Cache Valley Virus: A Comparison Across Both Lineages and Reassortant Strains Using in vitro and in vivo Models

Cache Valley virus (CVV) is an emerging mosquito-borne orthobunyavirus of significant concern to One Health. CVV was first isolated from Culiseta inornata mosquitoes in Cache Valley, Utah in 1956 and has sporadically emerged to cause epizootics in livestock, particularly affecting small ruminants. CVV is a known teratogenic virus, and its infection has been associated with spontaneous abortions and several birth defects in ruminants such as sheep, goats, and cattle. Seven human cases have been reported to date, presenting symptoms such as headache, fever, nausea and in severe cases, neurological disease such as encephalitis, meningitis, and organ failure. Four human fatalities have been documented to date. CVV is endemic to North America and has been detected in mosquito, wildlife, and human samples across Canada, United States, and Mexico. CVV strains are phylogenetically classified into two genetic lineages. Recent mosquito surveillance studies indicated that lineage II strains originating from Mexico have displaced lineage I isolates in Connecticut, New York, and Canada, since 2010. Furthermore, as a result of coinfection and segment reassortment between CVV lineages, reassortant isolates have emerged and has increased the genetic diversity of this virus. Importantly, recent case reports in humans have been associated with infection by these reassortant CVV strains. Pathogenesis studies in immune-compromised mice showed significant disease including weight loss, encephalitis, and mortality. To expand on our previous murine model studies and gain a better understanding of the pathogenicity of CVV isolates from both lineages as well as reassortant isolates, we explored pathogenesis with an emphasis on neuropathogenesis in several murine models. Herein, we explored the pathogenesis of three CVV strains from lineage I, lineage II, and reassortant viruses in immune-competent and immune-compromised murine models, as well as different inoculation routes. Our results show significant strain-specific differences in pathogenesis with clear differences in weight loss, viremia, organ loads, and mortality, among our models used. Considering our comparative pathogenesis data as a surrogate for understanding differences in human pathogenesis, our data suggests increased neuropathogenesis among the lineage II and one of the reassortant viruses studied. Our studies identify a unique and highly neurovirulent reassortant strain of CVV that presents significantly more disease than lineage I and II strains in several murine models. Altogether, our results suggest significant strain- and lineage-specific differences in CVV neuropathogenesis and suggests a plausible increased risk of neurological disease may be associated with currently circulating lineage II strains. CVV continues to remain an important agricultural and human pathogen and further research is needed to understand its ecology, the factors that may contribute to its risk of emergence, and intervention strategies to prevent its emergence and/or diminish its disease burden are urgently needed.

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