Exploring the modulatory effects of aspirin on vaginal immunity
| dc.contributor.author | Taverner, Morgan | |
| dc.contributor.examiningcommittee | McKinnon, Lyle (Medical Microbiology and Infectious Diseases) | |
| dc.contributor.examiningcommittee | Card, Catherine (Medical Microbiology and Infectious Diseases) | |
| dc.contributor.supervisor | Murooka, Thomas | |
| dc.contributor.supervisor | Fowke, Keith | |
| dc.date.accessioned | 2025-01-10T21:32:54Z | |
| dc.date.available | 2025-01-10T21:32:54Z | |
| dc.date.issued | 2024-12-16 | |
| dc.date.submitted | 2025-01-03T02:08:41Z | en_US |
| dc.date.submitted | 2025-01-10T19:15:04Z | en_US |
| dc.degree.discipline | Medical Microbiology and Infectious Diseases | |
| dc.degree.level | Master of Science (M.Sc.) | |
| dc.description.abstract | Introduction: Human cohort studies associate bacterial vaginosis (BV) with adverse reproductive health outcomes such as genital inflammation and increased HIV acquisition risk. We developed a bacterial challenge model to investigate BV-associated barrier disruption, elevated cytokine production, and increased T cell activation. Damping of genital inflammation needs to be part of a comprehensive HIV-prevention strategy along with pre-exposure prophylaxis (PrEP). Acetylsalicylic Acid (ASA) is an anti-inflammatory drug that is widely available, affordable, and accepted in Kenya. Human cohort studies in this region found that ASA modulates mucosal immunity by reducing HIV targets (CD4+CCR5+ T cells) in the female reproductive tract (FRT), but its broad impact on the vaginal mucosa is unknown. In this thesis, I addressed whether ASA could dampen BV-associated inflammation, CD4 T cell activation, and epithelial barrier disruption in vivo and whether these effects can lower HIV acquisition risk. Methods: C57BL/6 mice were intravaginally challenged with BV-associated anaerobes Mobiluncus mulieris or Gardnerella vaginalis, with daily dosing of 32 mg/kg of ASA. In vivo assessment of vaginal epithelial layer function using Lucifer yellow dye, immunophenotyping of vaginal T cell subsets, and transcript-level analyses of FRT-draining lymph nodes by qPCR and RNAseq were performed to evaluate the therapeutic effects of ASA. Results: ASA was found to have a potential to mitigate the disruption of vaginal epithelial barrier function associated with Mobiluncus mulieris challenge. Similarly, ASA was found to reduce neutrophil recruitment to the lamina propria of the FRT of Mobiluncus mulieris challenged mice. ASA treatment was found to alter pathways associated with cell activation and recruitment in the FRT-draining lymph nodes, and qPCR analysis of this compartment associated ASA with reduced TH17-associated cytokine transcripts. At the cellular level, ASA treatment was also found to counter the elevated frequency of TH17 cells in the FRT and lymph nodes associated with bacterial challenge. Significance and Impact: Short-term ASA treatment significantly lowered key readouts of vaginal mucosal inflammation induced by BV-associated bacteria, such as the recruitment of TH17 cell subsets, pro-inflammatory cytokine production, and barrier disruption. Further testing is required to assess whether this translates to reduced HIV susceptibility. | |
| dc.description.note | February 2025 | |
| dc.description.sponsorship | Research Manitoba | |
| dc.identifier.uri | http://hdl.handle.net/1993/38779 | |
| dc.language.iso | eng | |
| dc.subject | HIV | |
| dc.subject | Aspirin | |
| dc.subject | Inflammation | |
| dc.subject | Female Reproductive Tract | |
| dc.subject | Th17-mediated Responses | |
| dc.subject | Mouse Model | |
| dc.subject | Immunomodulation | |
| dc.title | Exploring the modulatory effects of aspirin on vaginal immunity | |
| local.subject.manitoba | no | |
| oaire.awardTitle | Team Grant: HIV/AIDS Biomedical and Clinical Research - Prevention - Focused | |
| project.funder.identifier | http://dx.doi.org/10.13039/501100000024 | |
| project.funder.name | Canadian Institutes of Health Research |