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

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.

Active Infection of Human Blood Monocytes by Chikungunya Virus Triggers an Innate Immune Response

“…From there, the virus will find its way into the blood vessels before dissemination to the target tissues/or organs (17). Although the exact route and mechanisms of early infection is poorly defined (18), previous studies from other alphaviruses have indicated the involvement of different immune cell populations in the skin (19)(20)(21)(22), and migrating cells such as macrophages and/or dendritic cells (DCs) (19). The events taking place during the acute blood phase of CHIKV infections have not been clearly defined.…”

Concepts and Mechanisms: Crossing Host Barriers

“…As mother-to-child transmission is rare in antepartum but frequent in the context of intrapartum maternal viremia, and the placenta is not a site of viral replication, this favors a model of vertical transmission via placental breaches that forms around the term during parturition, as described for a number of other viruses associated with elevated maternal viremia during delivery, such as HIV, HBV, and arboviruses such as Dengue virus or West Nile virus (Couderc et al 2008;Gerardin et al 2008).…”

A Mouse Model of Chikungunya Virus–Induced Musculoskeletal Inflammatory Disease

“…Neonatal mice and mice deficient in the type I interferon receptor were found to be highly susceptible to CHIKV infection. 19 Although CHIKV was detected in muscle and joint tissue in these mice, the pathological outcomes in these tissues were not addressed, 19 and these models may be more relevant for studying the pathogenesis of atypical CHIKV disease. Ziegler et al 20 described severe skeletal muscle necrosis and inflammation after CHIKV infection of outbred strains of mice.…”