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

Sebastian Aguirre, Ana M. Maestre, Sarah Pagni, Jenish R. Patel, Timothy Savage, Delia Gutman, Kevin Maringer, Dabeiba Bernal-Rubio, Reed S. Shabman, Viviana Simon, Juan R. Rodriguez-Madoz, Lubbertus C.F. Mulder, Glen N. Barber, Ana Fernandez-Sesma

Research output: Contribution to journalArticle

267 Scopus citations

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.

Original languageEnglish (US)
Article numbere1002934
JournalPLoS pathogens
Volume8
Issue number10
DOIs
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Aguirre, S., Maestre, A. M., Pagni, S., Patel, J. R., Savage, T., Gutman, D., Maringer, K., Bernal-Rubio, D., Shabman, R. S., Simon, V., Rodriguez-Madoz, J. R., Mulder, L. C. F., Barber, G. N., & Fernandez-Sesma, A. (2012). DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING. PLoS pathogens, 8(10), [e1002934]. https://doi.org/10.1371/journal.ppat.1002934