(L to R) Co-senior author Paul Thomas, PhD, and co-first author Robert Mettelman, PhD, St. Jude Department of Host-Microbe Interactions.
St. Jude Children’s Research Hospital scientists have identified a link between a SARS-CoV-2 protein and the onset of multisystem inflammatory syndrome in children (MIS-C). MIS-C is a pediatric disorder characterized by widespread inflammation throughout the body. The new findings describe a case of molecular mimicry, where a section of a protein from SARS-CoV-2 closely resembles the human protein SNX8, confusing the immune system and sparking inflammation. The findings were published today in Nature.
The researchers found that a region of the SARS-CoV-2 nucleocapsid (N) protein shares high sequence and immunogenic similarities to SNX8, a protein predominantly expressed in immune cells. Consequently, the human immune system that reacts to N mistakes SNX8 as an invader and triggers an inflammatory response. Understanding this mimicry mechanism, the elements of the immune system that are involved, and why it occurs in a subset of children could help physicians better address MIS-C.
Before the study, clinicians had observed that MIS-C typically manifests after SARS-CoV-2 (COVID) infection, but whether the onset was connected to SARS-CoV-2 infection was unknown. “MIS-C has been recognized as a problem downstream of SARS-CoV-2 infection in children since the beginning of the pandemic, and it's very similar to other post-viral inflammatory conditions that have evaded understanding in terms of etiology for a number of years,” said co-senior author Paul Thomas, PhD, St. Jude Department of Host-Microbe Interactions.
Reflecting on the clinical impact, co-senior author Adrienne Randolph, MD, MSc, Boston Children’s Hospital, noted, “Every time COVID peaked in an area, about 30 days later, there would be a peak of children presenting with what looked like septic shock in our network of ICUs, except they were negative for all kinds of infection. If we hadn’t intervened and supported them, they could have died.”
This is the first study to identify molecular mimicry as one of the immunological mechanisms behind the development of MIS-C. “Understanding this mechanism going forward may help improve diagnosis and treatment,” Thomas added.
Molecular mimic linking SARS-CoV-2 infections and MIS-C
Believing that there may be a link between SARS-CoV-2 proteins and the syndrome, the researchers used samples from patients with MIS-C to identify autoantigens (self proteins recognized by the immune system which trigger an autoimmune response) associated with the condition. They found candidate autoantigens derived from SNX8, ERFL and KDELR1 proteins. SNX8 plays a role in regulating the antiviral pathway associated with MIS-C pathogenesis, making it the prime suspect.
Scientists identified a part of SNX8 that is structurally similar to SARS-CoV-2 N that stimulates an autoimmune response in cases of MIS-C. This finding provides evidence of molecular mimicry as a mechanism contributing to MIS-C and connects SARS-CoV-2 infection with the onset of MIS-C.
“The biggest takeaway is that our study now directly links the disease with components of the actual SARS-CoV-2 virus,” said co-first author and postdoctoral fellow Robert Mettelman, PhD, St. Jude Department of Host-Microbe Interactions.
Echoing this sentiment, co-senior author Joseph DeRisi, PhD, University of California San Francisco, stated, "We've identified the smoking gun – what made these kids so sick. This discovery opens the door to understanding why so many of these post-infectious, horribly inflammatory autoimmune events occur.”
While this research marks a significant breakthrough in understanding MIS-C, its implications extend beyond the specific disorder. “There are other diseases that are similar to MIS-C,” Mettelman added. “The immune mechanism we describe can be explored in additional autoimmune and inflammatory contexts where a viral infection is thought to trigger disease onset.”
These findings showcase a bright future for the improved diagnosis and treatment of MIS-C. “We are trying to understand the relationship between these responses and the full development of the disease,” Thomas said. “We are aiming to see if there is a diagnostic setting where we could use this to predict who's going to develop this disease and if early interventions can be applied.”
Authors and funding
The study’s other authors are Mikhail Pogorelyy, Walid Awad, and Allison Kirk, St. Jude; Aaron Bodansky, Joseph Sabatino, Jr., Colin Zamecnik, John Pluvinage, Michael Wilson, Sara Vazquez, Haleigh Miller, Andrew Kung, Elze Rackaityte, Jayant Rajan, Hannah Kortbawi, Caleigh Mandel-Brehm, Kelsey Zorn, David Yu, James Asaki, Matt Zinter, Mark Anderson, and Joseph DeRisi, University of California San Francisco; Janet Chou, Harvard Medical School; Kristin Moffitt and Adrienne Randolph, Harvard Medical School and Boston Children’s Hospital; Tanya Novak, Boston Children’s Hospital and Harvard Medical School; Anthea Mitchell, Chung-Yu Wang, and Aditi Saxena, Chan Zuckerberg Biohub SF; Laura Loftis, Baylor College of Medicine; Charlotte Hobbs, University of Mississippi Medical Center; Keiko Tarquinio, Emory University; Michele Kong, University of Alabama at Birmingham; Julie Fitzgerald, University of Pennsylvania, Paula Espinal, Nicklaus Children’s Hospital; Tracie Walker and Stephanie Schwartz, University of North Carolina at Chapel Hill Children’s Hospital; Hillary Crandall, University of Utah and Primary Children’s Hospital; Katherine Irby, Arkansas Children’s Hospital; Mary Allen Staat, Cincinnati Children’s Hospital Medical Center; Courtney Rowano, Indiana University School of Medicine and Riley Hospital for Children; Jennifer Schuster, Children’s Mercy Kansas City; Natasha Halasa, Vanderbilt University; Shira Gertz, Cooperman Barnabas Medical Center; Elizabeth Mack, Medical University of South Carolina; Aline Maddux, University of Colorado School of Medicine and Children’s Hospital; Natalie Cvijanovich, UCSF Benioff Children’s Hospital; Laura Zambrano and Angela Campbell, Centers for Disease Control and Prevention; and the Overcoming COVID-19 Network Study Group Investigators.
The study was supported by the Pediatric Scientist Development Program and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12-HD000850), the Centers for Disease Control and Prevention (75D30120C07725, 75D30121C10297 and 75D30122C13330), the National Institute of Allergy and Infectious Diseases (R01AI154470, 5R01AI154470-03, 2R01AI136514-06, and 3P01AI165077-01S1 ), the Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship award (F32AI157296), and ALSAC, the fundraising awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.