title: 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 (NiggA) and a virulent strain (NiggV). NiggAand NiggVelicited upper tract pathology in 54% and 91% of mice, respectively. miRNA expression analysis in NiggV-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 NiggVbut not NiggAled to decreased expression of Dicer and Ago 2, suggesting that NiggVinteraction with host cells inhibits expression of the miRNA biogenesis machinery, leading to increased cytokine expression and pathology.
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA vlyeruva@uams.edu.|Arkansas Children's Research Institute, Little Rock, Arkansas, USA.|Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA.
authors: Laxmi
authors: L
authors: Yeruva
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Arkansas Children's Research Institute, Little Rock, Arkansas, USA.|Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA.
authors: Dakota L
authors: DL
authors: Pouncey
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Arkansas Children's Research Institute, Little Rock, Arkansas, USA.|Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA.
authors: Michael R
authors: MR
authors: Eledge
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Arkansas Children's Research Institute, Little Rock, Arkansas, USA.|Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA.
authors: Sudeepa
authors: S
authors: Bhattacharya
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA.
authors: Chunqiao
authors: C
authors: Luo
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Arkansas Children's Research Institute, Little Rock, Arkansas, USA.
authors: Erin W
authors: EW
authors: Weatherford
authors: Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, California, USA.
authors: David M
authors: DM
authors: Ojcius
authors: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Arkansas Children's Research Institute, Little Rock, Arkansas, USA.|Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA.
authors: Roger G
authors: RG
authors: Rank
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002690:Chlamydia Infections / Q000235:genetics* / Q000382:microbiology*; D023502:Chlamydia muridarum / Q000472:pathogenicity*; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D014774:Virulence / Q000235:genetics*
chemical_list: D016207:Cytokines; D035683:MicroRNAs
keywords: Ago2; Chlamydia; Dicer; miRNA