Author ORCID Identifier
https://orcid.org/0000-0001-6000-6285
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Microbiology & Immunology
First Advisor
Jason Carlyon
Abstract
Orientia tsutsugamushi is a neglected obligate intracellular bacterium that causes scrub typhus, a globally emerging potentially lethal vector-borne disease. O. tsutsugamushi remodels its intracellular environment using ankyrin repeat (AR)-containing effectors (Anks). Many Anks carry the same functional domains consisting of N-terminal ankyrin repeats, an intervening sequence region (ISR), and an F-box motif located within the poorly characterized Pox protein Repeats of ANkyrin C-terminal (PRANC) domain. Nuclear factor kappa-b (NF-kB), a central activator of innate and adaptive immunity, is inhibited by Orientia Ank1 and Ank6 which bear these domains. The precise mechanism is unknown but requires the ISR, PRANC, and F-box domains. Here, we show that unlike cowpox virus, which produces effectors with similar domain architecture, Orientia Ank1 and Ank6 do not block immunity by inhibiting necroptosis, nor do they inhibit NF-kB solely through blocking degradation of the NF-kB inhibitor p105. We discovered that four different O. tsutsugamushi strains inhibit NF-kB using a cohort of ten Anks that inhibit NF-kB nuclear accumulation. NF-kB inhibition requires a fully functional C-terminally placed F-box or a PRANC domain plus a novel functional region, the lamin-binding domain (LBD), which binds lamin A and its phosphorylated variant, pSer22-lamin A. Lamin A activates NF-kB by an unknown mechanism and pSer22-lamin A promotes chromatin accessibility to transcription factors. We revealed that O. tsutsugamushi globally reduces chromatin accessibility particularly at binding motifs for the NF-kB coactivator activator protein 1 (AP-1). These data yield new insights into host cell biology and reveal a novel mechanism for pathogenic NF-kB inhibition.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-20-2025