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Novel murine models for studying Cache Valley virus pathogenesis and in utero transmission.

ABSTRACT: Cache Valley virus (CVV) is a prevalent emerging pathogen of significant importance to agricultural and human health in North America. Emergence in livestock can result in substantial agroeconomic losses resulting from the severe embryonic lethality associated with infection during pregnancy. Although CVV pathogenesis has been well described in ruminants, small animal models are still unavailable, which limits our ability to study its pathogenesis and perform preclinical testing of therapeutics. Herein, we explored CVV pathogenesis, tissue tropism, and disease outcomes in a variety of murine models, including immune -competent and -compromised animals. Our results show that development of CVV disease in mice is dependent on innate immune responses, and type I interferon signalling is essential for preventing infection in mice. IFN-αβR^-/- mice infected with CVV present with significant disease and lethal infections, with minimal differences in age-dependent pathogenesis, suggesting this model is appropriate for pathogenesis-related, and short- and long-term therapeutic studies. We also developed a novel CVV in utero transmission model that showed high rates of transmission, spontaneous abortions, and congenital malformations during infection. CVV infection presents a wide tissue tropism, with significant amplification in liver, spleen, and placenta tissues. Immune-competent mice are generally resistant to infection, and only show disease in an age dependent manner. Given the high seropositivity rates in regions of North America, and the continuing geographic expansion of competent mosquito vectors, the risk of epidemic and epizootic emergence of CVV is high, and interventions are needed for this important pathogen.

SUBMITTER: Lopez K

PROVIDER: S-EPMC8381923 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:One of the most intriguing issues in the hepatitis E virus (HEV) field is the significant increase in mortality rates of the mother and fetus when infection occurs in the second and third trimesters of gestation. A virus that is normally self-limiting and has a mortality rate of less than one percent in otherwise healthy individuals steeply rises by up to 30% in these pregnant populations. Answering this pivotal question has not been a simple task. HEV, in general, has been a difficult pathogen to understand in the laboratory setting. A historical lack of ability to efficiently propagate the virus in tissue culture models has led to many molecular aspects of the viral lifecycle being understudied. Although great strides have been made in recent years to adapt viruses to cell culture, this field remains behind other viruses that are much easier to replicate efficiently in vitro. Some of the greatest discoveries regarding HEV have come from using animal models for which naturally occurring strains of HEV have been identified, including pigs and chickens, but key limitations have made animal models imperfect for studying all aspects of human HEV infections. In addition to the difficulties working with HEV, pregnancy is a very complicated biological process with an elaborate interplay between many different host systems, including hormones, cardiovascular, kidneys, respiratory, gastrointestinal, epithelial, liver, metabolic, immune, and others. Significant differences between the timing and interplay of these systems are notable between species, and making direct comparisons between animals and humans can be difficult at times. No simple answer exists as to how HEV enhances mortality in pregnant populations. One of the best approaches to studying HEV in pregnancy is likely a combinatorial approach that uses the best combination of emerging in vitro and in vivo systems while accounting for the deficiencies that are present in each model. This review describes many of the current HEV animal model systems and the strengths and weaknesses of each as they apply to HEV pregnancy-associated mortality. We consider factors that are critical to analyzing HEV infection within the host and how, despite no perfect animal model for human pregnancy mortality existing, recent developments in HEV models, both in vitro and in vivo, are advancing our overall understanding of HEV in the pregnant host.

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Novel murine models for studying Cache Valley virus pathogenesis and in utero transmission.

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