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

J Virol. 2022 Jan 12;96(1):e0114321. doi: 10.1128/JVI.01143-21. Epub 2021 Oct 20.

Abstract

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes both debilitating acute and chronic disease. Previous work has shown that type I interferons (IFNs) play a critical role in limiting CHIKV pathogenesis and that interferon alpha (IFN-α) and interferon beta (IFN-β) control acute CHIKV infection by distinct mechanisms. However, the role of type I IFNs, especially specific subtypes, during chronic CHIKV disease is unclear. To address this gap in knowledge, we evaluated chronic CHIKV pathogenesis in mice lacking IFN-α or IFN-β. We found that IFN-α was the dominant subtype that controls chronic disease. Despite detecting a varying type I IFN response throughout the course of disease, IFN-α acts within the first few days of infection to control the levels of persistent CHIKV RNA. In addition, using a novel CHIKV-3'-Cre tdTomato reporter system that fate maps CHIKV-infected cells, we showed that IFN-α limits the number of cells that survive CHIKV at sites of dissemination, particularly dermal fibroblasts and immune cells. Though myofibers play a significant role in CHIKV disease, they were not impacted by the loss of IFN-α. Our studies highlight that IFN-α and IFN-β play divergent roles during chronic CHIKV disease through events that occur early in infection and that not all cell types are equally dependent on type I IFNs for restricting viral persistence. IMPORTANCE Chikungunya virus (CHIKV) is a reemerging global pathogen with no effective vaccine or antiviral treatment for acute or chronic disease, and the mechanisms underlying chronic disease manifestations remain poorly defined. The significance of our research is in defining IFN-α, but not IFN-β, as an important host regulator of chronic CHIKV pathogenesis that acts within the first 48 hours of infection to limit persistent viral RNA and the number of cells that survive CHIKV infection 1 month post-infection. Loss of IFN-α had a greater impact on immune cells and dermal fibroblasts than myofibers, highlighting the need to delineate cell-specific responses to type I IFNs. Altogether, our work demonstrates that very early events of acute CHIKV infection influence chronic disease. Continued efforts to delineate early host-pathogen interactions may help stratify patients who are at risk for developing chronic CHIKV symptoms and identify therapeutics that may prevent progression to chronic disease altogether.

Keywords: chikungunya virus; host-pathogen interactions; innate immunity; interferons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Chikungunya Fever / metabolism*
  • Chikungunya Fever / virology*
  • Chikungunya virus / physiology*
  • Disease Models, Animal
  • Disease Susceptibility
  • Host-Pathogen Interactions*
  • Interferon-alpha / metabolism*
  • Interferon-beta / metabolism*
  • Mice
  • Mice, Knockout
  • RNA, Viral
  • Virus Replication

Substances

  • Interferon-alpha
  • RNA, Viral
  • Interferon-beta