PERK-mediated antioxidant response is key for pathogen persistence in ticks.

A crucial phase in the lifecycle of tick-borne pathogens is the time spent colonizing and persisting within the arthropod. Tick immunity is emerging as a key force shaping how transmissible pathogens interact with the vector. How pathogens remain in the tick despite immunological pressure remains unknown. In persistently infected , we found that (Lyme disease) and (granulocytic anaplasmosis) activate a cellular stress pathway mediated by the endoplasmic reticulum receptor PERK and the central regulatory molecule, eIF2α. Disabling the PERK pathway through pharmacological inhibition and RNAi significantly decreased microbial numbers. RNA interference of the PERK pathway not only reduced the number of and colonizing larvae after a bloodmeal, but also significantly reduced the number of bacteria that survive the molt. An investigation into PERK pathway-regulated targets revealed that and induce activity of the antioxidant response regulator, Nrf2. Tick cells deficient for expression or PERK signaling showed accumulation of reactive oxygen and nitrogen species in addition to reduced microbial survival. Supplementation with antioxidants rescued the microbicidal phenotype caused by blocking the PERK pathway. Altogether, our study demonstrates that the PERK pathway is activated by transmissible microbes and facilitates persistence in the arthropod by potentiating an Nrf2-regulated antioxidant environment.