Biology subjects

Cherpes, T. L.

Publications and source records attributed to Cherpes, T. L..

3 recordsLinked to original sources

bioRxiv2025

Chlamydia-induced ex vivo activation of B cells from mice, nonhuman primates, and humans produces large numbers of uniformly activated antigen presenting cells

Chlamydia trachomatis (Ct) is a clinically important pathogen that causes ocular and genital infections. While genital Ct infection in women is typically persistent and asymptomatic, the host responses that dampen inflammation while gradually eradicating this bacterium are only partially defined. Herein, we show that Ct promotes human B cell activation via TLR2-mediated signaling of MyD88-dependent pathways and non-antigen-specific B cell receptor signaling that engages the CD19 and CD79a/b complex. We also found that ex vivo Chlamydia-induced activation of B cells from the peripheral blood of humans or rhesus macaques (RM), or from murine splenocytes, generates cells with a phenotype characteristic of an activated antigen presenting cell (APC). Consistent with this phenotype, intravenous injection of Chlamydia-activated B cells (CAB) loaded with various cognate antigens (Ag) elicited robust Ag-specific T cell immunity in several experimental models. Specifically, RM injected with CAB loaded with a model Ag developed Ag-specific CD8+ T cell immunity and mice injected with Ag-loaded CAB formed CD8+ T cell immune responses that protected against virus challenge and tumor development. As Chlamydia nonspecifically activated B cells to form large numbers of uniformly activated APC readily loaded with cognate Ag, our studies suggest that CAB may offer foundation for a cellular vaccine platform that elicits robust Ag-specific CD8+ T cell immunity against a variety of tumors and microbial pathogens.

immunology↗

bioRxiv2024

Exogenous ephrin-A3 administration restores vaginal epithelial barrier function in progestin-treated mice

Desmosomes are junctional complexes that confer mechanical strength and enhance epithelial barrier function at mucosal surfaces by anchoring intermediate filaments to plasma membrane. While these roles are less explored in vaginal vs. cutaneous epithelium, we previously reported that treating mice with the progestin depot medroxyprogesterone acetate (DMPA) reduces vaginal epithelial levels of the desmosomal cadherins desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and weakens vaginal epithelial barrier function. We also showed these effects were avoided by treating mice with DMPA and a conjugated equine estrogen vaginal cream. The current investigation further explored the effects of sex steroids on vaginal epithelial integrity, identifying ephrin-A3 (EFNA3) as a key regulator of desmosomal cadherin gene expression. We observed topical administration of recombinant EFNA3 (rEFNA3) promotes vaginal DSG1 expression in a biphasic dose-dependent manner and partially reverses the loss of vaginal epithelial barrier function induced by DMPA treatment. Consistent with this effect, morbidity and mortality elicited by genital herpes simplex virus type 2 infection were delayed, but not prevented, in mice administered DMPA and rEFNA3 vs. DMPA and vehicle. Together, these studies identify EFNA3 as an important regulator of desmosomal function in vaginal epithelium and improve current understanding of sex steroid-mediated mechanisms that control vaginal epithelial barrier function.

immunology↗

bioRxiv2023

Loss of genital epithelial barrier function is greater with depot-medroxyprogesterone acetate than intravaginal rings that release etonogestrel and ethinyl estradiol

The injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing(R) is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing(R)re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract.

immunology↗