A pan-orthohantavirus preclinical human lung xenograft mouse model

Abstract

Orthohantaviruses are emerging zoonotic viruses that can infect humans via the respiratory tract. There is a clear unmet need for an in vivo model to study orthohantavirus infection in physiologically relevant tissue and to determine the broad reactivity of novel orthohantavirus countermeasures. Here, we describe the use of a human lung xenograft mouse model to study the permissiveness for different orthohantavirus species and to assess its utility for preclinical testing of pan-orthohantavirus therapeutics. Following infection of xenografted human lung tissues, distinct orthohantavirus species differentially replicated in the human lung and subsequently spread systemically. The different orthohantaviruses primarily targeted the endothelium, respiratory epithelium and macrophages. Treatment of these mice with a virus neutralizing antibody could block orthohantavirus infection and dissemination. This model will facilitate progress in the fundamental understanding of pathogenesis and virus-host interactions for orthohantaviruses. Furthermore, it is an invaluable tool for preclinical evaluation of novel candidate pan-orthohantavirus intervention strategies.