The unfolded protein response triggers the immune deficiency pathway in ticks

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 are unclear. Here, we show that the Unfolded Protein Response (UPR) initiates the IMD network in Ixodes scapularis ticks. The endoplasmic reticulum (ER) stress receptor, IRE1α, 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 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 the Lyme disease-causing spirochete Borrelia burgdorferi and the rickettsial agents Anaplasma phagocytophilum and A. marginale (anaplasmosis). Altogether, our study uncovers the upstream signaling requirements of the IMD pathway in ticks. We propose that this mode of IMD network activation is evolutionarily ancient, predating the classically defined pathway in insects.

Immune Reactions of Vector Insects to Parasites and Pathogens

“…For example, the tick Ixodes scapularis lacks genes encoding upstream regulators of the Imd pathway, including Imd, and FADD [313]. Despite the absence of these regulators, the remaining Imd pathway is active against infection by tick-borne pathogenic bacteria such as Borrelia burgdorferi and is triggered by cellular stress responses centring on the evolutionary conserved unfolded protein response (UPR) [314]. We speculate that this could also be true for hemimetabolous vector insects.…”