Location: Animal Disease ResearchTitle: The unfolded-protein response triggers the arthropod immune deficiency pathway
|SIDAK-LOFTIS, LINDSAY - Washington State University|
|ROSCHE, KRISTIN - Washington State University|
|PENCE, N - Washington State University|
|UJCZO, JESSIE - Former ARS Employee|
|HURTADO, JOANNA - Washington State University|
|FISK, ELIS - Washington State University|
|GOODMAN, A - Washington State University|
|PETERS, JOHN - Washington State University|
|SHAW, DANA - Washington State University|
Submitted to: mBio
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/27/2022
Publication Date: 7/18/2022
Citation: Sidak-Loftis, L.C., Rosche, K.L., Pence, N., Ujczo, J.K., Hurtado, J., Fisk, E.A., Goodman, A.G., Noh, S.M., Peters, J.W., Shaw, D.K. 2022. The unfolded-protein response triggers the arthropod immune deficiency pathway. mBio. Article e00703-22. https://doi.org/10.1128/mbio.00703-22.
Interpretive Summary: Arthropod-borne diseases continue to be a substantial source of morbidity and mortality worldwide. Factors influencing the ability of arthropods to harbor and transmit pathogens are incompletely understood. It is now known that arthropod immunity is an important force in shaping vector competency. For example, humoral defense networks recognize and restrict invading microbes. However, little is know about the mechanisms involved in triggering these humoral defenses. This work demonstrates that cellular stress, specifically the unfolded protein response, triggers the tick immune system, which in turn influences the ability of a tick to transmit pathogens. This work is broadly applicable to ticks and tick borne pathogens and may provide targets for future strategies to prevent transmission of these pathogens.
Technical Abstract: The insect immune deficiency (IMD) pathway is a defense mechanism that senses and responds to Gram negative bacteria. Ticks lack genes encoding upstream components that initiate the IMD pathway. Despite this deficiency, core signaling molecules are present and functionally restrict tick-borne pathogens. The molecular events preceding activation remains undefined. Here, we show that the Unfolded Protein Response (UPR) initiates the IMD network. The endoplasmic reticulum (ER) stress receptor, IRE1a, is phosphorylated in response to tick-borne bacteria, but does not splice the mRNA encoding XBP1. Instead, through protein modeling and reciprocal pulldowns, we show that Ixodes IRE1a complexes with TRAF2. Disrupting IRE1a-TRAF2 signaling blocks IMD pathway activation and diminishes the production of reactive oxygen species. Through in vitro, in vivo, and ex vivo techniques we demonstrate that the UPR-IMD pathway circuitry limits the Lyme disease-causing spirochete Borrelia burgdorferi and the rickettsial agents Anaplasma phagocytophilum and A. marginale (anaplasmosis). Altogether, our study uncovers a novel linkage between the UPR and the IMD pathway in arthropods.