TY - JOUR
T1 - SARS-CoV-2 suppresses TLR4-induced immunity by dendritic cells via C-type lectin receptor DC-SIGN
AU - van der Donk, Lieve E. H.
AU - Bermejo-Jambrina, Marta
AU - van Hamme, John L.
AU - Volkers, Mette M. W.
AU - van Nuenen, Ad C.
AU - Kootstra, Neeltje A.
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 nr. 114025008 to TBHG) and European Research Council (Advanced grant 670424 to TBHG). LEHvdD was supported by the Netherlands Organization for Scientific Research (NWO) (Grant number: 91717305). MBJ was supported by a Work Visit Grant of the Amsterdam institute for Infection and Immunity and by an APART-MINT Fellowship of the Austrian Academy of Sciences at the Institute of Hygiene and Medical Microbiology of the University of Innsbruck (Grant number 11978). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 2023 van der Donk 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.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.
AB - SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.
UR - http://www.scopus.com/inward/record.url?scp=85174528745&partnerID=8YFLogxK
U2 - https://doi.org/10.1371/journal.ppat.1011735
DO - https://doi.org/10.1371/journal.ppat.1011735
M3 - Article
C2 - 37844099
SN - 1553-7366
VL - 19
JO - PLoS pathogens
JF - PLoS pathogens
IS - 10
M1 - e1011735
ER -