Nocardia brasiliensis Induces an Immunosuppressive Microenvironment That Favors Chronic Infection in BALB/c Mice

Abstract

ABSTRACT Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4 + Foxp3 + regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 ( P < 0.05) in footpad tissue and spleen. Treg subpopulations peaked at days 7 and 15 ( P < 0.01) in the footpad and spleen, respectively. Transforming growth factor β1 (TGF-β1) and interleuki-10 (IL-10) are cytokines known for their immunosuppressive effects. During early and chronic infections, these cytokines were elevated with increased TGF-β1 levels from days 3 to 30 ( P < 0.01) and sustained IL-10 expression throughout infection compared to uninfected mice. IL-6 production was increased at day 3 ( P < 0.01), whereas gamma interferon (IFN-γ), IL-17A, and IL-23 levels were highest at day 15 postinfection ( P < 0.01) when a decrease in the bacterial load (>1 log) was also observed ( P < 0.05). After these changes, at 30 to 60 days postinfection, IFN-γ production was decreased, whereas the expression of anti-inflammatory cytokines and the bacterial load again increased ( P < 0.05). The increment in Treg cells and the related cytokine profile correlated with reduced inflammation at day 15 ( P < 0.05) in the footpad. We conclude that N. brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection.