As COVID-19 cases increase across the country, researchers have started to solve one of the lingering mysteries from the early days of the pandemic – why some children suddenly went into organ failure after seemingly fighting off the virus.
This phenomenon was dubbed multisystem inflammatory syndrome in children (MIS-C), according to UCSF. While many of the children recovered from the condition with aggressive treatment, most doctors were in the dark about what caused it until a study was published this week in the Nature journal.
A team of scientists from UC San Francisco, Chan Zuckerberg Biohub San Francisco, St. Jude Children’s Research Hospital and Boston Children’s Hospital worked on the study. UCSF said its implications go beyond just COVID-19 and may help treat other autoimmune diseases.
“The researchers found that the children’s immune systems had latched onto a part of the coronavirus that closely resembles a protein found in the heart, lungs, kidneys, brain, skin, eyes and GI tract, and launched a catastrophic attack on their own tissues,” explained the hospital.
During the pandemic, MIS-C affected around one in every 2,000 children under age 18 with COVID.
“Every time COVID peaked in an area, about 30 days later, there’d be a peak of these kids presenting with what looked like septic shock in our network of ICUs, except they were negative for all kinds of infection,” said Adrienne Randolph, a critical care pediatrician at Boston Children’s Hospital and co-senior author of the study. “If we hadn’t intervened and supported them, they could have died.”
Randolph tracked the cases, collected samples from a national network of pediatric ICUs and founded the Overcoming COVID-19 project. Co-senior author Mark Anderson, who directs the Diabetes Center at UCSF and is a CZ Biohub SF Investigator, suggested that Aaron Bodansky, a critical care fellow in UCSF’s Department of Pediatrics and lead author of the paper, use the Phage Immunoprecipitation Sequencing (PhIP-Seq) to further investigate the samples.
Joe DeRisi, president of Chan Zuckerberg Biohub San Francisco and corresponding author “had already used PhIP-Seq to understand severe neurological symptoms, as well as the link between viral infections and multiple sclerosis,” said UCSF.
“We thought, could there be some sort of trigger with the immune system that leads to MIS-C?” Anderson said. So, they used the tool – which screens blood for autoantibodies – to compare samples from children who did develop the condition to those who did not.
With the PhIP-Seq, they found that one third of the MIS-C cases had autoantibodies that attacked an obscure human protein called SNX8. Though obscure, the protein is found throughout the body.
“The scientists spent months hunting for a link between these autoantibodies and SARS-CoV-2. Then, late one night while looking at SNX8 on his computer screen with Bodansky, DeRisi had a flash of insight,” UCSF explained. “What if the human protein resembled a portion of SARS-CoV-2’s N protein?”
When they found a match, it blew their minds, said DeRisi.
“Next, the team screened the MIS-C kids’ antibodies against proteins from the virus,” UCSF continued. “The antibodies were targeting the very part of the N protein that matched SNX8. But antibodies from the healthy kids targeted other parts of the N protein that did not resemble a human protein.”
Since SNX8 is hidden inside cells and antibodies only go after threats floating in the blood, the team suspected that killer T cells were involved in the autoimmune reaction. These cells screen the content of human cells to destroy infections.
UCSF called it a “case of mistaken molecular identity.”
Indeed, Joe Sabatino, UCSF professor of neurology and co-author of the paper, found that some T cells from the MIS-C patients did seem to target SNX8. Paul Thomas, professor of host-microbe interactions at St. Jude, and his team also screened T cells from some of the MIS-C patients for matches with human SNX8 and the viral N protein.
“Just taking these T-cells from patients directly, without any expansion, we found clusters of T cells that were specific for these two different target proteins,” said Thomas, a co-senior author of the paper. “It gives us an overwhelming amount of confidence that this response, associated with the autoantibody profile, is naturally elicited in a subset of these patients.”
ICUs now see only a few cases of MIS-C per year, said UCSF. However, there has been a recent spike in COVID cases in people of all ages across the country, according to U.S. Centers for Disease Control and Prevention data.
“This summer we’re having an incredibly large COVID-19 infection wave,” U.S. Epidemiologist and data scientist, Dr. Katelyn Jetelina told WWJ this week. “I think it’s surprised a lot of us epidemiologists and scientists, and in fact, it’s as big as our typical winter wave. Thankfully… because immunity has been building up where our hospitals are not overflowing, but those that are most vulnerable, those that haven’t been up to date on their COVID vaccines are still going to the hospital. And unfortunately, we’re seeing about 600 deaths per week.”
In addition to helping children who develop MIS-C, researchers said the recent study findings may be a key to unlocking other autoimmune conditions.
“We hope this kind of approach can help break new ground in understanding similar diseases of immune dysregulation that have stumped us for decades, like multiple sclerosis or type 1 diabetes,” said Bodansky.