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Upregulation of inflammatory genes and pathways links obesity to severe COVID-19

ABSTRACT: 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 K18-hACE2 mice were fed an obesity-inducing western diet (WD) for over 3 months before intranasal infection with SARS-CoV2. After infection, the WD-fed K18-hACE2 mice lost more body weight and had more severe lung inflammation than normal chow (NC)-fed mice. Bulk RNAseq analysis of lungs and adipose tissue revealed that a diverse landscape of various immune cells, inflammatory markers, and pathways are upregulated in obese COVID-19 patients or the WD-fed K18-hACE2 mice when compared with their respective control groups. When compared with infected NC-fed mice in the lung, the infected WD-fed mice had upregulation of IL-6, a well-established marker for severe COVID-19. These results indicate that obesity-accelerated severe COVID-19 caused by SARS-CoV-2 infection in the K18-hACE2 mouse model can be used for dissecting the cellular and molecular mechanisms underlying pathogenesis. Furthermore, in the transcriptome analysis of the lung and adipose tissue obtained from deceased COVID-19 patients, we found upregulation of an array of genes and pathways associated with Inflammation. Both the K18-hACE2 mouse model and human COVID-19 patient data support a link between inflammation and an obesity-accelerated COVID-19 disease phenotype.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE267021 | GEO | 2024/05/21

REPOSITORIES: GEO

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Project description:Rapid emergence of antigenic distinct SARS-CoV-2 variants implies a greater risk of reinfection as viruses can escape neutralizing antibodies induced by vaccination or previous viral exposure. Disease severity during COVID-19 depends on many variables such as age-related comorbidities, host immune status and genetic variation. The host immune response during infection with SARS-CoV-2 may contribute to disease severity, which can range from asymptomatic to severe with fatal outcome. Furthermore, the extent of host immune response activation may rely on underlying genetic predisposition for disease or protection. To address these questions, we performed immune profiling studies in mice with different genetic backgrounds - transgenic K18-hACE2 and wild-type 129S1 mice – subjected to reinfection with the severe disease-causing SARS-CoV-2 B.1.351 variant, 30 days after experimental milder BA.1 infection. BA.1 preinfection conferred protection against B.1.351-induced morbidity in K18-hACE2 mice but aggravated disease in 129S1 mice. We found that he cytokine/chemokine profile in B.1.351 re-infected 129S1mice is similar to that during severe SARS-CoV-2 infection in humans and is characterized by a much higher level of IL-10, IL-1β, IL-18 and IFN-γ , whereas in B.1.351 re-infected K18-hACE2 mice, the cytokine profile echoes the signature of naïve mice undergoing viral infection for the first time. Interestingly, the enhanced pathology observed in 129S1 mice upon reinfection cannot be attributed to a less efficient induction of adaptive immune responses to the initial BA.1 infection, as both K18-hACE2 and 129S1 mice exhibited similar B and T cell responses at 30 DPI against BA.1, with similar anti-BA.1 or B.1.351 spike-specific ELISA binding titers, levels of germinal center B-cells, and SARS-CoV-2-Spike specific tissue-resident T-cells. Long-term effects of BA.1 infection are associated with differential transcriptional changes in bronchoalveolar lavage-derived CD11c+ immune cells from K18-hACE2 and 129S1, with K18-hACE2 CD11c+ cells showing a strong antiviral defense gene expression profile whereas 129S1 CD11c+ cells showed a more pro-inflammatory response. In conclusion, initial infection with BA.1 induces cross-reactive adaptive immune responses in both K18-hACE2 and 129S1 mice, however the different disease outcome of reinfection seems to be driven by differential responses of CD11c+ cells in the alveolar space.

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Upregulation of inflammatory genes and pathways links obesity to severe COVID-19

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