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

Autor:	Rosche KL; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA., Hurtado J; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA.; School of Molecular Biosciences, Washington State University, Pullman, Washington, USA., Fisk EA; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA., Vosbigian KA; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA., Warren AL; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA., Sidak-Loftis LC; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA., Wright SJ; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA., Ramirez-Zepp E; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA., Park JM; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA., Shaw DK; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA.; School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 01. Date of Electronic Publication: 2023 Jun 01.
DOI:	10.1101/2023.05.30.542958
Abstrakt:	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 Ixodes scapularis , we found that Borrelia burgdorferi (Lyme disease) and Anaplasma 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 vivo RNA interference of the PERK pathway not only reduced the number of A. phagocytophilum and B. burgdorferi 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 A. phagocytophilum and B. burgdorferi induce activity of the antioxidant response regulator, Nrf2. Tick cells deficient for nrf2 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 Ixodes PERK pathway is activated by transmissible microbes and facilitates persistence in the arthropod by potentiating an Nrf2-regulated antioxidant environment.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu