Research links inflammatory proteins with COVID-19 severity
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Investigators have identified inflammatory proteins, known as neutrophil extracellular traps, that may contribute to the onset of cardiac complications among patients with COVID-19 infection, according to study results published in Blood.
“Our studies in experimental models of sepsis have shown that inhibition of neutrophil extracellular traps [NET] formation using neonatal NET-inhibitory factor [nNIF] improves survival and illness severity among patients with COVID-19,” Christian Con Yost, MD, associate professor in the department of pediatrics at University of Utah Health, told Healio. “We therefore decided to explore the role of NET formation in COVID-19 infection, given the reports of critical illness and blood clotting that leads to death of ICU patients due to acute respiratory distress syndrome.”
Con Yost spoke with Healio about what prompted this study, the clinical implications of the findings and the next steps for research on this topic.
Question: What prompted this study?
Answer: My laboratory group studies the role of NETs in neonatal and adult sepsis, as well as other inflammatory syndromes such as inflammatory bowel disease and stroke. NETs are generated by a regulated cell death pathway for certain white blood cells, such as neutrophils, and are part of the innate immune response to infection. In short, a neutrophil initiates cell death in a certain way that leads to decondensation of the usually tightly packed DNA in the nucleus, mixes it with the antimicrobial factors contained in the cytoplasm and spews it out into the extracellular space, where it can trap and kill bacteria. NETs form a three-dimensional lattice that traps microbes with the very sticky DNA and kills them using the antimicrobial factors decorating the strands of DNA. It is a sort of kamikaze approach to cell death, and the neutrophil aims to take as many microbes with it as it dies.
However, many have written about the “dark side” of NET formation. Dysregulated NET formation — too much in the wrong place at the wrong time — participates in the pathogenesis of many inflammatory syndromes such as sepsis, atherosclerosis, cancer, thrombosis and autoimmune diseases, such as lupus and stroke. Our studies examining NET formation by the neutrophils of newborn babies led us to discover an endogenous inhibitor of NET formation that circulates in the bloodstream of babies before birth. The 29 amino acid peptide generated by the placenta, nNIF, robustly inhibits NET formation by neutrophils.
Q: What are the implications of the findings?
A: This paper is the first prospective study to correlate NET formation with COVID-19 disease severity. We believe that NET formation in blood of patients may serve as a biomarker for COVID-19 severity. Furthermore, our elucidation of NET-associated clotting and platelets and prothrombotic factors leading to clots suggests that these clots may be more resistant to anticoagulants, such as heparin.
We additionally tested nNIF in polymorphonuclear leukocytes stimulated to form NET by incubation with COVID-19 patient plasma. We found that COVID-19 patient plasma induced NETs robustly by neutrophils isolated from healthy adults, but that pretreatment with nNIF blocked NET formation in these in vitro experiments. This suggests that nNIF might have potential to improve thrombosis and sepsis outcomes among patients with COVID-19. We have partnered with a Utah biotechnology company to study nNIF as a potential treatment for COVID-19 infection.
Q: Did any of your findings surprise you?
A: The findings are very consistent with results in other models of infection. However, one surprising finding was that COVID-19 plasma contained significant amounts of prothrombotic and NET-inducing factors. We have studied plasma from patients with sepsis from non-SARS-CoV-2 infections and have not seen this degree of NET induction or propensity to blood clotting. We now plan to study the COVID-19 patient plasma in detail to find out why this is so.
Q: Are there plans for additional research on this?
A: Our initial cohort in COVID-19 remains small, which is a weakness of the current study. We plan to continue to enlarge our cohort and further solidify the correlations between NETs, blood clotting and COVID-19 disease severity. We also are responding to the NIH call for grant proposals to study COVID-19 and SARS-CoV-2 infection with a plan to comprehensively study neutrophil activation and NET formation, platelet gene expression and activation, and the use of nNIF to improve outcomes in animal models of SARS-CoV-2 infection. We have research partners at the Institute for Antiviral Studies at Utah State University, Cold Spring Harbor Laboratories in New York and PEEL Therapeutics Inc. — a Utah biotechnology company aiming to develop NET-inhibitory peptides as a treatment for COVID-19 and other inflammatory diseases, such as sepsis or cancer.
For more information:
Christian Con Yost, MD, can be reached at University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132; email: christian.yost@u2m2.utah.edu.
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