Regulation of cytoskeletal reorganization by chlamydia

The National Institute of Allergy and Infectious Diseases awarded Thomas Jefferson University $558,367 on September 3, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct research on the regulation of cytoskeletal reorganization by Chlamydia trachomatis.

The research investigates how Chlamydia trachomatis, an intracellular bacterium responsible for sexually transmitted infections and infectious blindness, hijacks host cell cytoskeletal pathways to establish and maintain its intracellular niche. The project focuses on identifying the molecular mechanisms underlying the formation and maintenance of actin and microtubule scaffolds around the bacterial inclusion, their role in redirecting host organelles and nutrients, and their contribution to pathogenesis in vivo. The work builds on preliminary findings identifying two new inclusion membrane proteins involved in cytoskeletal reorganization and tests hypotheses about how Chlamydia initially forms these scaffolds and their individual roles in bacterial development.

Performance occurs in Philadelphia, Pennsylvania, with a period of performance extending from the award date through August 31, 2031. This is a Project Grant, the standard NIH research award mechanism for investigator-initiated biomedical research.

Abstract

Chlamydia trachomatis is an intracellular bacterium that causes significant human morbidity. IT is the most common etiological agent of bacterial sexually transmitted diseases and infectious blindness. Without a preventive vaccine, IT is crucial to identify chlamydia's intracellular survival strategies and how they influence disease progression. To survive within its host, chlamydia must establish and maintain its intracellular niche, known as the inclusion. Chlamydia accomplishes this by CO-opting the host cell and hijacking critical cellular pathways. Of particular interest is the reorganization of the host cytoskeleton around the inclusion triggered by chlamydia. By building actin and microtubule scaffolds around the inclusion, chlamydia extensively redirects host organelles and nutrients to the inclusion, while also creating a physical barrier to protect the expanding inclusion membrane, which is crucial for chlamydia development. Our laboratory has a long-standing interest in studying these events as we seek to identify the molecular platform involved in forming and maintaining these cytoskeletal scaffolds, as well as their role in vivo. Our previous work has established that the inclusion membrane protein called inac plays a significant role in stabilizing these scaffolds. Yet, fundamental questions remain: (1) how does chlamydia initially form cytoskeletal scaffolds, (2) what is the role of individual scaffolds in chlamydia development, and (3) to what extent do these scaffolds contribute to chlamydia pathogenesis in vivo? These remain significant knowledge gaps in our understanding of chlamydia's intracellular survival strategies. This project proposes to answer these outstanding questions using multidisciplinary in vivo and in vitro approaches. Based on our preliminary results, which identify two new inclusion proteins involved in cytoskeletal reorganization, we propose testing the hypothesis that chlamydia sequentially uses distinct protein complexes to remodel the host cytoskeleton and control chlamydia pathogenesis. Overall, the results obtained from this work will identify the function of two new chlamydial proteins and their associated host-binding partners, reveal new elements in the molecular platform used by chlamydia to coordinate cytoskeletal reorganization, elucidate the contribution of new chlamydial proteins and cytoskeletal scaffolds to chlamydia pathogenesis in vivo, and, importantly, identify new virulence factors. The universal role of the cytoskeleton in regulating processes from cell shape and stability to cancer metastasis, immunity, and wound repair underscores the broad impact of this study.