Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced byIrf3deficiencyin vitrobut requires other variantsin vivo, not linked to the type I interferon response

Abstract

Zika virus (ZIKV) is a Flavivirus responsible for recent epidemics in Pacific Islands and in the Americas. In humans, the consequences of ZIKV infection range from asymptomatic infection to severe neurological disease such as Guillain-Barré syndrome or fetal neurodevelopmental defects, suggesting the influence of host genetic factors. We previously reported similar diverse outcomes of ZIKV infection in mice of the Collaborative Cross, a collection of inbred strains with large genetic diversity. CC071 was the most susceptible strain with severe symptoms and lethality. Here, we investigated viral replication in mouse embryonic fibroblasts from CC071 and two resistant strains. CC071 showed enhanced viral replication associated with delayed induction of type-I interferons (IFN-I). Using a combination of genetic approaches, we identified a loss of function (LOF) mutation in theIrf3gene, specific to CC071, and demonstrated that it fully explains the defective IFN-I response and uncontrolled viral replication in CC071 MEFs. However, this mutation was not sufficient to induce the high plasma viral load and clinical severity observed in CC071 mice, indicating the involvement of other susceptibility genes in vivo. Considering the susceptibility of the CC071 strain to multiple viruses, our results provide new insight into the role of Irf3 in innate antiviral response.