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DENV inhibits type I IFN production in infected cells by cleaving human STING

Aguirre, S, Maestre, AM, Pagni, S, Patel, JR, Savage, T, Gutman, D, Maringer, K, Bernal-Rubio, D, Shabman, RS, Simon, V , Rodriguez-Madoz, JR, Mulder, LCF, Barber, GN and Fernandez-Sesma, A (2012) DENV inhibits type I IFN production in infected cells by cleaving human STING PLoS Pathogens, 8 (10).

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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.

Item Type: Article
Subjects : Biosciences
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Aguirre, SUNSPECIFIEDUNSPECIFIED
Maestre, AMUNSPECIFIEDUNSPECIFIED
Pagni, SUNSPECIFIEDUNSPECIFIED
Patel, JRUNSPECIFIEDUNSPECIFIED
Savage, TUNSPECIFIEDUNSPECIFIED
Gutman, DUNSPECIFIEDUNSPECIFIED
Maringer, KUNSPECIFIEDUNSPECIFIED
Bernal-Rubio, DUNSPECIFIEDUNSPECIFIED
Shabman, RSUNSPECIFIEDUNSPECIFIED
Simon, VUNSPECIFIEDUNSPECIFIED
Rodriguez-Madoz, JRUNSPECIFIEDUNSPECIFIED
Mulder, LCFUNSPECIFIEDUNSPECIFIED
Barber, GNUNSPECIFIEDUNSPECIFIED
Fernandez-Sesma, AUNSPECIFIEDUNSPECIFIED
Date : 4 October 2012
Identification Number : 10.1371/journal.ppat.1002934
Copyright Disclaimer : © 2012 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
Depositing User : Symplectic Elements
Date Deposited : 22 Feb 2017 14:39
Last Modified : 31 Oct 2017 19:09
URI: http://epubs.surrey.ac.uk/id/eprint/813602

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