SARS-CoV-2 infection induces persistent adipose tissue damage in aged golden Syrian hamsters

Abstract

Coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) is primarily a respiratory illness. However, various extrapulmonary manifestations have been reported in patients with severe forms of COVID-19. Notably, SARS-CoV-2 was shown to directly trigger white adipose tissue (WAT) dysfunction, which in turn drives insulin resistance, dyslipidemia, and other adverse outcomes in patients with COVID-19. Although advanced age is the greatest risk factor for COVID-19 severity, published data on the impact of SARS-CoV-2 infection on WAT in aged individuals are scarce. Here, we characterized the response of subcutaneous and visceral WAT depots to SARS-CoV-2 infection in young adult and aged golden hamsters. In both age groups, infection was associated with a decrease in adipocyte size in the two WAT depots; this effect was partly due to changes in tissue’s lipid metabolism and persisted for longer in aged hamsters than in young-adult hamsters. In contrast, only the subcutaneous WAT depot contained crown-like structures (CLSs) in which dead adipocytes were surrounded by SARS-CoV-2-infected macrophages, some of them forming syncytial multinucleated cells. Importantly, older age predisposed to a unique manifestation of viral disease in the subcutaneous WAT depot during SARS-CoV-2 infection; the persistence of very large CLSs was indicative of an age-associated defect in the clearance of dead adipocytes by macrophages. Moreover, we uncovered age-related differences in plasma lipid profiles during SARS-CoV-2 infection. These data suggest that the WAT’s abnormal response to SARS-CoV-2 infection may contribute to the greater severity of COVID-19 observed in elderly patients.

Diabetes Mellitus, Energy Metabolism, and COVID-19

“…The inflammatory and antiviral response to SARS-CoV-2 infection is more prominent in visceral than subcutaneous fat ( 107 ) ( Fig. 1 ), and alterations in visceral adipose tissue are more persistent in old compared with young hamsters infected with the virus ( 176 ). Preclinical studies have shown that SARS-CoV-2 infection induces adipocyte dysfunction ( Fig.…”

Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters

“…The consequences of a SARS-CoV-2 infection in aged hamsters have rarely been addressed 41 , 42 . Relative to young hamsters, aged animals had higher expression of genes encoding RNA-dependent RNA polymerase (RdRp) and envelope (E) protein and viral particles at 3 and 7 days post-infection (dpi) (Fig.…”

“…Only a few studies have addressed the effect of advanced age on experimental SARS-CoV-2 infections in hamsters 41 , 42 , 57 – 60 . With the exception of Selvaraj et al 41 and Bogard et al 42 , these studies used middle-aged animals, aged from 5 to 8 months.…”

“…Only a few studies have addressed the effect of advanced age on experimental SARS-CoV-2 infections in hamsters 41 , 42 , 57 – 60 . With the exception of Selvaraj et al 41 and Bogard et al 42 , these studies used middle-aged animals, aged from 5 to 8 months. As the life expectancy of golden hamsters is typically 20–24 months, we chose to study 22-month-old hamsters (equivalent to ~80-year-old humans).…”

“…Young (2-month-old) and aged (22-month-old) male Syrian golden hamsters ( Mesocricetus auratus ), equivalent to young adult (~20 years old) and aged (~80 years old) humans, respectively, were purchased from Janvier Laboratory. Animals were infected with 100 µl of DMEM containing (or not, for mock (control) animals) 2 × 10 4 TCID 50 (50% of the tissue culture infectious dose) of SARS-CoV-2 (hCoV-19_IPL_France strain of SARS-CoV-2) 33 , 42 . For tissue collection, animals were euthanized with an intraperitoneal injection of euthasol (140 mg kg −1 ).…”