DENV inhibits type I IFN production in infected cells by cleaving human STING.
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.
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.
Sebastian
S
Aguirre
Ana M
AM
Maestre
Sarah
S
Pagni
Jenish R
JR
Patel
Timothy
T
Savage
Delia
D
Gutman
Kevin
K
Maringer
Dabeiba
D
Bernal-Rubio
Reed S
RS
Shabman
Viviana
V
Simon
Juan R
JR
Rodriguez-Madoz
Lubbertus C F
LC
Mulder
Glen N
GN
Barber
Ana
A
Fernandez-Sesma
D000330:Aedes; D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003713:Dendritic Cells / Q000378:metabolism* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity*; D057809:HEK293 Cells; D006801:Humans; D057131:Immune Evasion; D007370:Interferon Type I / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication; D000099197:STING Protein
D007370:Interferon Type I; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C532857:STING1 protein, human; D000099197:STING Protein