期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 52, 期 4, 页码 646-655出版社
WILEY
DOI: 10.1002/eji.202149656
关键词
Dendritic cells; Innate immune response; Intracellular viral sensors; SARS-CoV-2; Toll-like receptor 4
类别
资金
- Netherlands Organisation for Health Research and Development
- Stichting Proefdiervrij (ZonMW MKMD COVID-19) [114025008]
- European Research Council [670424]
- Amsterdam Institute for Infection Immunity
- Netherlands Organization for Scientific Research (NWO) [91717305]
- NWO
- Bill & Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD) [INV-002022]
This study suggests that SARS-CoV-2 does not directly activate TLR4, but instead utilizes intracellular viral sensors for sensing and infecting host cells. This finding may explain the lack of efficient immune response to SARS-CoV-2 early during infection.
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.
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