MiR-378b Modulates Chlamydia-Induced Upper Genital Tract Pathology.

Stephanie R Lundy,Darin Carroll,Francis O Eko,Kobe Abney,Yusuf O Omosun,Debra Ellerson,Joseph U Igietseme

doi:10.3390/pathogens10050566

Abstract

Genital Chlamydia trachomatis infection causes severe reproductive pathologies such as salpingitis and pelvic inflammatory disease that can lead to tubal factor infertility. MicroRNAs (miRNAs) are evolutionarily conserved regulators of mammalian gene expression in development, immunity and pathophysiologic processes during inflammation and infection, including Chlamydia infection. Among the miRNAs involved in regulating host responses and pathologic outcome of Chlamydia infection, we have shown that miR-378b was significantly differentially expressed during primary infection and reinfection. In this study, we tested the hypothesis that miR-378b is involved in the pathological outcome of Chlamydia infection. We developed miR-378b knockout mice (miR-378b−/−) using Crispr/Cas and infected them along with their wild-type (WT) control with Chlamydia to compare the infectivity and reproductive pathologies. The results showed that miR-378b−/− mice were unable to clear the infection compared to WT mice; also, miR-378b−/− mice exhibited a relatively higher Chlamydia burden throughout the duration of infection. However, gross pathology results showed that miR-378b−/− mice had significantly reduced uterine dilatations and pathologic lesions after two infections compared to WT mice. In addition, the pregnancy and fertility rates for infected miR-378b−/− mice showed protection from Chlamydia-induced infertility with fertility rate that was comparable to uninfected WT mice. These results are intriguing as they suggest that miR-378b is important in regulating host immune responses that control Chlamydial replication and drive the inflammation that causes complications such as infertility. The finding has important implications for biomarkers of Chlamydial complications and targets for prevention of disease.

Highlights

Genital infection by the Gram negative, obligate intracellular bacterium, Chlamydia trachomatis, is the most common bacterial sexually transmitted disease worldwide and of high public health concern [1,2]
The finding suggested miR-378b expression may play a key role in Chlamydial pathogenesis. miR-378b is a member of the miR-378b family that includes miR-378a-3p, miR-378b, miR-378c, miR-378d, and miR-378e
Genital tract tissues excised from female wild-type and miR-378b−/− mice infected with 1 × 105 Infectious Units (IFUs) C. muridarum were evaluated for pathological lesions

Summary

Introduction

Genital infection by the Gram negative, obligate intracellular bacterium, Chlamydia trachomatis, is the most common bacterial sexually transmitted disease worldwide and of high public health concern [1,2]. There are an estimated 130 million cases of genital Chlamydia infections worldwide, with an estimated 4 million new cases occurring annually in the United States alone [3]. Any sexually active individual is at risk of Chlamydia infection; two-thirds of new infections occur among young women between 15 and 24 [1,4]. Chlamydia migrates into the upper genital tract leading to disease complications in the uterus (endometritis) and fallopian tubes (salpingitis) [1,2]. Chlamydia causes symptomatic and asymptomatic pelvic inflammatory disease (PID) experienced by 2–5% of women with an untreated infection. PID is known to cause irreversible damage to the uterus, fallopian tubes, and surrounding tissues leading to pelvic pain, tubal factor infertility, and potentially fatal ectopic pregnancy [1,2]

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