Are overactive immune cells causing COVID-19-related deaths?

Are overactive immune cells causing COVID-19-related deaths?

Asthma and coronavirus disease - COVID-19 The reason, according to the NETwork, is that immune cells called neutrophils, which are among the most abundant of white blood cells, become overactive. These cells usually detect the presence of bacteria. To counter these invaders, the neutrophils shoot out part of their DNA content in a filmy web enriched with destructive enzymes. This is called a NET and can trap bacteria and digest them. However, excessive NET production is linked to ARDS, because of the accompanying damage they cause to the lungs. What are NETs? NETs are composed of segments of DNA along with globular protein domains in threadlike form. These gather to form larger, thicker strands that can form networks. The presence of NETs allows neutrophils to kill microbes outside the cell while minimizing host cell damage. The kill is accomplished by antimicrobial proteins like neutrophil elastase, cathepsin G, and histones, all of which bind closely to DNA. These are present at high concentrations in the NET, to attach to the entangled microbe, disarm it and destroy it. The NETs may also serve the purpose of walling off the bacteria to prevent its spread. Finally, the sequestration of these toxic proteases in the NET keeps them from damaging nearby healthy tissue. The hypothesis is driven by the many similar features shared by ARDS, a condition known to be caused by NETs, and severe COVID-19. Says researcher Betsy Barnes, “As samples from patients become available, it will be important to determine whether the presence of NETs associates with disease severity and particular clinical characteristics of COVID-19.” Tracing the role of NETs in disease and death Another researcher, Mikala Egeblad, traces the first report of NETs back to 2004. However, she notes, they are still unfamiliar to most people, including many scientists. The NETwork includes people who have already been researching NETs in relation to other medical conditions. The clinical description of severe or critical COVID-19 disease rang alarm bells for these scientists, therefore. Another scientist at the RI-MUHC, Jonathan Spicer, says NETs are also found to occur in patients with cancer or sepsis (the occurrence of infection in the bloodstream and seeding to multiple organs), conditions which are also associated with the presence of these microthrombi or small blood clots. How is the finding useful? The consortium is now analyzing the presence of NETs in COVID-19 samples. If, as they think, the overactivation of neutrophils leading to excessive production of NETs is responsible for severe clinical cases of COVID-19, it may indicate a new line of treatments to produce an improvement in their condition. For instance, they could explore the role and efficacy of medications used in other illnesses that involve NET, as well as in other conditions that result from neutrophil activity, such as cystic fibrosis, rheumatoid arthritis (RA) and gout. Autoimmune diseases like RA could be the result of exposure of histone complexes outside the cell, stimulating antibody production. They also play a role in abnormal clot formation and are linked to the occurrence of stroke. Such drugs could conceivably reduce NET activity in patients with severe COVID-19, limiting the need for mechanical ventilation and making healthcare available for a more significant number of patients with this condition. Journal reference: Betsy J. Barnes, Jose M. Adrover, Amelia Baxter-Stoltzfus, Alain Borczuk, Jonathan Cools-Lartigue, James M. Crawford, Juliane Daßler-Plenker, Philippe Guerci, Caroline Huynh, Jason S. Knight, Massimo Loda, Mark R. Looney, Florencia McAllister, Roni Rayes, Stephane Renaud, Simon Rousseau, Steven Salvatore, Robert E. Schwartz, Jonathan D. Spicer, Christian C. Yost, Andrew Weber, Yu Zuo, Mikala Egeblad; Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med 1 June 2020; 217 (6): e20200652. doi: https://doi.org/10.1084/jem.20200652



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