Obesity-Induced Metabolic Priming Exacerbates SARS-CoV-2 Inflammation

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Davanzo, Gustavo Gastao ; Castelucci, Bianca Gazieri ; de Souza, Gabriela Fabiano ; Muraro, Stefanie Primon ; dos Reis, Larissa Menezes ; de Oliveira, Isabella Bonilha ; Fachi, Jose Luis ; Virgilio-da-Silva, Joao Victor ; Bercot, Marcelo Rodrigues ; Fernandes, Mariane Font ; de Oliveira, Sarah ; Araujo, Nathalia Vitoria Pereira ; Ribeiro, Guilherme ; de Castro, Gisele ; Costa, Webster Leonardo Guimaraes ; Santoro, Adriana Leandra ; Rodrigues-Luiz, Gabriela Flavia ; do Carmo, Helison Rafael P. ; Breder, Ikaro ; Mori, Marcelo A. ; Farias, Alessandro S. ; Martins-de-Souza, Daniel ; Guarnieri, Joseph W. ; Wallace, Douglas C. ; Vinolo, Marco Aurelio Ramirez ; Proenca-Modena, Jose Luiz ; Beheshti, Afshin ; Sposito, Andrei C. ; Moraes-Vieira, Pedro M.

• Document type: Journal article
• Source: IMMUNOLOGY; v. 175, n. 3, p. 16-pg., 2025-04-23.

Abstract

Despite the early recognition that individuals living with obesity are more prone to develop adverse outcomes during COVID-19, the mechanisms underlying these conditions are still unclear. During obesity, an accumulation of free fatty acids (FFAs) in the circulation promotes low-grade inflammation. Here, we show that FFAs induce epigenetic reprogramming of monocytes, exacerbating their inflammatory profile after SARS-CoV-2 infection, a mechanism named metabolic-primed immunity. Monocytes from people with obesity or primed with palmitate, a central component of circulating FFAs, presented elevated viral load and higher gene expression of IL-6. Palmitate-primed monocytes upregulate fatty acid oxidation and FFAs entry into the mitochondria. FFA-derived acetyl-CoA is then converted into citrate, exiting the mitochondria and is used to support H3K18 histone acetylation, which regulates IL-6 accessibility. Ingestion of palm oil by lean and healthy individuals increased circulating FFAs levels and was sufficient to exacerbate the inflammatory profile of monocytes upon SARS-CoV-2 infection. Our findings demonstrate that obesity-derived FFAs induce the metabolic priming of monocytes, which exacerbates the inflammatory response observed in people with severe COVID-19. (AU)

• FAPESP's process: 21/08354-2 - The interplay between the immune system and metabolism as a key determinant of the aging process
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 20/16030-0 - Immunometabolic adaptation of tissue resident macrophages in health and disease
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/04579-7 - Study of the risk factors associated with greater severity to COVID-19 and mapping of the metabolic pathways required for the anti-SARS-CoV-2 response
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 16/18031-8 - HIF-1 alpha in metabolic and functional control of adipose tissue resident macrophages in diabetes induced by obesity
• Grantee: Gustavo Gastão Davanzo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/15313-8 - Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation
• Grantee: Marco Aurélio Ramirez Vinolo
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2