2. Academic Validation
  3. Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19

Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19

  • Sci Immunol. 2023 Feb 23;eadf0348. doi: 10.1126/sciimmunol.adf0348.
Bibo Zhu 1 2 3,  Xiaoqin Wei 1 2 3,  Harish Narasimhan 1 4,  Wei Qian 1 2,  Ruixuan Zhang 1 2 3,  In Su Cheon 1 2 3,  Yue Wu 1 2 3,  Chaofan Li 1 2 3,  Russell G Jones 5,  Mark H Kaplan 6,  Robert A Vassallo 4,  Thomas J Braciale 1 7,  Lindsay Somerville 8,  Jerry R Colca 9,  Akhilesh Pandey 10 11,  Patrick E H Jackson 2,  Barbara J Mann 2 4,  Connie M Krawczyk 5,  Jeffrey M Sturek 8,  Jie Sun 1 2 3 4
Affiliations

Affiliations

  • 1 Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA.
  • 2 Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
  • 3 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • 4 Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
  • 5 Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA.
  • 6 Department of Microbiology and Immunology, Indiana University of School of Medicine, Indianapolis, IN 46202, USA.
  • 7 Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
  • 8 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
  • 9 Cirius Therapeutics, Kalamazoo, MI 49007, USA.
  • 10 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • 11 Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
PMID: 36821695 DOI: 10.1126/sciimmunol.adf0348
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.

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