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© Aguirre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Aguirre S, Maestre AM, Pagni S, Patel JR, Savage T, et al. (2012) DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING. PLoS Pathog 8(10): e1002934. doi:10.1371/journal.ppat.1002934

Abstract

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.

Details

Title
DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING
Author
Aguirre, Sebastian; Maestre, Ana M; Pagni, Sarah; Patel, Jenish R; Savage, Timothy; Gutman, Delia; Maringer, Kevin; Bernal-Rubio, Dabeiba; Shabman, Reed S; Simon, Viviana; Rodriguez-Madoz, Juan R; Mulder, Lubbertus CF; Barber, Glen N; Fernandez-Sesma, Ana
Section
Research Article
Publication year
2012
Publication date
Oct 2012
Publisher
Public Library of Science
ISSN
15537366
e-ISSN
15537374
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1289109650
Copyright
© Aguirre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Aguirre S, Maestre AM, Pagni S, Patel JR, Savage T, et al. (2012) DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING. PLoS Pathog 8(10): e1002934. doi:10.1371/journal.ppat.1002934