Towards harnessing inflammation during chikungunya virus infection
Towards harnessing inflammation during chikungunya virus infection
Global warming and deforestation are accelerating the spread of arboviruses like the Chikungunya virus (CHIKV). Transmitted by Aedes mosquitoes, CHIKV causes debilitating joint pain that becomes chronic in a significant subset of patients. Monocytes and macrophages are central to the immune response, yet their precise roles in CHIKV infection have been unclear.
This thesis of Juan Valdes Lopez investigates how these human immune cells respond to CHIKV. We found that while both cell types permit viral replication, they employ distinct antiviral strategies. Monocytes depend on the conventional type I interferon (IFN-I) pathway for defense. In contrast, macrophages suppress the virus independently of IFN-I, utilizing interleukin-27 (IL-27) as a novel alternative mechanism. IL-27 production is regulated by specific immune sensors (TLR1/2, TLR3, TLR4) and transcription factors (NF-κB and IRF1). Interestingly, IL-27 functions like an interferon by activating JAK-STAT signaling to induce a potent antiviral state. Furthermore, CHIKV infection dynamically reshapes the monocyte compartment, expanding intermediate and non-classical subsets. This shift is driven by viral RNA sensors (TLR3, TLR8, RIG-I) and IFN-I-STAT1 signaling, potentially facilitating viral pathogenesis and chronicity.
The findings reveal key immunopathological pathways, demonstrating how CHIKV manipulates host immunity to establish persistent inflammation. Targeting monocyte differentiation and the newly identified IL-27-STAT1 axis could provide innovative therapeutic strategies for chronic chikungunya disease, advancing our understanding of innate antiviral immunity.