Ehrlichia chaffeensis mediates Hedgehog and Hippo signaling to activate an anti-apoptotic cellular program

Ehrlichia chaffeensis is a gram-negative intracellular bacterium responsible for the emerging zoonotic disease, human monocytic ehrlichiosis (HME). HME is the most prevalent and life-threatening tick-borne disease in the United States. In the past two decades, the incidence of HME has increased 10-fold; however, the number of reported cases is underestimated by 100-fold due to underreporting and underdiagnosis. Ehrlichia chaffeensis hijacks mononuclear phagocytes to escape host defenses through mechanisms executed by tandem repeat protein (TRP) effectors secreted by the type 1 secretion system. In the past decade, tandem repeat protein TRP120 has emerged as a model moonlighting effector. Remarkably, TRP120 has been defined as a nucleomodulin, ligand mimic and ubiquitin ligase. Molecular mimicry is a survival strategy utilized by an array of pathogens to facilitate host-pathogen interactions and exploit host machinery. Recent publications from our laboratory demonstrate that TRP120 is a ligand mimic that directly interacts with various receptors to reprogram the host cell by activating the Wnt and Notch signaling pathways via a novel tandem repeat short linear motif (SLiM). Interestingly, we demonstrate that TRP120 utilizes a Hedgehog SLiM to activate Hedgehog signaling and the Wnt SLiM to mediate Hippo signaling during infection to prevent intrinsic apoptosis. We demonstrate the activation of Hedgehog and Hippo transcription factor and co-activator Gli-1 and Yap through the interaction of TRP120 with Hedgehog and Hippo receptors during infection. Further, studies demonstrate that E. chaffeensis regulates apoptotic downstream targets of Hedgehog and Hippo signaling, including GLUT-1 BCL-2, BCL-xL and Bax. In summary, we determined that E. chaffeensis TRP120 interacts with Hedgehog and Hippo receptors and modulates Hedgehog and Hippo signaling via tandem repeat SLiMs to maintain an anti-apoptotic profile for ehrlichial survival. This study reports the first example of bacterial mimicry of Hedgehog and Hippo pathway ligands and highlights a pathogenic signaling mechanisms which may be utilized for the development of antimicrobial therapeutics.

Name thesis:degree_name

Cell Biology (Doctoral)

Discipline thesis:degree_discipline

Biomedical Sciences

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2023

Author dc:creator

• Byerly, Caitlan 08/31/1994-

Advisor dc:contributor.advisor

• McBride, Jere

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12484

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12484