Immune-Mediated Protection and Pathogenesis of Chikungunya Virus

Abstract

Chikungunya virus (CHIKV) is a re-emerging alphavirus that causes debilitating acute and chronic arthritis. Infection by CHIKV induces a robust immune response that is characterized by production of type I IFNs, recruitment of innate and adaptive immune cells, and development of neutralizing Abs. Despite this response, chronic arthritis can develop in some individuals, which may be due to a failure to eliminate viral RNA and Ag and/or persistent immune responses that cause chronic joint inflammation. In this review, based primarily on advances from recent studies in mice, we discuss the innate and adaptive immune factors that control CHIKV dissemination and clearance or contribute to pathogenesis.

Figure 1

Overview of CHIKV and immune-mediated pathogenesis in mice. CHIKV infection of the footpad results in edema and inflammation from viral infection, cell death, cytokine production, and immune cell infiltration. Foot swelling is biphasic with the first (1) peak occurring 2–3 dpi followed by a second (2) peak at 6–7 dpi. (1) CHIKV infects fibroblasts (orange cells), mesenchymal cells, and osteoblasts. In this figure, infection is indicated with viral RNA present inside a cell with a plasma membrane colored orange. PRRs are triggered during cellular infection resulting in activation of transcription factors, ultimately producing type I IFNs. Type I IFN and the ISG response are necessary to prevent severe disease. In addition, PRR and IFN signaling induce secretion of pro-inflammatory cytokines and chemokines, which recruit innate and adaptive immune cells to the site of infection driving inflammation. Depletion of NK cells reduces foot swelling suggesting a pathogenic role. Macrophages (MΦ) and inflammatory monocytes have dual protective and pathogenic roles in CHIKV arthritis. Depletion of macrophages reduces swelling, but also can result in a neutrophil-mediated immunopathogenesis. Osteoblasts can be infected by CHIKV, which promotes osteoclastogenesis and bone reabsorption. γδ⁺ T cells prevent monocyte recruitment and joint inflammation. (2) CHIKV infection induces a neutralizing antibody (NAb) response that eliminates infectious virus from circulation and tissues. Effector CD4⁺ T cells are recruited to musculoskeletal tissues and secrete IFN-γ. Depletion of CD4⁺ T cells results in reduced joint swelling. Enhancement of the FoxP3⁺ CD4⁺ Treg response results in reduced joint swelling, cytokine production, and effector CD4⁺ T cell activation. Surprisingly, CD8⁺ T cells do not seem to function in acute pathogenesis or viral clearance, at least in mice. CHIKV RNA and antigen persists in joint tissues for extended periods and may serve as pathogen-associated molecular patterns for chronic immune activation and inflammation. Macrophages and monocytes are suggested to be a reservoir for chronic infection.