Graduation Date

Spring 5-9-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Immunology, Pathology & Infectious Disease

First Advisor

Rey Carabeo, Ph.D.

Second Advisor

Amanda Brinkworth, Ph.D.

Abstract

The cervical epithelium is a key interface for Chlamydia-host interactions as it serves as the primary site of infection. In response to infection, soluble factors are produced in the local microenvironment including interferons (IFNs). These drive the expression of IFN-stimulated genes (ISGs) via the JAK-STAT pathway through autocrine and paracrine signaling creating an antimicrobial state that limits infection, making cytokine pathways common targets of pathogen subversion. However, the mechanisms underlying Chlamydia-driven manipulation of host innate immunity, and its impact on bystander cell responses are not well understood. In these studies, we demonstrated that Chlamydia actively attenuates the IFN response in infected epithelial cells by targeting crucial JAK-STAT signaling components early in infection leading to the concomitant decrease in IFN-induced ISG expression. This subversion extended beyond responses to exogenous IFNs, as autonomous activation of STATs during infection was also reduced, putting forward a pathogen-driven mechanism in downregulating this epithelial innate immune mechanism. Moreover, longitudinal analysis over an extended infection period revealed that the epithelial IFN response is dynamic rather than uniformly suppressed. An initial transient activation marked by increased phosphorylation of STAT1 and expression of downstream target IRF1 were detected before rapid downregulation, with attenuation evident as early as 24 hours post-infection. Despite suppression in infected cells, this early activation triggered a cell contact-independent IFN response in bystander uninfected cells through paracrine stimulation mediated by soluble factors. Profiling at single-cell level revealed enrichment of IFN response genes in infection-exposed bystander uninfected cells. The induction of this IFN response negatively impacted chlamydial inclusion size, identifying the bystander response as a critical component of host anti-chlamydial defense and a key regulator of chlamydial growth. Taken together, this study provides a more refined understanding of the immunobiology underlying Chlamydia-cervical epithelial interactions.

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Available for download on Monday, October 26, 2026

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