MicroRNAs Modulate Pathogenesis Resulting from Chlamydial Infection in Mice

Abstract

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-1␤, tumor necrosis factor alpha (TNF-␣), 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.

T Cell-Independent Gamma Interferon and B Cells Cooperate To Prevent Mortality Associated with Disseminated Chlamydia muridarum Genital Tract Infection

“…Our comparison of the C. muridarum sequences available in GenBank indicated that many independent laboratory stocks express MOMPs identical to the MOMP expressed by CM001, suggesting that this represents the wild-type conformation. In the case of the parental Nigg stock, prolonged cell culture (21,36) in the absence of selective immune pressure appears to have supported the outgrowth of variants, predominantly those represented by CM002 and the remaining isolates that we characterized, but also isolates with other ompA mutations (24). Yeruva et al recently reported their isolation of a virulent clone from the Nigg stock that they determined was virulent based on its ability to kill Rag1 Ϫ/Ϫ mice (36).…”

“…In the case of the parental Nigg stock, prolonged cell culture (21,36) in the absence of selective immune pressure appears to have supported the outgrowth of variants, predominantly those represented by CM002 and the remaining isolates that we characterized, but also isolates with other ompA mutations (24). Yeruva et al recently reported their isolation of a virulent clone from the Nigg stock that they determined was virulent based on its ability to kill Rag1 Ϫ/Ϫ mice (36). It would be interesting to determine if the ompA in this clone is identical to that in CM001.…”

Intestinal Lipid Metabolism Genes Regulated by miRNAs

“…Related studies have found that levels of miR-31-5p were enhanced in inflamed mucosa from patients with ulcerative colitis and Chron‘s disease, and play a fundamental role in epithelial cell regeneration ( Gupta et al, 2019 ; Tian et al, 2019 ). Mir-99b-5p is a marker of inflammation in tissues other than the intestine ( Hildebrand et al, 2018 ) and miR-200b-5p was linked with the heightened expression of interleukin 8 (IL-8), CXCL2, IL-1β, tumor necrosis factor alpha (TNF-α), and IL-6 in upper genital tract disease ( Yeruva et al, 2017 ). Further, increased intestinal permeability or incorrect intestinal differentiation can induce an inflammatory response in the intestinal microcirculation, which may be accompanied by a rise in the expression of Olr1 ( Al-Banna and Lehmann, 2013 ).…”

“…tract disease (Yeruva et al, 2017). Further, increased intestinal permeability or incorrect intestinal differentiation can induce an inflammatory response in the intestinal microcirculation, which may be accompanied by a rise in the expression of Olr1 (Al-Banna and Lehmann, 2013).…”

Innate immunity, the hepatic extracellular matrix, and liver injury: mathematical modeling of metastatic potential and tumor development in alcoholic liver disease.

“…The current study is the first to report the effect of arsenite exposure on miRNA expression in BMDMs. In particular, miR-155, miR-21 and miR-146a have been identified as primary players due to their expression levels following TLR activation [170,[199][200][201] [202,203]. Other miRNAs have been also identified to be up regulated in response to TLR ligands such as miR-132 [204], miR-9 [205], miR-147 [202] and miR-346 [206].…”