Interferon Alpha, but Not Interferon Beta, Acts Early To Control Chronic Chikungunya Virus Pathogenesis

Area of Science:

• Virology and Immunology
• Host-pathogen interactions
• Infectious diseases

Background:

• Chikungunya virus (CHIKV) causes debilitating acute and chronic arthritic disease.
• Type I interferons (IFNs) are critical for limiting CHIKV, with IFN-α and IFN-β having distinct roles in acute infection.
• The specific roles of type I IFNs, particularly subtypes, in chronic CHIKV disease are not well understood.

Purpose of the Study:

• To investigate the role of specific type I interferon subtypes (IFN-α and IFN-β) in chronic Chikungunya virus (CHIKV) pathogenesis.
• To determine how early immune responses influence the development of chronic CHIKV disease.
• To identify specific cell types affected by IFN-α during chronic CHIKV infection.

Main Methods:

• Evaluation of chronic CHIKV pathogenesis in mice genetically deficient in IFN-α or IFN-β.
• Utilized a novel CHIKV-3'-Cre tdTomato reporter system for fate mapping of infected cells.
• Assessed viral RNA levels and cell survival at sites of dissemination.

Main Results:

• IFN-α, not IFN-β, was identified as the dominant subtype controlling chronic CHIKV disease.
• IFN-α acts within the first few days of infection to limit persistent CHIKV RNA levels.
• IFN-α restricts the survival of CHIKV-infected cells, particularly dermal fibroblasts and immune cells, but not myofibers.

Conclusions:

• IFN-α and IFN-β play divergent roles in chronic CHIKV disease, with early events being critical.
• Loss of IFN-α significantly impacts immune cells and dermal fibroblasts, indicating cell-specific responses to type I IFNs.
• Early host-pathogen interactions during acute CHIKV infection profoundly influence chronic disease development, suggesting potential therapeutic targets.