Identification of Rab18 as an Essential Host Factor for BKPyV Infection Using a Whole Genome RNA Interference Screen

Abstract

BK polyomavirus (BKPyV) is a human pathogen first isolated in 1971. BKPyV infection is ubiquitous in the human population, with over 80% of adults worldwide being seropositive for BKPyV. BKPyV infection is usually asymptomatic; however, BKPyV reactivation in immunosuppressed transplant patients causes two diseases, polyomavirus-associated nephropathy and hemorrhagic cystitis. To establish a successful infection in its host cells, BKPyV must travel in retrograde transport vesicles to reach the nuclei. To make this happen, BKPyV requires the cooperation of host cell proteins. To further identify host factors associated with BKPyV entry and intracellular trafficking, we performed a whole-genome siRNA screen on BKPyV infection of primary human renal proximal tubular epithelial cells. The results revealed the importance of the Ras-related protein Rab18 and syntaxin 18 for BKPyV infection. Our subsequent experiments implicated additional factors that interact with this pathway, and suggest a more detailed model of the intracellular trafficking process, indicating that BKPyV reaches the ER lumen through a retrograde transport pathway between the late endosome and the ER.