Title |
Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19
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Published in |
Science Immunology, April 2023
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DOI | 10.1126/sciimmunol.adf0348 |
Pubmed ID | |
Authors |
Bibo Zhu, Xiaoqin Wei, Harish Narasimhan, Wei Qian, Ruixuan Zhang, In Su Cheon, Yue Wu, Chaofan Li, Russell G. Jones, Mark H. Kaplan, Robert A. Vassallo, Thomas J. Braciale, Lindsay Somerville, Jerry R. Colca, Akhilesh Pandey, Patrick E. H. Jackson, Barbara J. Mann, Connie M. Krawczyk, Jeffrey M. Sturek, Jie Sun |
Abstract |
The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, SARS-CoV-2 infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyper-inflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease following influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized HIF-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development following SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 43 | 28% |
United Kingdom | 7 | 5% |
Japan | 6 | 4% |
India | 4 | 3% |
Canada | 4 | 3% |
Germany | 3 | 2% |
France | 3 | 2% |
Mexico | 2 | 1% |
Chile | 1 | <1% |
Other | 9 | 6% |
Unknown | 71 | 46% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 111 | 73% |
Scientists | 34 | 22% |
Practitioners (doctors, other healthcare professionals) | 6 | 4% |
Science communicators (journalists, bloggers, editors) | 2 | 1% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 33 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Master | 5 | 15% |
Researcher | 4 | 12% |
Student > Ph. D. Student | 4 | 12% |
Student > Bachelor | 3 | 9% |
Professor > Associate Professor | 2 | 6% |
Other | 4 | 12% |
Unknown | 11 | 33% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 6 | 18% |
Immunology and Microbiology | 5 | 15% |
Chemical Engineering | 2 | 6% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 6% |
Unspecified | 2 | 6% |
Other | 5 | 15% |
Unknown | 11 | 33% |