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 - https://doi.org/10.1002/eji.202149656
DO - https://doi.org/10.1002/eji.202149656
M3 - Article
C2 - 35099061
SN - 0014-2980
VL - 52
SP - 646
EP - 655
JO - European journal of immunology
JF - European journal of immunology
IS - 4
ER -