The Major Cellular Sterol Regulatory Pathway Is Required for Andes Virus Infection

PLoS Pathogens

Craig B. Wilen¹  Frances Male¹  Kenneth Briley Jr.¹  Chukwuka A. Didigu¹  Nirav Malani¹  Frederic D. Bushman¹  Josiah Petersen¹  Emily A. Bruce¹  Amber M. Riblett¹  Robert W. Doms¹  Fang-Hua Lee¹  Sara Cherry¹  Mary Jane Drake¹  Paul Bates² 

[1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America

关键词: Cholesterol;    Andes virus;    Genetic screens;    Small interfering RNAs;    Sterols;    Vesicular stomatitis virus;    Virions;    Gene regulation;   

DOI  :  10.1371/journal.ppat.1003911

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The Bunyaviridae comprise a large family of RNA viruses with worldwide distribution and includes the pathogenic New World hantavirus, Andes virus (ANDV). Host factors needed for hantavirus entry remain largely enigmatic and therapeutics are unavailable. To identify cellular requirements for ANDV infection, we performed two parallel genetic screens. Analysis of a large library of insertionally mutagenized human haploid cells and a siRNA genomic screen converged on components (SREBP-2, SCAP, S1P and S2P) of the sterol regulatory pathway as critically important for infection by ANDV. The significance of this pathway was confirmed using functionally deficient cells, TALEN-mediated gene disruption, RNA interference and pharmacologic inhibition. Disruption of sterol regulatory complex function impaired ANDV internalization without affecting virus binding. Pharmacologic manipulation of cholesterol levels demonstrated that ANDV entry is sensitive to changes in cellular cholesterol and raises the possibility that clinically approved regulators of sterol synthesis may prove useful for combating ANDV infection.

【 授权许可】

CC BY