COVID-19 Immunology: Netherlands Study Finds That SARS-CoV-2 Infection Activates Dendritic Cells Via Cytosolic Receptors Rather Than Extracellular TLRs

COVID-19 Immunology: A new study by led by researchers from University of Amsterdam-Netherlands along with support by scientists from Weill Medical College of Cornell University-USA has found that SARS-CoV-2 infections typically activate the human dendritic cells via cytosolic receptors rather than by extracellular Toll-like receptors (TLRs).

 
Typically, the human immune system needs to recognize pathogens such as SARS-CoV-2 to initiate antiviral immunity.
 
Dendritic cells (DCs) are professional antigen-presenting cells that link innate and adaptive immunity and are critical for the induction of protective immune responses against pathogens.
 
The dendritic cells (DCs) are also crucial for inducing antiviral immunity and are therefore equipped with both extracellular and intracellular pattern recognition receptors to sense pathogens.
 
It remains unclear whether SARS-CoV-2 is sensed by pattern recognition receptors (PRRs) leading to immune activation.
 
To date however, it is unknown if and how SARS-CoV-2 activates DCs. Certain research suggests that SARS-CoV-2 is sensed by extracellular Toll-like receptor 4 (TLR4).
 
The study team had previously shown that DCs do not express ACE2, and are therefore not infected by SARS-CoV-2.
 
In this study, the study team shows that DCs do not become activated by exposure to viral Spike proteins or SARS-CoV-2 virus particles.
 
These study findings suggest that TLR4 and other extracellular TLRs do not sense SARS-CoV-2.
 
The team then expressed ACE2 in DCs and SARS-CoV-2 efficiently infected these ACE2-positive DCs. Notably, infection of ACE2-positive DCs induced an antiviral immune response.
 
Hence the study findings suggest that infection of DCs is required for induction of immunity, and thus that intracellular viral sensors rather than extracellular TLRs are important in sensing SARS-CoV-2. Lack of sensing by extracellular TLRs might be an escape mechanism of SARS-CoV-2 and could contribute to the aberrant immune responses observed during COVID-19.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.09.02.458667v1
 
The range of symptomatic profiles of patients suffering from the COVID-19 disease 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 often dangerous 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.
 
The study team suggests that an aberrant inflammatory reaction associated with COVID-19 could be a result of escape from direct sensing by toll-like receptors (TLRs).
 
The ze:16px">COVID-19 Immunology study team further indicates that this phenomenon might underlie the lack of efficient immunity to the SARS-CoV-2 virus early during infection.
 
It has been known that 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.
 
The toll-like receptors (TLRs) constitute the most important family of PRRs.
 
Certain 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.
 
The 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.
 
The 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.
 
Typically the SARS-CoV-2 spike (S) protein also uses the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry into the host cell.
 
Importantly 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. https://pubmed.ncbi.nlm.nih.gov/32383269/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543713/
 
Hence TLR4 signaling could be involved in the induction of pro-inflammatory mediators.
 
The research 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.
 
It was found that 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 study 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.
 
Interestingly 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.
 
The study team ectopically expressed ACE2 in human monocyte-derived DCs and repeated treatment with SARS-CoV-2 virus particles.
 
Surprisingly, 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.
 
These findings suggest 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. https://pubmed.ncbi.nlm.nih.gov/33440148/
 
https://www.biorxiv.org/content/10.1101/2021.02.10.430677v1
 
Corresponding author Dr Teunis B.H. Geijtenbeek from the Department of Experimental Immunology, Amsterdam institute for Infection and Immunity, Amsterdam University Medical Centers told Thailand Medical News, “The study findings imply 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.”
 
He further added, “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.”
 
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