A Mouse Model for Chikungunya: Young Age and Inefficient Type-I Interferon Signaling Are Risk Factors for Severe Disease

Top Cited Papers
Open Access
Abstract
Chikungunya virus (CHIKV) is a re-emerging arbovirus responsible for a massive outbreak currently afflicting the Indian Ocean region and India. Infection from CHIKV typically induces a mild disease in humans, characterized by fever, myalgia, arthralgia, and rash. Cases of severe CHIKV infection involving the central nervous system (CNS) have recently been described in neonates as well as in adults with underlying conditions. The pathophysiology of CHIKV infection and the basis for disease severity are unknown. To address these critical issues, we have developed an animal model of CHIKV infection. We show here that whereas wild type (WT) adult mice are resistant to CHIKV infection, WT mouse neonates are susceptible and neonatal disease severity is age-dependent. Adult mice with a partially (IFN-α/βR+/−) or totally (IFN-α/βR−/−) abrogated type-I IFN pathway develop a mild or severe infection, respectively. In mice with a mild infection, after a burst of viral replication in the liver, CHIKV primarily targets muscle, joint, and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to other tissues including the CNS, where it specifically targets the choroid plexuses and the leptomeninges. Together, these data indicate that CHIKV-associated symptoms match viral tissue and cell tropisms, and demonstrate that the fibroblast is a predominant target cell of CHIKV. These data also identify the neonatal phase and inefficient type-I IFN signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates. Chikungunya virus (CHIKV) is transmitted by mosquito bites. CHIKV has recently re-emerged and is responsible for a massive outbreak in the Indian Ocean region and India. It has also reached Italy, indicating that CHIKV has a great potential to spread globally. Infection from CHIKV typically induces a mild disease in humans, characterized by a flu-like syndrome associated with muscle and joint pain and rash. Cases of severe infection involving the central nervous system (CNS) have recently been described, notably in neonates. We have developed the first animal model for CHIKV infection and studied the pathophysiology of the resulting disease. We show here that mouse neonates are susceptible to CHIKV and neonatal disease severity is age-dependent. Adult mice with a partial or complete defect in type-I interferon pathway develop a mild or severe infection, respectively. In mice with a mild infection, CHIKV primarily targets muscle, joint and skin fibroblasts, a cell and tissue tropism similar to that observed in biopsy samples of CHIKV-infected humans. In case of severe infections, CHIKV also disseminates to the CNS. Our work indicates that CHIKV-associated symptoms perfectly match viral tissue and cell tropisms, and demonstrate that the fibroblast is a prominent target cell of CHIKV. It also identifies the neonatal phase and inefficient type-I interferon signaling as risk factors for severe CHIKV-associated disease. The development of a permissive small animal model will expedite the testing of future vaccines and therapeutic candidates.