Increased Indoleamine 2,3-Dioxygenase 1 (IDO-1) Activity and Inflammatory Responses during Chikungunya Virus Infection

Abstract

Chikungunya virus (CHIKV) infection causes intense cytokine/chemokine inflammatory responses and debilitating joint pain. Indoleamine2,3–dioxygenase 1 (IDO-1) is an enzyme that initiates the tryptophan degradation that is important in initial host innate immune defense against infectious pathogens. Besides that, IDO-1 activation acts as a regulatory mechanism to prevent overactive host immune responses. In this study, we evaluated IDO-1 activity and cytokine/chemokine patterns in CHIKV patients. Higher IDO-1 (Kyn/Trp ratio) activation was observed during the early acute phase of CHIKV infection and declined in the chronic phase. Importantly, increased concentrations of Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Interferon γ (IFN-γ), C-C motif chemokine ligand 2/Monocyte Chemoattractant Protein-1 (CCL2/MCP-1) and C-X-C motif chemokine ligand 10/Interferon Protein-10 (CXCL10/IP-10) were found in the acute phase of infection, while C-C motif chemokine ligand 4/Macrophage Inflammatory Protein 1 β (CCL4/MIP-1β) was found at increased concentrations in the chronic phase. Likewise, CHIKV patients with arthritis had significantly higher concentrations of CCL4/MIP-1β compared to patients without arthritis. Taken together, these data demonstrated increased IDO-1 activity, possibly exerting both antiviral effects and regulating exacerbated inflammatory responses. CCL4/MIP-1β may have an important role in the persistent inflammation and arthritic symptoms following chikungunya infection.

Chikungunya patient transcriptional signatures faithfully recapitulated in a C57BL/6J mouse model

“…Most of the top cytokines and transcriptional regulators ( Figure 4 ) are well described in the CHIKV literature, and as expected are dominated by interferon (IFN) and Th1 responses ( 1 , 15 , 40 , 41 , 54 , 60 , 63 – 66 ). Perhaps surprising is the absence of CCL2/CCR2 as an USR, even though CCL2 is a highly significant DEG, and is well described for CHIKV infections ( 45 , 55 , 67 ).…”

Indoleamine 2, 3-dioxygenase 1 inhibitory compounds from natural sources

“…However, if the tissue remains inflamed for a long time, inflammation can also damage healthy tissue and induce secondary repair, including fibrosis. Proinflammatory cytokines, such as interferon gamma, and other inflammatory signaling molecules, including the lipid mediator prostaglandin E2 and lipopolysaccharide pathogen particles, induce the overexpression of IDO1 (Baumgartner et al, 2019;Alves de Souza et al, 2022). The activation of IDO1 in response to these inflammatory factors induces immune tolerance and eventually controls hyperinflammation (Zhai et al, 2020).…”