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How Stress and Immunity Intertwine to Regulate Vector Competence of Ticks
Dana K Shaw1,4, Lindsay C Sidak-Loftis1, Kristin L Rosche1, Natasha Pence2#, Jessica K Ujczo3, Joanna Hurtado1,4, Elis Fisk1,
Alan G Goodman4, Susan M Noh1,3, John W Peters2
1 Veterinary Microbiology and Pathology, Washington State University, Pullman, WA.
2Institute of Biological Chemistry, Washington State University, Pullman, WA.
3United States, Department of Agriculture, Agricultural Research Service, Animal Disease Research Unit, Pullman, WA
4School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.
Department of Chemistry, Dartmouth College, Hanover, NH, USA.
The North American deer tick, Ixodes scapularis, transmits 7 pathogens relevant to human health including Borrelia
burgdorferi (Lyme disease) and Anaplasma phagocytophilum (Anaplasmosis). The ability of an arthropod to harbor and
transmit pathogens is termed “vector competency”. The arthropod immune system can influence vector competency,
but the molecular details of tick immunity remain vague. For example, the immune deficiency (IMD) pathway is a
defense mechanism that has been well-characterized in insects and senses/responds to Gram negative bacteria.
However, ticks lack genes encoding upstream components that initiate the IMD pathway. Despite this deficiency, core IMD pathway signaling molecules are present and functionally restrict Gram negative-like bacterial pathogens B. burgdorferi and A. phagocytophilum. The molecular events leading to IMD pathway activation in ticks has remained unclear. We have found that the Unfolded Protein Response (UPR) functions upstream to activate the IMD pathway. The
endoplasmic reticulum (ER) stress receptor, IRE1α, is phosphorylated in response to tick-borne bacteria, but does not
splice XBP1. Instead, through protein modeling and reciprocal pulldowns, we show that Ixodes IRE1α complexes with
TRAF2. Disrupting IRE1α-TRAF2 signaling blocks IMD pathway activation and diminishes the production of antimicrobial
effectors. Through in vitro, in vivo and ex vivo techniques we demonstrate that the UPR-IMD pathway circuitry limits B.
burgdorferi and the rickettsial agents A. phagocytophilum and A. marginale. Collectively, our findings provide an
explanation for how the core IMD pathway is activated independent of canonical upstream regulators.
This work is supported by the National Institutes of Health (R21AI139772 and R01AI162819 to D.K.S., T32GM008336 to
J.H., R01GM138592 to J.W.P.)