Research on SARS-CoV-2 and dendritic cells may explain why virus is so virulent

Symptomatic profiles of patients suffering from the coronavirus disease 2019 (COVID-19) vary from mild respiratory symptoms to severe pneumonia, multi-organ failure, and death. Increasing evidence suggests that disease severity not only depends on viral infection but also on an unwarranted host pro-inflammatory response, also known as the cytokine storm.

The cytokine storm is the consequence of hyperinflammation driven by innate immunity and is associated with unfavorable immune response, tissue damage, and poor prognosis in COVID-19 patients.

In a recent study released on the bioRxiv* preprint server, the researchers suggest that an aberrant inflammatory reaction associated with COVID-19 could be a result of escape from direct sensing by toll-like receptors (TLRs). Moreover, the researchers indicate that this phenomenon might underlie the lack of efficient immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early during infection.

Study: SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs. Image Credit: Kateryna Kon / Shutterstock

TLRs and dendritic cells

The cells of the innate immune system express pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and subsequently orchestrate an immune response against pathogens. This response forms the first line of defense.

Toll-like receptors (TLRs) constitute the most important family of PRRs. Some of these TLRs are located on the cell surface, where they are responsible for recognizing extracellular invaders such as bacteria, fungi, and viruses. Others are located within the cells, where they are responsible for recognizing intracellular invaders like viruses.

Dendritic cells (DCs), which are one of the key cells of innate immune system, function as a bridge between innate and adaptive immunity. DCs express various PRR families, particularly TLRs, which get triggered upon interaction with viruses.

TLRs subsequently command DCs to instruct T- and B-cells, the vital elements of the adaptive immune system, to mount an efficient antiviral immune response.

Like SARS-CoV, the SARS-CoV-2 spike (S) protein also uses the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry into the host cell. However, recent in silico analyses suggest that besides interacting with ACE2, the S protein could also potentially interact with members of the TLR family, in particular TLR4, which is abundantly expressed on DCs. Therefore, TLR4 signaling could be involved in the induction of pro-inflammatory mediators.

About the study

The team studied the induction of TLR4, which is an extracellular TLR, activation in TLR4-expressing cell line and human monocyte-derived primary DCs after exposure to either recombinant S protein, SARS-CoV-2 pseudovirus or primary SARS-CoV-2 particles. None of the treatments induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived DCs inherently express TLR4 but not ACE2, and these were not observed to be infected by primary SARS-CoV-2 virus particles.

The team also investigated cytokine induction by human monocyte-derived DCs. Exposure of DCs to agonists for extracellular TLRs resulted in the induction of the type I interferon (IFN) response, as well as cytokines. However, exposure to the primary SARS-CoV-2 isolate did not lead to induction of any cytokines or type I IFN, thereby indicating that primary SARS-CoV-2 particles are not sensed by any extracellular PRRs on DCs such as TLR2, TLR4, and TLR5.

Next, the team ectopically expressed ACE2 in human monocyte-derived DCs and repeated treatment with SARS-CoV-2 virus particles. Here, the viral particles lead to infection, as well as the production of cytokines and pro-inflammatory cytokine interleukin (IL)-6 in ACE2 expressing DCs. This result suggests that replication of SARS-CoV-2 triggers cytosolic/intracellular viral sensors. Other studies have also suggested the involvement of intracellular viral sensors such as RIG-I or MDA5 in SARS-CoV-2 infection.


“Our data implies that extracellular transmembrane TLRs do not sense SARS-CoV-2 virus particles.”

In the event of inefficient DC activation, epithelial cell infection, subsequent inflammation, and tissue damage might account for initial immune activation and inflammation. This activation could also contribute to the subsequent release of PAMPs and damage-associated molecular patterns (DAMPs). However, it remains unclear whether these secondary signals are able to correctly instruct DCs and whether this might trigger the strong inflammatory responses observed during COVID-19.

“Our finding that SARS-CoV-2 is not recognized by TLR4 might therefore be an escape mechanism leading to inefficient DC activation and subsequent aberrant inflammatory response.”

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • van der Donk LEH, Eder J, van Hamme JL, Brouwer PJM, Brinkkemper M, van Nuenen AC, van Gils MJ, Sanders RW, Kootstra NA, Bermejo-Jambrina M and Geijtenbeek TBH. SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs. bioRxiv, 2021. doi:, ​

Posted in: Medical Research News | Disease/Infection News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Bacteria, Cell, Cell Line, Coronavirus, Coronavirus Disease COVID-19, Cytokine, Cytokines, Dendritic Cell, Enzyme, fungi, Immune Response, Immune System, immunity, Inflammation, Interferon, Interleukin, Intracellular, Monocyte, Pathogen, Pneumonia, Protein, Pseudovirus, Receptor, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Virus

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Namita Mitra

After earning a bachelor’s degree in Veterinary Sciences and Animal Health  (BVSc) in 2013, Namita went on to pursue a Master of Veterinary Microbiology from GADVASU, India. Her Master’s research on the molecular and histopathological diagnosis of avian oncogenic viruses in poultry brought her two national awards. In 2013, she was conferred a doctoral degree in Animal Biotechnology that concluded with her research findings on expression profiling of apoptosis-associated genes in canine mammary tumors. Right after her graduation, Namita worked as Assistant Professor of Animal Biotechnology and taught the courses of Animal Cell Culture, Animal Genetic Engineering, and Molecular Immunology.

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