Biology subjects

Kaushic, C.

Publications and source records attributed to Kaushic, C..

4 recordsLinked to original sources

bioRxiv2026

Transcriptomic profiling reveals estradiol and progesterone specific microRNA signatures differentially regulate mRNA targets in vaginal epithelial cells

Epithelial cells of the female reproductive tract (FRT) form a protective barrier and serve as the first line of defense against sexually transmitted infections (STIs). They recognize pathogens, release cytokines and initiate innate immune responses. Sex hormones 17{beta}-estradiol (E2) and progesterone (P4) fluctuate throughout the menstrual cycle and influence epithelial cell functions. Generally, E2 confers protection against viral STIs like HIV-1 and HSV-2, whereas P4 increases susceptibility. However, the underlying mechanisms remain incompletely understood. MicroRNAs, small non-coding RNAs that regulate gene expression by inhibiting translation of target mRNAs, significantly influence viral infections, by promoting or restricting viral pathogenesis. Here, we examined the effect of sex hormones on microRNA expression in vaginal epithelial cells (VECs), the first responders to pathogens in the FRT. Using next generation sequencing analysis, the effect of physiological concentrations of E2 or P4 on microRNA transcription profile of VECs grown in air-liquid interface cultures was characterized. Thirteen miRNAs were uniquely regulated by E2 and 102 by P4, with 29 miRNAs that overlapped between both. The top four differentially expressed miRNAs from both treatments were validated by RT-qPCR. The mRNA targets of unique E2-miRNAs were involved in adherens junction, tight junction and chemokine signaling pathways; whereas the mRNA targets of unique P4-miRNAs were involved in MAPK signaling pathway. Interestingly, several miRNAs regulated by E2- (eg. hsa-miR-9-3p, hsa-miR-200c- 5p, hsa-miR-548c-5p) and by P4 (eg. hsa-let-7f-5p, hsa-miR-16-5p, hsa-miR-27b-3p) targeted genes related to cell cycle pathway. Together, these findings indicate that microRNAs regulated by E2 and P4 influence mRNAs in the pathways associated with cell adhesion, cell growth and development and innate immune responses, critical for maintenance of epithelial barrier integrity and regulating pathogen susceptibility in the vaginal tract. These hormone-regulated miRNAs may serve as potential targets for therapeutic interventions.

immunology↗

bioRxiv2023

Human vaginal microbiota colonization is regulated by female sex 1 hormones in a mouse model

Clinically, a Lactobacillus rich vaginal microbiota (VMB) is considered optimal for reproductive outcomes, while a VMB populated by anaerobes is associated with dysbiosis and the clinical condition bacterial vaginosis (BV), which is linked to increased susceptibility to sexually transmitted infections and adverse reproductive outcomes. Mouse models that mimic eubiotic and dysbiotic VMB are currently lacking but could play a critical role in improving protective interventions. In this study, probiotic, eubiotic, and dysbiotic models were first developed in normal mice, using probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14, eubiotic Lactobacillus crispatus, or dysbiotic Gardnerella vaginalis strains. Following a single administration, L. rhamnosus and L. reuteri persisted in the mouse vaginal tract for up to eight days, L. crispatus persisted for up to three days, and G. vaginalis persisted for up to two days, as measured by quantitative plating assays and qPCR. Colonization of G. vaginalis was facilitated by the presence of mucin. Endogenous sex hormones were manipulated by either ovariectomizing (OVX) mice or administering 17{beta}-estradiol and progesterone pellets in OVX mice. The lack of endogenous hormones in OVX mice dramatically decreased VMB bacterial load compared to normal mice. None of the exogenous bacteria including Lactobacilli could colonize OVX mice for more than 24 hours. Treatment with 17{beta}-estradiol but not progesterone restored the endogenous microbiota and colonization with Lactobacilli and G. vaginalis. Interestingly, 17{beta}-estradiol treated mice had significantly increased levels of glycogen, compared to OVX and progesterone-treated mice. These results suggest there is a dynamic interaction between sex hormones and the VMB, which can affect bacterial diversity and the ability for a VMB to colonize.

microbiology↗

bioRxiv2021

IgA Potentiates NETosis in Response to Viral Infection

IgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces. As such, IgA plays a key role in protection against a variety of mucosal pathogens, including viruses. In addition to neutralizing viruses directly, IgA can also stimulate Fc-dependent effector functions via engagement of Fc alpha receptors (FcRI) expressed on the surface of certain immune effector cells. Neutrophils are the most abundant leukocyte, express FcRI, and are often the first to respond to sites of injury and infection. Here, we describe a novel function for IgA:virus immune complexes (ICs) during viral infections. We show that IgA:virus ICs potentiate NETosis - the programmed cell death pathway through which neutrophils release neutrophil extracellular traps (NETs). Mechanistically, IgA:virus ICs potentiated a suicidal NETosis pathway via engagement of FcRI on neutrophils through a toll-like receptor (TLR)-independent, NADPH oxidase complex-dependent pathway. NETs also were capable of trapping and inactivating viruses, consistent with an antiviral function.

immunology↗

bioRxiv2018

Medroxyprogesterone acetate mediated alteration in the vaginal microbiota and microenvironment in a Kenyan sex worker cohort

AbstractThe hormonal contraceptive Medroxyprogesterone Acetate (MPA) is associated with increased risk of Human Immunodeficiency Virus (HIV), via incompletely understood mechanisms. Increased diversity in the vaginal microbiota modulates genital inflammation and is associated with increased HIV-1 acquisition. However, the effect of MPA on diversity of the vaginal microbiota is relatively unknown. In a cohort of female Kenyan sex workers, negative for sexually transmitted infections (STIs), with Nugent Scores <7 (N=58 of 370 screened), MPA correlated with significantly increased diversity of the vaginal microbiota as assessed by 16S rRNA gene sequencing. MPA was also significantly associated with low vaginal glycogen and -amylase, factors implicated in vaginal colonization by lactobacilli, bacteria believed to protect against STIs. Furthermore, increased diversity of the vaginal microbiota correlated with activation of vaginal HIV-1 target cells. Results were recapitulated in humanized mice where MPA treatment was associated with increased diversity of the vaginal microbiota, low glycogen, and enhanced HIV-1 susceptibility. Together these results suggest MPA-induced hypo-estrogenism may alter key metabolic components necessary for vaginal colonization by certain bacterial species including lactobacilli, and allow for greater bacterial diversity in the vaginal microbiota. Bacterial diversity in the vaginal microbiota correlates with activation of HIV-1 target cells, which might thus contribute to enhanced susceptibility to HIV-1.

molecular biology↗