DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING

PLoS Pathogens

Dabeiba Bernal-Rubio¹  Ana Fernandez-Sesma²  Sarah Pagni³  Kevin Maringer³  Timothy Savage³  Sebastian Aguirre³  Ana M. Maestre³  Lubbertus C. F. Mulder³  Juan R. Rodriguez-Madoz³  Reed S. Shabman³  Glen N. Barber³  Delia Gutman⁴  Jenish R. Patel⁴  Viviana Simon⁵ 

[1] Department of Cell Biology, University of Miami School of Medicine, Miami, Florida, United States of America;Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York City, New York, United States of America;Department of Microbiology and the Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York City, New York, United States of America;Mount Sinai Graduate School of Biological Sciences, Mount Sinai School of Medicine, New York City, New York, United States of America;School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom

关键词: Dengue virus;    Proteases;    Dendritic cells;    Interferons;    Viral replication;    RNA extraction;    Small interfering RNAs;    Monocytes;   

DOI  :  10.1371/journal.ppat.1002934

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Dengue virus (DENV) is a pathogen with a high impact on human health. It replicates in a wide range of cells involved in the immune response. To efficiently infect humans, DENV must evade or inhibit fundamental elements of the innate immune system, namely the type I interferon response. DENV circumvents the host immune response by expressing proteins that antagonize the cellular innate immunity. We have recently documented the inhibition of type I IFN production by the proteolytic activity of DENV NS2B3 protease complex in human monocyte derived dendritic cells (MDDCs). In the present report we identify the human adaptor molecule STING as a target of the NS2B3 protease complex. We characterize the mechanism of inhibition of type I IFN production in primary human MDDCs by this viral factor. Using different human and mouse primary cells lacking STING, we show enhanced DENV replication. Conversely, mutated versions of STING that cannot be cleaved by the DENV NS2B3 protease induced higher levels of type I IFN after infection with DENV. Additionally, we show that DENV NS2B3 is not able to degrade the mouse version of STING, a phenomenon that severely restricts the replication of DENV in mouse cells, suggesting that STING plays a key role in the inhibition of DENV infection and spread in mice.

【 授权许可】

CC BY