BREAKING! Stanford Study Shows That SARS-CoV-2 Infects Mature Adipocytes And Adipose Tissue Macrophages, Eliciting An Inflammatory Response

A new study by led by researchers from Stanford University School of Medicine along with scientists from University Hospital and Comprehensive Cancer Center Tübingen-Germany, University Hospital of Basel-Switzerland, Beth Israel Deaconess Medical Center-USA and Chan Zuckerberg Biohub, San Francisco-USA has found that the SARS-CoV-2 coronavirus also infects the human adipose tissue especially the mature adipocytes and adipose tissue macrophages, in the process eliciting an inflammatory response 2 consistent with severe COVID-19.

 
The ongoing COVID-19 pandemic, caused by the viral pathogen SARS-CoV-2, has taken the lives of more than 5.05 million humans and infected almost a quarter of a billion people globally.
 
Obesity has been associated with adverse COVID-19 outcomes, but the underlying mechanism is unknown.
 
The study team demonstrate that human adipose tissue from multiple depots is permissive to SARS-CoV-2 infection and that infection elicits an inflammatory response, including the secretion of known inflammatory mediators of severe COVID-19.
 
The study findings identify two cellular targets of SARS-CoV-2 infection in adipose tissue: mature adipocytes and adipose tissue macrophages.
 
Adipose tissue macrophage infection is largely restricted to a highly inflammatory subpopulation of macrophages, present at baseline, that is further activated in response to SARS-CoV-2 infection. Preadipocytes, while not infected, adopt a proinflammatory phenotype.
 
The study findings further demonstrate that SARS-CoV-2 RNA is detectable in adipocytes in COVID-19 autopsy cases and is associated with an inflammatory infiltrate.
 
The study findings collectively indicate that adipose tissue supports SARS-CoV-2 infection and pathogenic inflammation and may explain the link between obesity and severe COVID-19.
 
The study findings were published on a preprint server and is currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.10.24.465626v1
 
The study team discovered that a reason obesity is a known risk factor for more severe COVID-19 is because the virus can infect fat cells.
 
Importantly in lab experiments and in autopsies of patients who died of COVID-19, the study team found the virus infects two types of cells found in fat tissue: mature fat cells, called adipocytes, and immune cells called macrophages.
 
Lead author Dr Catherine Blish of Stanford University School of Medicine told Thailand Medical News, "Infection of fat cells led to a marked inflammatory response, consistent with the type of immune response that is seen in severe cases of COVID-19.These data suggest that infection of fat tissue and its associated inflammatory response may be one of the reasons why obese individuals do so poorly when infected with SARS-CoV-2.”
 
Significantly, one of the most intriguing findings was that SARS-CoV-2 infection of adipose stromal-vascular cells (SVC) was primarily restricted to just one of two macrophage clusters. The two macrophage populations were defined as: C2-macrophages, an inflammatory cluster with IL1B and CCL3 as its most distinguishing transc ripts, and C12-macrophages, characterized by significant enrichment of HLA class II transcripts and LYZ and alarmin S100A8 expression.
 
C2-macrophages were predominately infected, with over 85% of C2 cells within infected SVC carrying SARS-CoV-2 transcripts. These two clusters do not fall into a classical M1 and M2 classification: instead, macrophages activated in response to adipose tissue signals may exhibit a unique phenotype. The C2 macrophages express transcripts characteristic of PVMs (perivascular macrophages), which have been previously described in adipose tissue and are highly phagocytic. PVMs can become virally infected: in the brain, PVMs have been shown to become infected by HIV and SIV.
 
Interestingly, SARS-CoV-2 infection further drives the C2/C12 dichotomy as chemokine markers are further upregulated while LYZ and HLA expression is further downregulated in infected SARS-CoV-2 transcript-containing C2 cells versus their bystander counterparts. LYZ is of particular interest as prior studies have shown that lysozyme can play a role in antiviral activity, which suggests that low lysozyme levels (as found in the susceptible C2 cluster) may be advantageous for the virus. For example, influenza infection reduces lysozyme secretion in neutrophils and the combination of lysozyme and lactoferrin therapy reduces Bovine viral diarrhea virus titers in vitro.
 
This data suggests that lysozyme therapy could reduce SARS-CoV-2 levels in the adipose tissue.
 
Another significant study finding is the dramatic inflammatory response following SARS-CoV-2 infection of adipose tissue, particularly within the SVC.
 
Across multiple experiments, at both the RNA and protein level, the study team saw increased expression of cytokines, ISGs and other molecules related to inflammation and antiviral pathways 24 hours after SVC infection.
 
Many of the molecules found upregulated upon SARS-CoV-2 infection are associated with COVID-19 severity ie. IP-10, PDGFAA, PDGFAB/BB, IL-4, and MCSF all have been reported to be elevated in the serum of critically ill COVID-19 patients, MIF has been described as a predictor of poor outcome on mechanically ventilated COVID-19 patients, and VEGF may play a crucial role in COVID-19 related brain inflammation.
 
The study also detected increased type I interferon transcripts and ISG15 in SVC of both SAT (subcutaneous)  and VAT (visceral) and hpi, indicative of a persistent antiviral response during viral replication.
 
While significantly less dramatic, the study also saw trends for increased inflammatory cytokine and chemokines following infection of mature adipocytes.
 
Notably, the study team observed both induction of transcripts (CCL8 and CCL3) and demonstrated secretion of chemokines (MCP2 and MCP3) in infected SVC cultures that can attract macrophages. This is entirely consistent with the autopsy finding of an inflammatory infiltrate associated with SARS-CoV-2+  cells and suggests that the antiviral response may be dragging more susceptible macrophages to the site of infection.
 
This study findings suggest that targeted inhibition of inflammation in the adipose tissue could improve outcomes in COVID-19 subjects. In fact, therapeutics targeting inflammation of the adipose tissue during obesity-induced inflammation have been proposed as a treatment for metabolic disease. For instance, salicylate, a cyclooxygenase inhibitor, reduces inflammation of the adipose tissue in obese individuals and has been proposed as a therapeutic strategy in COVID-19 patients due to its anti-inflammatory properties and antiviral activity against both DNA and RNA viruses.
 
Therefore, drugs reducing inflammation of the adipose tissue in obese individuals should be further explored in COVID-19 subjects.
 
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