Adipose tissue in COVID-19: detection of SARS-CoV-2 in adipocytes and activation of the interferon-alpha response

Abstract

Objective Obesity is a recognized risk factor for the progression to severe forms of COVID-19, yet the mechanisms of the association are unclear. Methods Subcutaneous abdominal adipose tissue specimens of subjects deceased from COVID-19 (n = 23) were compared to those of controls dying abruptly from causes other than infectious (accidental trauma, sudden cardiac death). Alterations of lung parenchyma consistent with moderate to severe disease were detected in all COVID-19 cases, not in controls. Investigations included: histopathologic features, detection of virus antigens and genome, characterization of infiltrating leukocytes, transcription levels of immune-related genes. Results By RT-PCR, the SARS-CoV-2 genome was detected in the adipose tissue of 13/23 (56%) cases of the COVID-19 cohort. The virus nucleocapsid antigen was detected in the cytoplasm of 1–5% adipocytes in 12/12 COVID-19 cases that were virus-positive by PCR in the adipose tissue (one case could not be assessed due insufficient tissue). The adipose tissue of COVID-19 cases showed leukocyte infiltrates and upregulation of the interferon-alpha pathway. After adjusting for age and sex, the activation score of IFN-alpha was directly related with transcription levels of the ACE2 gene, a key entry factor of SARS-CoV-2. Conclusions In lethal COVID-19 cases, the SARS-CoV-2 nucleocapsid antigen has been detected in a sizeable proportion of adipocytes, showing that the virus may directly infect the parenchymal cells of subcutaneous fat. Infection appears to activate the IFN alpha pathway and to attract infiltrating leukocytes. Due to the huge numbers of adipocytes in adults, the adipose tissue represents a significant reservoir for SARS-CoV-2 and an important source of inflammatory mediators.

SARS-CoV-2 infection drives an inflammatory response in human adipose tissue through infection of adipocytes and macrophages

“…Although we show infection of adipocytes with SARS-CoV-2, we were surprised that we did not detect corresponding expression of ACE2 , the canonical SARS-CoV-2 entry receptor, in fresh adipose tissue. Prior reports of ACE2 RNA expression in whole adipose tissue relied primarily on bulk transcriptomic approaches and suggested that ACE2 expression could be influenced by factors including diet, obesity, and COVID-19 ( 23 , 24 , 90 – 92 ). In freshly isolated mature adipocytes, we only sporadically detected ACE2 RNA, whereas it was consistently identified in differentiated preadipocytes, consistent with another recent report ( 26 ).…”

COVID-19: Reducing the risk via diet and lifestyle

“…A third suggestion is that increased angiotensin-converting enzyme (ACE2) expression in adipose tissue of obese individuals could make it a vulnerable target for COVID-19 infection, especially given the higher expression of ACE2 in adipocytes, compared to lung tissue [34] , [35] . Evidence that SARS-CoV-2 can directly infect adipocytes [36] supports the hypothesis that adipose tissue represents an important viral reservoir for increased viral shedding [37] , [38] . This had previously been reported in studies on influenza, with elevated viral loads in exhaled breath, prolonged viral shedding, and obesogenic environments favouring the emergence of novel, more virulent virus strains [39] , [40] , [41] .…”

The Endocrine Adipose Organ: A System Playing a Central Role in COVID-19

“…The presence of SARS-CoV-2 in the adipocytes of fat from COVID-19 patients has been demonstrated in a very recent paper that also showed chronic inflammation with upregulation of the interferon-alpha pathway [50]. Of note, interferon-alpha stimulates the expression of ACE2 and this type of condition has been reported in chronic lung diseases that appear to stimulate gene expression programs promoting both the cellular entry of SARS-CoV-2 and the severity of COVID-19 [51].…”