Our lab investigates how obligate intracellular bacterial pathogens manipulate host cellular processes to establish infection and evade immune defenses. We focus on two distinct pathogen models: Chlamydia trachomatis and Orientia tsutsugamushi, both of which significantly impact global human health. C. trachomatis is a leading cause of preventable blindness and sexually transmitted infections, while O. tsutsugamushi causes scrub typhus, a severe and sometimes fatal disease endemic to the Asia-Pacific region. To thrive within host cells, these pathogens deploy a diverse arsenal of secreted effector proteins to hijack host cellular machinery, suppress immune defenses, and sustain intracellular survival.

Current Projects in the Lab:

1.) Role of C. trachomatis Effectors in Manipulating the Centrosome and Cell Cycle
C. trachomatis infection is linked to centrosome amplification, multipolar spindles, and multinucleation—hallmarks of cervical and ovarian cancers, where C. trachomatis is a recognized risk factor. We identified the effector protein CteG as a key driver of centrosome amplification through its interaction with centrin-2 (CETN2). This project explores how CteG and other bacterial effectors manipulate the centrosome and cell cycle to enhance infection and evaluates their potential contributions to oncogenic transformation. These insights aim to guide strategies for reducing the cancer risk associated with C. trachomatis infections.

2.) Role of CT584 in Disrupting Nucleocytoplasmic Transport and Host Immune Responses
Despite eliciting a robust immune response, including IFN-γ production, C. trachomatis establishes persistent infections. Viruses often disrupt mRNA export by targeting nucleoporins and Rae1 to suppress ISG expression and dampen host defenses. Through mass spectrometry, we identified CT584 as the first bacterial effector to target nucleoporins and Rae1. This project aims to determine whether CT584 secretion and localization to both infected and bystander cells enable C. trachomatis to suppress immune defenses and establish persistence.

3.) Unveiling the Role of Inc Proteins in Building and Protecting the Chlamydia Inclusion
All Chlamydia species replicate within a host-derived vacuole, the inclusion, modified by over 50 type III secreted inclusion membrane proteins (Incs). Our research has shown that specific Incs, such as IncC and CpoS, are critical for maintaining inclusion integrity and preventing premature lysis and host cell death. We are investigating how IncC-host interactions and CpoS-Inc complexes redirect host vesicular trafficking to the inclusion while evading recognition by degradative machinery. These studies aim to uncover how intracellular pathogens construct and safeguard their unique replicative compartments.

4.) Development of Genetic Tools for Manipulating O. tsutsugamushi
Scrub typhus, caused by O. tsutsugamushi, poses a significant threat to global health, yet our understanding of how this pathogen co-opts host processes remains limited. To address this gap, we are developing a genetic manipulation system for O. tsutsugamushi, enabling the identification and characterization of secreted effectors. Specifically, we are investigating whether TPR (tetratricopeptide repeat) proteins represent novel secreted factors critical for modulating host-pathogen interactions. This work aims to elucidate the molecular mechanisms underlying O. tsutsugamushi pathogenesis and guide therapeutic development.

To learn more about our work and lab, visit our website: Weber Lab