%0 Journal Article
%T Upregulation of inflammatory genes and pathways links obesity to severe COVID-19.
%A Currey J
%A Ellsworth C
%A Khatun MS
%A Wang C
%A Chen Z
%A Liu S
%A Midkiff C
%A Xiao M
%A Ren M
%A Liu F
%A Elgazzaz M
%A Fox S
%A Maness NJ
%A Rappaport J
%A Lazartigues E
%A Blair R
%A Kolls JK
%A Mauvais-Jarvis F
%A Qin X
%J Biochim Biophys Acta Mol Basis Dis
%V 1870
%N 7
%D 2024 Jun 26
%M 38942338
%F 6.633
%R 10.1016/j.bbadis.2024.167322
%X Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a study in which 2-3-month-old K18-hACE2 (K18) mice were fed a western high-fat diet (WD) or normal chow (NC) over 3 months before intranasal infection with a sublethal dose of SARS-CoV2 WA1 (a strain ancestral to the Wuhan variant). After infection, the WD-fed K18 mice lost significantly more body weight and had more severe lung inflammation than normal chow (NC)-fed mice. Bulk RNA-seq analysis of lungs and adipose tissue revealed a diverse landscape of various immune cells, inflammatory markers, and pathways upregulated in the infected WD-fed K18 mice when compared with the infected NC-fed control mice. The transcript levels of IL-6, an important marker of COVID-19 disease severity, were upregulated in the lung at 6-9 days post-infection in the WD-fed mice when compared to NC-fed mice. Transcriptome analysis of the lung and adipose tissue obtained from deceased COVID-19 patients found that the obese patients had an increase in the expression of genes and the activation of pathways associated with inflammation as compared to normal-weight patients (n = 2). The K18 mouse model and human COVID-19 patient data support a link between inflammation and an obesity-accelerated COVID-19 disease phenotype. These results also indicate that obesity-accelerated severe COVID-19 caused by SARS-CoV-2 WA1 infection in the K18 mouse model would be a suitable model for dissecting the cellular and molecular mechanisms underlying pathogenesis.