Divergent myelopoiesis and macrophage polarization underlie host susceptibility to chronic Chlamydia trachomatis infection

Abstract

Chronic genital infection with Chlamydia trachomatis is associated with immune suppression and pathogen persistence, but the mechanisms underlying this phenomenon remain poorly defined. Here, we show that chronic C. trachomatis genital infection differentially reprograms myelopoiesis and macrophage polarization in genetically distinct mouse strains. In BALB/c mice, infection expanded bone marrow progenitors with enhanced colony-forming potential but skewed their differentiation toward immunosuppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs). These cells accumulated in the spleen, blood, and genital tract, secreted IL-10 and TGF{beta}, and suppressed T cell proliferation, thereby impairing IFN{gamma}-driven clearance. In contrast, C57BL/6 mice exhibited C/EBP{beta}-driven myelopoiesis favoring M1 polarization, elevated IL-12 and nitric oxide production, and robust Th1 responses that facilitated bacterial elimination. Together, these findings demonstrate that host genetic background dictates divergent innate programming during C. trachomatis infection, and that the balance between M1- and M2/MDSC-dominated myelopoiesis determines whether infection resolves or progresses to chronicity.