Scientists have finally unravelled one of the enduring mysteries of the pandemic – and what caused some children to develop a severe inflammatory syndrome weeks after a Covid infection, landing many of them in ICUs.
The condition, called multi-system inflammatory syndrome, or MIS-C, is serious but rare. Early in the pandemic, children began arriving in emergency departments with symptoms that included persistent high fevers, vomiting, fatigue and heart inflammation.
Some needed intensive care and ventilators, reports NPR.
“They’d come to the ICU because they also had inflammation of their hearts, which weren’t able to pump enough to get blood to all of the organs in their body and keep them alive. So it’s really a very serious disease,” recalled Dr Aaron Bodansky, an assistant professor of paediatrics at the University of California-San Francisco School of Medicine.
At the time, Bodansky said, doctors could not answer a pressing question for families: why is this happening? He said they knew the syndrome had to be related to Covid, but they didn’t know how.
Now, researchers finally have discovered what led to many of these cases.
Out-of-control reaction
As Bodansky and his colleagues report in the journal Nature, many children who developed MIS-C had an out-of-control immune response to Covid as a result of mistaken identity. Basically, their immune systems locked on to a part of the coronavirus that closely resembles a protein found in immune cells throughout the body.
That caused the immune system to mistakenly target itself instead of the virus, said Joe DeRisi, president of Chan Zuckerberg Biohub San Francisco, and a senior author of the study. “And that causes inflammation, we believe, to spin out of control.
“Think of it like collateral damage or friendly fire.”
The study drew on samples collected from patients with MIS-C through a national network of paediatric ICUs called Overcoming Covid-19. The researchers analysed those samples using a sophisticated sequencing technology that allowed them to identify the targets of past immune responses.
DeRisi said it essentially allowed them to ask, “What are your antibodies seeing in you?”
A particular protein
The analysis revealed that a third of the MIS-C cases had autoantibodies to a protein called SNX8, which is part of the body’s normal antiviral response and is found in immune cells all over the body, said Bodanksy.
A second analysis found that protein turned out to look a lot like a part of the coronavirus. In children who developed MIS-C, their immune systems happened to latch on to that section of the coronavirus as a target, which led them to also produce autoantibodies that targeted SNX8.
A further analysis, conducted with collaborators at St Jude Children’s Research Hospital, looked at the T-cells in youngsters who developed MIS-C.
Killer T-cells normally attack invaders in the body. But the analysis revealed that in children with MIS-C, their T-cells couldn’t tell the difference between the body’s own immune cells and the virus, DeRisi said.
At the height of the pandemic, only a small subset of children – about one out of every 2 000 – who got infected with Covid went on to develop MIS-C. Most recovered fully.
More rare today, but still happening
These days, the condition is even rarer and occurs mostly in unvaccinated children, said DeRisi.
But Bodanksy notes that some children still develop life-threatening immune responses after other infections.
He hopes their work will inspire other researchers to use novel tools to better understand those cases, too.
“We can, if we focus, find answers and understand specifically what is happening in these children, if we have the will to do it.”
Study details
Molecular mimicry in multisystem inflammatory syndrome in children
Aaron Bodansky, Robert Mettelman, Joseph Sabatino Jr et al.
Published in Nature on 7 August 2024
Abstract
Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, 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.
Nature article – Molecular mimicry in multisystem inflammatory syndrome in children (Open access)
See more from MedicalBrief archives:
Severe multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection
Two US research reports on multi-system inflammation syndrome in children
Children with multi-system inflammatory syndrome post-COVID-19 — Small UK study