Impact of host responses on mpox pathogenesis and tecovirimat efficacy in the Collaborative Cross mouse model of genetic diversity

The host response to infection is a critical determinant of disease severity. However, host responses that dictate the outcome of mpox (monkeypox) virus disease are largely unknown. Furthermore, although antiviral therapies can effectively treat mpox infection, it is not known how they can be optimally used to resolve disease symptoms, or the role of the host response in antiviral efficacy. Current experimental models for studying host responses to mpox or treatment with antiviral drugs are not genetically diverse and thus are unable to faithfully reproduce these responses in human patients, which limits their utility in addressing these knowledge gaps. We propose using the Collaborative Cross, a panel of mice with increased genetic diversity, to study the host responses to infection that lead to distinct mpox disease outcomes. We will screen a panel of genetically diverse mice to identify those that develop different presentations of mpox disease severity, and then investigate host responses in affected tissues that lead to distinct outcomes. We will also test the ability of tecovirimat (TPOXX), an antiviral drug used to treat mpox, to ameliorate mpox disease features such as skin lesions when treatment is initiated at different times following infection. We will also evaluate host responses associated with effective TPOXX treatment, as well as assess the risk of TPOXX resistance. This proposed project will provide crucial insight into the role of the host in determining mpox disease severity, as well as optimize using TPOXX to treat mpox most effectively and with the greatest benefit to patients. In addition to filling critical knowledge gaps, this project will also produce a model that will be an invaluable resource to the scientific community for both studying mpox infection and disease and developing improved vaccines and therapies.