Obesity exacerbates SARS‐CoV‐2 infection in K18‐hACE2 mice

Abstract

Hypertension and obesity are considered risk factors for severe coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The aim of the current study was to examine whether hypertension and obesity alter SARS‐CoV‐2 infection, the development of the disease and possible underlying mechanisms, using the K18‐hACE2 transgenic mice.Three groups of male K18‐hACE2 mice (5 mice/group, 5‐month‐old) were infected intranasally with SARS‐CoV‐2 (strain USA_WA1/2020, 104 PFU in 100 µl). Prior to infection, one group of mice was fed a hypercaloric diet (HCD, high fat high sucrose diet) for 3 months to model obesity; the second group of mice, on regular diet (RD), was infused with Angiotensin (Ang)‐II (600 ng/kg/min) for 3 weeks to model hypertension; and the third group of mice on RD served as control. Body weight was monitored daily post infection (dpi), and all mice were sacrificed at 7 dpi. RNA was extracted from kidney, heart, and lung, and RT‐qPCR was performed to measure tissue viral load and cytokine expression. Tissue damage was assessed on formalin‐fixed and paraffin‐embedded sections.The three groups of mice suffered similar weight loss following infection (~15% by 7 dpi). Compared to control and hypertensive groups, in which the viral loads were similar across the tissues examined (lung, heart, and kidney), viral load in the heart of obese mice was significantly higher than in the lung and the kidney (Heart: 7.26 ±0.2 vs. Lung: 3.75 ±0.2 vs. Kidney: 2.48 ±0.4, expressed as Log10 of viral copy number per 100 ng RNA, p<0.05, two‐way ANOVA). In addition, compared to control mice, obese mice showed increased expression of CXCL1/KC in both kidney (HCD: 1.98 ±0.3 vs. RD: 0.74 ±0.1, p<0.05) and lung (HCD: 7.05 ±1.1 vs. RD: 2.39 ±0.3, p<0.05), and increased expression of IL‐17 in the lung (HCD: 1.44 ±0.1 vs. RD: 0.92 ±0.1, p<0.05). Furthermore, obese mice showed the highest expression of IL‐6 (HCD: 3.96 ±0.9 vs. Ang‐II: 1.1 ±0.1 vs. RD: 1.56 ±0.4, p<0.05) and TNFα (HCD: 14.08 ±0.6 vs. Ang‐II: 7.14 ±0.8 vs. RD: 6.03 ±1.13 mRNA expression level, p<0.05, one‐way ANOVA) in the lung among the three groups. Finally, the obese mice showed the highest lung infiltration (HCD: 15.6 ±1.4 vs. Ang‐II: 8.1 ±2.2 vs. RD: 6.38 ±1.3 infiltrated area/total area in %, p<0.05, one‐way ANOVA).Our study suggests that obesity significantly increases tissue inflammation following SARS‐CoV‐2 infection, with the heart at particular risk of higher SARS‐CoV‐2 infection; in contrast, acute hypertension induced by Ang‐II infusion does not significantly alter SARS‐CoV‐2 infection or COVID‐19 disease course.