Researchers and clinicians recognized early in the pandemic that COVID-19 has a highly variable clinical course that ranges from asymptomatic carriage to mild infection, catastrophic organ damage, and death. Host factors appear to play key roles in the response to SAR-CoV-2 exposure.
“Different age groups are clearly affected differently by COVID-19,” said Dusan Bogunovic, PhD, Professor and Director of the Center for Inborn Errors of Immunity at the Icahn School of Medicine at Mount Sinai. “Initially, we thought that children were not affected by severe forms of the disease. Then children with Kawasaki-like symptoms began to present two or three months into the pandemic.”
Children who presented with what initially looked like Kawasaki disease had multisystem inflammatory syndrome in children (MIS-C), a novel pediatric inflammatory syndrome that included severe hyperinflammation and hemodynamic instability.
Dr. Bogunovic described the latest immune profile findings in MIS-C and Qian Zhang, MD, discussed type I interferon (IFN) response in severe COVID-19 during the session, Host Factors in COVID-19: Genetics, Immune Profiles & Autoantibodies, which was originally presented on Sunday, Nov. 7, and can be viewed by registered meeting participants through March 11, 2022.
Starting with an initial cohort of nine MIS-C patients, Dr. Bogunovic and his colleagues discovered that the serology of MIS-C is nearly identical to convalescent COVID-19, and MIS-C plasma powerfully neutralizes SARS-CoV-2 infection in vitro. At the same time, cytokine profiling showed a unique signature with robust upregulation of inflammatory, chemotactic, and mucosal immune cytokines. Overexpression of IL-6, CCL19, CCL3, and IL-17A indicated myeloid cell chemotaxis and mucosal inflammation, he explained.
High-dimensional immunophenotyping showed immune cell activation and egress to the periphery, Dr. Bgounovic continued. Mass cytometry revealed dendritic cell, non-classical monocyte, and lymphocyte activation and movement to the periphery. And at least half of the patients showed elevated levels of CD54 and CD64.
Autoantibody analysis showed increased production of autoantibodies that target organ systems central to MIS-C pathology, including the gastrointestinal tract, immune cells, cardiac and endothelial tissues, and known autoantigens. Primary targets include regulation of immune response, cell-cell adhesion, and pathways involved in the perception of smell. Protein analysis of 192 surface markers revealed 20 distinct clusters that suggest T-cell activation, but the mechanisms that underlie MIS-C immune profiles remain unclear, Dr. Bogunovic said.
IFN pathway and severe COVID-19
Multiple centers that are part of the global COVID Human Genetic Effort looking into host genetic factors found that defective type I interferon (IFN) response explains about 20% of life-threatening COVID-19 pneumonia. The defective response can be the result of genetic variants, either inherited or somatic, or age-related development of autoantibodies to type I IFNs, explained Dr. Zhang, a researcher at St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, and Necker Hospital for Sick Children in Paris, France.
“It was clear from the start that there was great variability in COVID-19 severity. We soon saw that inborn errors of type I IFN immunity underlie life-threatening COVID-19 pneumonia,” she said.
Respiratory epithelial cells that are deficient in the membrane protein IFNAR1 fail to produce type I IFNs, Dr. Zhang explained, leaving the cells less able to fight off SARS-CoV-2 infection. One contributor to IFNAR1 deficiency is a genetic variant in IRF7, a transcription factor present in plasmacytoid dendritic cells that is important in the activation of type I IFNs. X-linked recessive TLR7 variants can also contribute to type I IFN deficiency.
A defective TLR7 allele occurs in about six males per 100,000 and has been identified in more than 1% of young men with life-threatening COVID-19, Dr. Zhang said. Other variants in the type I IFN pathway can also contribute to type I IFN deficiency. But the cumulative effect of these variants is not enough to explain millions of COVID-19 deaths, she said.
Anti-cytokine autoantibodies fill part of the mortality gap.
Autoantibodies to cytokines are not unique to COVID-19, Dr. Zhang noted. Rheumatologists have known since the 1980s that patients with lupus and antiphospholipid syndrome-1 treated with IFNs can develop autoantibodies. More recent work has shown that autoantibodies to IFN-g leave the host more vulnerable to mycobacterial disease; autoantibodies to IL-17A and IL-17F contribute to candidiasis; and autoantibodies to IL-6 can worsen staphylococcal disease.
Neutralizing anti-type I IFN autoantibodies are present in 20% of patients with critical or severe COVID-19 and more than 18% of patients who died from COVID-19 are anti-type I IFN autoantibody positive, Dr. Zhang said. Autoantibodies to type I IFN are present before COVID-19 and are enriched in older adults, particularly older men. Deficient IFN response can also contribute to more severe influenza infection and impaired response to attenuated viral vaccines, such as measles and yellow fever.
“Autoantibody prevalence is low and steady in the general population until about age 60, then shows a sharp increase between 60 and 70,” Dr. Zhang said. “Type I IFN response is essential to control COVID-19 infection. That increase in autoantibodies leaves older people very susceptible to severe COVID-19.”