the Collaborative Cross (CC) was used to identify mice with additional RVF disease phenotypes when challenged via a peripheral foot-pad route to mimic mosquito-bite exposure. Wild-type Rift Valley fever virus (RVFV) challenge of 20 CC strains revealed three distinct disease phenotypes: early-onset hepatitis, mixed phenotype, and late-onset encephalitis. Strain CC057/Unc, with the most divergent phenotype, which died of late-onset encephalitis at a median of 11 days post-infection, is the first mouse strain to develop consistent encephalitis following peripheral challenge. CC057/Unc mice were directly compared to C57BL/6 mice, which uniformly succumb to hepatitis within 2–4 days of infection. Encephalitic disease in CC057/Unc mice was characterized by high viral RNA loads in brain tissue, accompanied by clearance of viral RNA from the periphery, low ALT levels, lymphopenia, and neutrophilia. In contrast, C57BL/6 mice succumbed from hepatitis at 3 days post-infection with high viral RNA loads in the liver, viremia, high ALT levels, lymphopenia, and thrombocytopenia. The identification of a strain of CC mice as an RVFV encephalitis model will allow for future investigation into the pathogenesis and treatment of RVF encephalitic disease and indicates that genetic background makes a major contribution to RVF disease variation.

Neuroinvasive flavivirus pathogenesis is restricted by host genetic factors in Collaborative Cross mice, independently of Oas1b

“…correlate with severe neurologic disease. CC mice can be useful models of relevant disease presentations that are not evident in conventional laboratory mouse lines, such as encephalitis caused by Rift Valley fever virus(34) or chronic WNV disease(58).Altogether, our results support a model in which CC045 mice are resistant to severe POWV disease due to reduced viral replication in myeloid cells and rapid clearance of viremia, reducing the probability of neuroinvasion, and that this resistance is independent of a role for Oas1b in restricting flavivirus pathogenesis. This model suggests that the resistance mechanism of CC045 mice acts in peripheral tissues, not within the CNS.…”

“…Notably, CC057 mice also were relatively resistant to RVFV, exhibiting a delayed disease course resulting in encephalitis rather than acute hepatitis (34). CC071 mice, which we identified as being highly susceptible to POWV, WNV, JEV, and SLEV previously have been found to be highly susceptible to SARS-CoV-2 (78) and RVFV (34) and were highly susceptible to ZIKV when treated with an IFNAR1-blocking antibody (79). Altogether this suggests that CC mice can reveal immune mechanisms that control pathogenesis of diverse viruses.…”

“…correlate with severe neurologic disease. CC mice can be useful models of relevant disease presentations that are not evident in conventional laboratory mouse lines, such as encephalitis caused by Rift Valley fever virus (34) or chronic WNV disease (58).…”

“…We also identified other Oas1b null CC lines (such as CC057) with more modest resistance phenotypes; future studies will investigate whether the resistant phenotype of CC057 mice derives from the same mechanism as CC045 mice. Notably, CC057 mice also were relatively resistant to RVFV, exhibiting a delayed disease course resulting in encephalitis rather than acute hepatitis (34). CC071 mice, which we identified as being highly susceptible to POWV, WNV, JEV, and SLEV previously have been found to be highly susceptible to SARS-CoV-2 (78) and RVFV (34) and were highly susceptible to ZIKV when treated with an IFNAR1-blocking antibody (79).…”

“…The CC captures the genetic diversity of laboratory mice, roughly on par with levels of common human genetic variation, in a reproducible manner, since each of the 63 lines has a known and fixed genome, providing a valuable tool for mapping complex traits (29)(30)(31)(32)(33). As such, the CC enables the identification and study of polymorphic host genes underlying complex phenotypes including the immune response to viral infection (29)(30)(31)(32)(33)(34)(35).…”