Induced nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO) detection in circulating monocyte subsets from Brazilian patients with Dengue-4 virus

Abstract

Among viral diseases transmitted by mosquitoes, dengue is characterized by its rapid dispersion around the world. Dengue severity is associated to a cytokine “storm” leading to vascular hemorrhagic manifestations, plasma leakage and shock, but also producing viral clearance. Macrophage/monocyte activation occurs during infection. Monocyte lineage cells are among those that allow virus replication. We investigated circulating human monocyte subsets - classical CD14⁺ CD16⁻ and non-classical CD14⁺ CD16⁺ - during DENV-4 infection in patients. Intracellular inducible nitric oxide synthase (iNOS) and indoleamine 2,3–dioxygenase (IDO) were detected in both monocyte subsets. Circulating CD14⁺ CD16⁺ monocyte frequency is mildly increased during DENV-4 infection. INOS is more intensely detected in CD14⁺ CD16⁻ than in CD16⁺ monocytes and IDO in CD14⁺ CD16⁺. DENV-4 patients show increase in NO, TNF-α, IFN-y, IP-10/CXL10, IL-10 and MCP-1/CCL2 plasma levels when compared to healthy individuals. The classical monocyte subset, CD14⁺ CD16⁻ was shown to be inversely correlated with IL-10 and IP-10/CXCL10 levels, while the non-classical CD14⁺ CD16⁺ is positively correlated with IL-10 cytokine. TNF-α, IL-10 cytokines and IP-10/CXL10 chemokine are positively correlated with the CD14⁺ iNOS⁺ monocyte population. Both CD14⁺ cells - CD16⁻ iNOS⁺ and CD16⁺ iNOS⁺ subsets - presented positive correlation with IL-10, IP-10/CXL10 and MCP-1/CCL2, besides TNF-α associated with CD16⁻ iNOS⁺ cells. CD14⁺ CD16⁻ IDO⁺ and CD16⁺ IDO⁺ populations correlated positively with IL-10. Furthermore, CD16⁻ IDO⁺ monocyte subset also presented a positive correlation with TNF-α and IP-10/CXCL10. According to these data, we considered that iNOS and IDO are activated in monocyte CD16⁻ and CD16⁺ subsets, likely exerting both antiviral effects and modulating exacerbated immunological responses during dengue fever.