A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe
Thérèse Couderc1, Fabrice Chrétien, Clémentine Schilte
1Groupe "Microorganismes et Barrières de l'Hôte", Institut Pasteur, Paris, France.
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-alpha/betaR(+/-)) or totally (IFN-alpha/betaR(-/-)) 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.
Insights
Chikungunya virus (CHIKV) infection causes mild disease in humans, but severe cases can affect the central nervous system (CNS). A new mouse model shows neonates and those with poor type-I interferon signaling are at higher risk for severe CHIKV disease.
Area of Science:
- Virology
- Immunology
- Pathophysiology
Background:
- Chikungunya virus (CHIKV) is a re-emerging arbovirus causing widespread outbreaks.
- CHIKV infection typically results in mild human disease, but severe cases, including CNS involvement, are increasingly reported, particularly in neonates.
- The underlying mechanisms of CHIKV pathogenesis and disease severity remain largely unknown.
Purpose of the Study:
- To develop a small animal model for studying Chikungunya virus infection and pathogenesis.
- To investigate the factors contributing to CHIKV disease severity and identify target cells and tissues.
Main Methods:
- Development and characterization of a CHIKV mouse model using wild-type (WT) and type-I interferon receptor-deficient (IFN-alpha/betaR(+/-) and IFN-alpha/betaR(-/-)) mice.
- Assessment of CHIKV susceptibility and disease severity based on age and immune status.
- Analysis of viral tissue tropism and cellular targets in infected mice.
Main Results:
- WT adult mice are resistant to CHIKV, while neonates are susceptible in an age-dependent manner.
- Mice with impaired type-I interferon signaling (partially or totally abrogated) develop mild or severe CHIKV infections, respectively.
- CHIKV primarily targets fibroblasts in muscle, joint, and skin in mild infections; severe infections show dissemination to the CNS, targeting choroid plexuses and leptomeninges.
Conclusions:
- Fibroblasts are a predominant target cell for CHIKV, explaining observed tissue tropisms and symptoms.
- Neonatal vulnerability and inefficient type-I interferon signaling are identified as significant risk factors for severe CHIKV disease.
- The established mouse model provides a valuable platform for evaluating Chikungunya virus vaccines and therapeutics.
