MicroRNAs Modulate Pathogenesis Resulting from Chlamydial Infection in Mice

Not all women infected with chlamydiae develop upper genital tract disease, but the reason(s) for this remains undefined. Host genetics and hormonal changes associated with the menstrual cycle are possible explanations for variable infection outcomes. It is also possible that disease severity depends on the virulence of the chlamydial inoculum. It is likely that the inoculum contains multiple genetic variants, differing in virulence. If the virulent variants dominate, then the individual is more likely to develop severe disease. Based on our previous studies, we hypothesized that the relative degree of virulence of a chlamydial population dictates the microRNA (miRNA) expression profile of the host, which, in turn, through regulation of the host inflammatory response, determines disease severity. Thus, we infected C57BL/6 mice with two populations of Chlamydia muridarum, each comprised of multiple genetic variants and differing in virulence: an attenuated strain (Nigg_A) and a virulent strain (Nigg_V). Nigg_A and Nigg_V elicited upper tract pathology in 54% and 91% of mice, respectively. miRNA expression analysis in Nigg_V-infected mice showed significant downregulation of miRNAs involved in dampening fibrosis (miR-200b, miR-200b-5p, and 200b-3p miR-200a-3p) and in transcriptional regulation of cytokine responses (miR-148a-3p, miR-152-3p, miR-132, and miR-212) and upregulation of profibrotic miRNAs (miR-142, and miR-147). Downregulated miRNAs were associated with increased expression of interleukin 8 (IL-8), CXCL2, IL-1β, tumor necrosis factor alpha (TNF-α), and IL-6. Infection with Nigg_V but not Nigg_A led to decreased expression of Dicer and Ago 2, suggesting that Nigg_V interaction with host cells inhibits expression of the miRNA biogenesis machinery, leading to increased cytokine expression and pathology.