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@article{a101e98c83c44338ac68fb9fd6ff8649,
title = "SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs",
abstract = "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan dysfunction. It remains unclear how SARS-CoV-2 infection leads to immune activation. The Spike (S) protein of SARS-CoV-2 has been suggested to trigger TLR4 and thereby activate immunity. Here, we have investigated the role of TLR4 in SARS-CoV-2 infection and immunity. Neither exposure of isolated S protein, SARS-CoV-2 pseudovirus nor primary SARS-CoV-2 isolate induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived DCs express TLR4 but not angiotensin converting enzyme 2 (ACE2), and DCs were not infected by SARS-CoV-2. Notably, neither S protein nor SARS-CoV-2 induced DC maturation or cytokines, indicating that both S protein and SARS-CoV-2 virus particles do not trigger extracellular TLRs including TLR4. Ectopic expression of ACE2 in DCs led to efficient infection by SARS-CoV-2 and, strikingly, efficient type I IFN and cytokine responses. These data strongly suggest that not extracellular TLRs but intracellular viral sensors are key players in sensing SARS-CoV-2. These data imply that SARS-CoV-2 escapes direct sensing by TLRs, which might underlie the lack of efficient immunity to SARS-CoV-2 early during infection.",
keywords = "Dendritic cells, Innate immune response, Intracellular viral sensors, SARS-CoV-2, Toll-like receptor 4",
author = "{van der Donk}, {Lieve E. H.} and Julia Eder and {van Hamme}, {John L.} and Brouwer, {Philip J. M.} and Mitch Brinkkemper and {van Nuenen}, {Ad C.} and {van Gils}, {Marit J.} and Sanders, {Rogier W.} and Kootstra, {Neeltje A.} and Marta Bermejo-Jambrina and Geijtenbeek, {Teunis B. H.}",
note = "Funding Information: This research was funded by the Netherlands Organisation for Health Research and Development together with the Stichting Proefdiervrij (ZonMW MKMD COVID‐19 Grant No. 114025008 to TBHG) and European Research Council (Advanced Grant No. 670424 to TBHG), and two COVID‐19 grants from the Amsterdam Institute for Infection & Immunity (to TBHG, RWS, and MJvG). LEHvdD was supported by the Netherlands Organization for Scientific Research (NWO) (Grant No. 91717305). This study was also supported by NWO through a Vici grant (to RWS), and by the Bill & Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD), Grant INV‐002022 (to RWS). Publisher Copyright: {\textcopyright} 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH",
year = "2022",
month = apr,
doi = "10.1002/eji.202149656",
language = "English",
volume = "52",
pages = "646--655",
journal = "European journal of immunology",
issn = "0014-2980",
publisher = "Wiley-VCH Verlag",
number = "4",

}

RIS

TY - JOUR

T1 - SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs

AU - van der Donk, Lieve E. H.

AU - Eder, Julia

AU - van Hamme, John L.

AU - Brouwer, Philip J. M.

AU - Brinkkemper, Mitch

AU - van Nuenen, Ad C.

AU - van Gils, Marit J.

AU - Sanders, Rogier W.

AU - Kootstra, Neeltje A.

AU - Bermejo-Jambrina, Marta

AU - Geijtenbeek, Teunis B. H.

N1 - Funding Information: This research was funded by the Netherlands Organisation for Health Research and Development together with the Stichting Proefdiervrij (ZonMW MKMD COVID‐19 Grant No. 114025008 to TBHG) and European Research Council (Advanced Grant No. 670424 to TBHG), and two COVID‐19 grants from the Amsterdam Institute for Infection & Immunity (to TBHG, RWS, and MJvG). LEHvdD was supported by the Netherlands Organization for Scientific Research (NWO) (Grant No. 91717305). This study was also supported by NWO through a Vici grant (to RWS), and by the Bill & Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD), Grant INV‐002022 (to RWS). Publisher Copyright: © 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH

PY - 2022/4

Y1 - 2022/4

N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan dysfunction. It remains unclear how SARS-CoV-2 infection leads to immune activation. The Spike (S) protein of SARS-CoV-2 has been suggested to trigger TLR4 and thereby activate immunity. Here, we have investigated the role of TLR4 in SARS-CoV-2 infection and immunity. Neither exposure of isolated S protein, SARS-CoV-2 pseudovirus nor primary SARS-CoV-2 isolate induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived DCs express TLR4 but not angiotensin converting enzyme 2 (ACE2), and DCs were not infected by SARS-CoV-2. Notably, neither S protein nor SARS-CoV-2 induced DC maturation or cytokines, indicating that both S protein and SARS-CoV-2 virus particles do not trigger extracellular TLRs including TLR4. Ectopic expression of ACE2 in DCs led to efficient infection by SARS-CoV-2 and, strikingly, efficient type I IFN and cytokine responses. These data strongly suggest that not extracellular TLRs but intracellular viral sensors are key players in sensing SARS-CoV-2. These data imply that SARS-CoV-2 escapes direct sensing by TLRs, which might underlie the lack of efficient immunity to SARS-CoV-2 early during infection.

AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan dysfunction. It remains unclear how SARS-CoV-2 infection leads to immune activation. The Spike (S) protein of SARS-CoV-2 has been suggested to trigger TLR4 and thereby activate immunity. Here, we have investigated the role of TLR4 in SARS-CoV-2 infection and immunity. Neither exposure of isolated S protein, SARS-CoV-2 pseudovirus nor primary SARS-CoV-2 isolate induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived DCs express TLR4 but not angiotensin converting enzyme 2 (ACE2), and DCs were not infected by SARS-CoV-2. Notably, neither S protein nor SARS-CoV-2 induced DC maturation or cytokines, indicating that both S protein and SARS-CoV-2 virus particles do not trigger extracellular TLRs including TLR4. Ectopic expression of ACE2 in DCs led to efficient infection by SARS-CoV-2 and, strikingly, efficient type I IFN and cytokine responses. These data strongly suggest that not extracellular TLRs but intracellular viral sensors are key players in sensing SARS-CoV-2. These data imply that SARS-CoV-2 escapes direct sensing by TLRs, which might underlie the lack of efficient immunity to SARS-CoV-2 early during infection.

KW - Dendritic cells

KW - Innate immune response

KW - Intracellular viral sensors

KW - SARS-CoV-2

KW - Toll-like receptor 4

UR - http://www.scopus.com/inward/record.url?scp=85124734990&partnerID=8YFLogxK

U2 - 10.1002/eji.202149656

DO - 10.1002/eji.202149656

M3 - Article

C2 - 35099061

VL - 52

SP - 646

EP - 655

JO - European journal of immunology

JF - European journal of immunology

SN - 0014-2980

IS - 4

ER -

ID: 21867394