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Neutrophil Explosion Creates a Web-Like Sticky Trap For Viruses Like SARS-CoV-2

Immunologists have uncovered the underlying mechanisms of IgA antibodies in neutralising viruses – through the activation of NETosis cell death and formation of sticky “spider-web” traps that catch and inactivate viral pathogens.

With the advent of COVID-19, vaccine development and delivery have been expedited at an unprecedented scale and speed to accommodate the global demand for immediate protection against the virus. Today, most vaccines against SARS-CoV-2 are being administered through injections, which are designed to quickly and efficiently boost antibody production in the bloodstream.

However, as a consequence, the antibodies are not as prevalent at sites where infections usually begin – the respiratory tract. To fill the gaps of present vaccination methods, scientists have been innovating strategies to boost antibody production against mucosal pathogens at infection-prone sites.

Recently, immunologists from McMaster University have uncovered the underlying processes of a “spider web” immune mechanism that traps and kills viral pathogens in the respiratory tract. Published in the Proceedings of the National Academy of Sciences, the study documents the process by which neutrophils, the most abundant white blood cells in the human body, explode when they bind to IgA antibodies that coat pathogens, thereby releasing DNA outside of the cell and creating a sticky tangle trap. This new knowledge is expected to help prevent infections before they even set in.

“Mechanisms that can stop the infection at the site where it enters our body can prevent the spread and serious complications,” explained the lead author of the study, Matthew Miller, who is also an associate professor at McMaster’s Michael G. DeGroote Institute for Infectious Disease Research and Canada’s Global Nexus for Pandemics and Biological Threats.

Up until recently, the process by which IgA antibodies neutralise viral pathogens has remained elusive. However, through extensive investigation, the team has successfully demonstrated how IgA-virus immune complexes stimulate neutrophils to undergo NETosis, an inflammatory type of programmed cell death that involves the release of neutrophil extracellular traps (NETs). These NETs are made of chromatin studded with antimicrobial effector proteins and have been shown to effectively trap and inactivate viruses.

Their study also reported that the potentiation of NETosis is not virus-specific, and so can be induced by lentiviruses pseudotyped with Influenza A viruses, HIV, and SARS-CoV-2 spike proteins. Suicidal NETosis was also initiated by IgA-virus immune complexes produced from antibodies of rheumatoid arthritis patients. With this versatile mechanism of NETosis, experts believe that initiating mucosal response at respiratory tracts may be an effective alternative to tackle SARS-CoV-2.

“We should be thinking carefully about next-generation COVID-19 vaccines that could be administered in the respiratory tract to stimulate antibodies. We don’t have many candidates right now that are focused on raising the mucosal response,” said Hannah Stacey, lead author of the project and a graduate student in the Miller Lab. She also explained that aerosol or spray administration of vaccines may be more appropriate to increase the number of antibodies in the respiratory tract.

Nevertheless, researchers are encouraged to proceed with caution and monitor the delicate balance of the immune system if they choose to explore therapeutics that rely on NETosis as these traps can cause unwanted inflammation and aggravate illnesses if the web formation is not regulated properly. To illustrate, during the early waves of the pandemic, before vaccines were available, NETs were found in the lungs of some patients and made breathing more difficult for them.

“An immune response that is meant to protect you can end up harming you if it’s not properly controlled,” stated Miller. “It’s important to understand the balance of the immune system. If you have a lot of these antibodies before you get infected, they are likely going to protect you, but if the infection itself stimulates a lot of those antibodies it might be harmful.” [APBN]

Source: Stacey et al. (2021). IgA Potentiates NETosis in Response to Viral Infection. bioRxiv.