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.

Monoclonal antibodies to Cache Valley virus for serological diagnosis

“…al (2021) showed that IFN plays an important role in disease of CVV in vivo . Similar to our results, six-week-old IFN-αβR -/- mice inoculated subcutaneously with 10 4 PFU of CVV became moribund by eight days post-infection [ 34 ]. Our previous studies have shown that the lack of α/β and γ IFN receptors in AG129 mice and subsequent downregulated IFN responses results in susceptibility to a host of other arboviruses [ 27 , 35 – 38 ].…”

“…AG129 mice have also been used to investigate sexual transmission and teratogenicity of Zika virus, another arbovirus of public health concern [ 39 ]. Likewise, pregnant IFN-αβR -/- mice have been used to study CVV vertical transmission resulting in spontaneous abortions and congenital malformations in vivo [ 34 ].…”

The influence of SARS‐CoV‐2 infection on expression of drug‐metabolizing enzymes and transporters in a hACE2 murine model

“…Plasma samples were not collected. Mice were immediately euthanized when moribund or upon weight loss greater than or equal to 20% of their original body weight, as previously described 11,12 …”

Cache Valley virus: an emerging arbovirus of public and veterinary health importance

“…Outbred ICR mice were resistant to CVV infection and viral-induced teratogenicity in pregnant mice (Edwards et al 1998). However, interferon receptor-deficient mice are susceptible to CVV infection via peripheral routes of inoculation and vertical transmission of the virus resulting in spontaneous abortions and congenital malformations (Lopez et al 2021, Skinner et al 2022). The lack of an effective interferon response in these mice leading to productive CVV infections is not surprising given that interferon has been shown to play an essential role in restricting growth of orthobunyavirids, including CVV and La Crosse virus (Hefti et al 1999, Kochs et al 2002, Rodrigues Hoffmann et al 2013).…”