Eur J Immunol . SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs

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Eur J Immunol


. 2022 Jan 31.
doi: 10.1002/eji.202149656. Online ahead of print.
SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs


Lieve E H van der Donk ¹ , Julia Eder ¹ , John L van Hamme ¹ , Philip J M Brouwer ² , Mitch Brinkkemper ² , Ad C van Nuenen ¹ , Marit J van Gils ² , Rogier W Sanders ^{2 3} , Neeltje A Kootstra ¹ , Marta Bermejo-Jambrina ¹ , Teunis B H Geijtenbeek ¹



Affiliations

• PMID: 35099061
• DOI: 10.1002/eji.202149656

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 multi-organ 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 Toll-like receptor 4 (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 dendritic cells (DCs) express TLR4 but not 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. This article is protected by copyright. All rights reserved.

Keywords: Dendritic cells; Innate immune response; Intracellular viral sensors; SARS-CoV-2; Toll-like receptor 4.