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

Abstract

ABSTRACTA 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 infectedIxodes scapularis, we found thatBorrelia burgdorferi(Lyme disease) andAnaplasma phagocytophilum(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.In vivoRNA interference of the PERK pathway not only reduced the number ofA. phagocytophilumandB. burgdorfericolonizing larvae after a bloodmeal, but also significantly reduced the number of bacteria that survive the molt. An investigation into PERK pathway-regulated targets revealed thatA. phagocytophilumandB. burgdorferiinduce activity of the antioxidant response regulator, Nrf2. Tick cells deficient fornrf2expression 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 theIxodesPERK pathway is activated by transmissible microbes and facilitates persistence in the arthropod by potentiating an Nrf2-regulated antioxidant environment.