The role of myeloid cells in the female genital tract during chlamydial infection – possible impact on control of chlamydia and on inflammation-induced tissue damage
Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
Final Report Abstract
The obligate intracellular bacterium Chlamydia (C.) trachomatis is the most common bacterial agent of sexually transmitted disease worldwide. Chlamydial genital infection may cause permanent tissue damage in the female genital tract, which can lead to severe and lifethreatening complications (e.g. ectopic pregnancy). The exact mechanisms of bacterial clearance and tissue damage are still unknown. The inflammatory infiltrate likely plays a crucial role herein. Our previous work had focused on the role of neutrophils herein, but little is known about the role of other myeloid cells in the female genital tract at steady state and during chlamydial infection. Here we characterised the tissue-associated immune cells with focus on the infiltrating myeloid cell populations in detail at steady state and in a C. muridarum genital infection model. We aimed to clarify their impact on the composition of the inflammatory infiltrate, bacterial load and chronic tissue damage using gene-deficient mice lacking cell types or signal components of the innate immune system (CCR2-KO mice deficient in recruitment of inflammatory monocytes, CX3CR1-GFP reporter mice and CX3CR1-KO mice deficient in the CX3CR1 marker for tissue-resident macrophages). We identified several myeloid subpopulations infiltrating the genital tract early during infection, with macrophage populations accumulating earlier than dendritic cell (DC) subpopulations. In wt mice, infiltrating cells showed dynamic changes of surface markers with high upregulation of MHCII, giving rise to different subpopulations. In CCR2-KO mice, the accumulation of macrophages was strongly reduced, suggesting that the increase in macrophage numbers in infected tissue is mainly caused by recruitment and differentiation of inflammatory monocytes. CCR2-deficiency did not affect infiltration of neutrophils, DCs or T-cells but reduced relative and absolute numbers of TNF/IFNg-producing CD4 and CD8 T cells. Either CCR2- and CX3CR1-deficiency led to a mild decrease in oviduct pathology. A defect in recruitment of inflammatory monocytes from bone marrow or a functional defect in tissue-resident macrophages was thus able to alleviate tissue damage. CD8 T cell activity had previously been shown to be crucially involved in the pathogenesis of chronic tissue damage. Analysis of the role of the chlamydial plasmid also revealed a correlation between monocyte/macrophage recruitment, CD8 T cell activity and chronic tissue damage. Our data indicate the presence of individual subgroups of monocytes/macrophages in the course of chlamydial infection, which may play differential roles in immune reaction, anti-bacterial defence and chronic tissue destruction. Taken together, our findings describe a link between the presence and activity of specific mononuclear phagocyte populations and the adaptive immune response, especially CD8 T cell activity, with relevance for the pathogenesis of tissue damage. We are confident that this project adds valuable knowledge regarding the dynamic role of the innate immune system in the female genital tract in the situation of infection with an obligate intracellular pathogen. We believe that our work is not only important for the chlamydia field, but also relevant for other diseases of the urogenital tract.
