Molecular mimicry in multisystem inflammatory syndrome in children

• 成果类型: Article
• 署名作者: Bodansky, Aaron; Mettelman, Robert C.; Sabatino, Joseph J., Jr.; Vazquez, Sara E.; Chou, Janet; Novak, Tanya; Moffitt, Kristin L.; Miller, Haleigh S.; Kung, Andrew F.; Rackaityte, Elze; Zamecnik, Colin R.; Rajan, Jayant, V; Kortbawi, Hannah; Mandel-Brehm, Caleigh; Mitchell, Anthea; Wang, Chung-Yu; Saxena, Aditi; Zorn, Kelsey; Yu, David J. L.; Pogorelyy, Mikhail, V; Awad, Walid; Kirk, Allison M.; Asaki, James; Pluvinage, John, V; Wilson, Michael R.; Zambrano, Laura D.; Campbell, Angela P.; Thomas, Paul G.; Randolph, Adrienne G.; Anderson, Mark S.; DeRisi, Joseph L.
• 署名单位: University of California System; University of California San Francisco; St Jude Children's Research Hospital; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Chan Zuckerberg Initiative (CZI); University of California System; University of California San Francisco; University of California System; University of California San Francisco; Centers for Disease Control & Prevention - USA; Centers for Disease Control & Prevention - USA; University of California System; University of California San Francisco
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6927
• DOI: 10.1038/s41586-024-07722-4
• 发表日期: 2024-08-15
• 页码: 622-+
• 关键词: autoreactive t-cells; define

摘要

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection(1,2), yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.