Citations 2
Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae
Wei, Xiaoqin , Qian, Wei , Narasimhan, Harish , Chan, T. K., Liu, Xue , Arish, Mohd , Young, Scott , Li, Chaofan , Cheon, In Su , Yu, Qing , Santos, Gislane de Almeida , Yeatts, Eric V., Spear, Olivia J., Yi, Mou, Hahn, Young S. , Kaplan, Mark H. , Sperling, Anne I. , Shim, Yun M. , Vassallo, Robert , Chen, Peter , Roden, Anja C. , Que, Jianwen , Chan, Ting , Young, Samuel , de Almeida Santos, Gislane , Zhao, Xiao-Yu , Yeatts, Eric V , Parimon, Tanyalak , Fang, Yinshan , Hahn, Young S , Bullock, Timothy N J , Somerville, Lindsay A , Kaplan, Mark H , Sperling, Anne I , Shim, Yun Michael , Vassallo, Robert , Chen, Peter , Ewald, Sarah E , Roden, Anja C , Que, Jianwen , Jiang, Dianhua , Sun, Jie , Li, Chaofan , Yi, Megan, Somerville, Lindsay , Sun, Jie
Science | March 6, 2025 | Volume: 387 | Issue: 6738 | Pages: No page available
Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8 high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.
Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19
Zhu, Bibo , Wei, Xiaoqin , Narasimhan, Harish , Qian, Wei , Zhang, Ruixuan , Cheon, In Su , Wu, Yue , Li, Chaofan , Jones, Russell G. , Kaplan, Mark H. , Vassallo, Robert , Braciale, Thomas J. , Somerville, Lindsay , Colca, Jerry R. , Pandey, Akhilesh , Jackson, Patrick , Mann, Barbara J. , Sun, Jie , Vassallo, Robert , Jackson, Patrick E H , Krawczyk, Connie M , Sturek, Jeffrey M , Sun, Jie , Pandey, Akhilesh , Kaplan, Mark H , Jones, Russell G , Li, Chaofan , Somerville, Lindsay A , Zhang, Ruixuan
Science Immunology | February 23, 2023 | Volume: 8 | Issue: 82 | Pages: No page available
The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (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 hyperinflammation, 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 after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor–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 after 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.