The Weber laboratory studies how obligate intracellular bacterial pathogens manipulate host cells to evade cell-autonomous immune defenses and establish environments that support bacterial replication. Our research focuses primarily on two medically important pathogens, Chlamydia trachomatis and Orientia tsutsugamushi. C. trachomatis is the most common bacterial cause of sexually transmitted infections worldwide and a leading cause of preventable blindness, while O. tsutsugamushi is the causative agent of scrub typhus, a potentially severe febrile illness that is increasingly recognized beyond its historically defined endemic regions. Despite occupying very different intracellular niches, both pathogens depend on secreted bacterial proteins to manipulate host cellular and immune pathways.

C. trachomatis replicates within a membrane-bound compartment called the inclusion, whereas O. tsutsugamushi escapes its entry vacuole and replicates directly within the host cell cytosol. These distinct lifestyles expose the bacteria to different cell-autonomous immune defenses and provide complementary systems for understanding how host cells recognize intracellular infection and how pathogens evade these defenses. Both organisms deliver effector proteins into host cells to remodel cellular processes, yet the functions of many of these proteins remain unknown.

Our laboratory combines bacterial genetics, molecular and cell biology, proteomics, and advanced microscopy to define how bacterial effectors interact with host proteins and alter innate immune and cellular pathways. We are particularly interested in how host cells recognize and respond to pathogen-modified intracellular environments and how bacterial effectors counteract these defenses.

Our current research focuses on four major areas:

1. Determine how C. trachomatis protects its intracellular niche from cell-autonomous immune defenses. We are investigating how the inclusion membrane proteins IncC and CpoS manipulate host membrane trafficking and antimicrobial pathways. A major focus is understanding how IncC interacts with interferon-induced transmembrane proteins (IFITMs) and how these interactions prevent recognition and delivery of the chlamydial inclusion to lysosomal and autophagic compartments.

2. Define how C. trachomatis suppresses interferon-mediated host defense. Interferons induce hundreds of antimicrobial genes that allow cells to recognize and restrict intracellular pathogens. We are investigating how the secreted chlamydial effector CebN targets the nuclear pore and disrupts nuclear trafficking, including the nuclear translocation of STAT1, to alter interferon-dependent antimicrobial responses.

3. Understand how chlamydial effectors induce centrosome amplification. C. trachomatis infection causes striking changes to centrosomes, cell division, and host cell architecture. We are defining how the effector CteG and additional bacterial proteins disrupt centrosome duplication and cytokinesis, why these changes benefit infection, and whether they have longer-term consequences for infected cells, including genomic instability and cellular transformation.

4. Identify mechanisms used by O. tsutsugamushi to manipulate host cells and evade immunity. Because O. tsutsugamushi replicates directly within the host cell cytosol, it encounters a very different set of immune defenses than vacuolar pathogens such as C. trachomatis. We are developing genetic approaches for O. tsutsugamushi and identifying secreted bacterial proteins that manipulate host signaling and cellular pathways. These studies provide an opportunity to uncover new mechanisms of cell-autonomous immunity and bacterial immune evasion.