Platelet Factor 4 (PF4) Enhances In Vitro Neutrophil Extracellular Traps (NET) Capture Of Coronaviruses: Clinical and Therapeutic Implications
Maki Ishizuka, M.D.
University of Pennsylvania
Philadelphia, Pennsylvania, U.S.
The novel coronavirus SARS-CoV-2 causes COVID-19, a highly pathogenic viral infection threatening millions. The majority of the individuals infected are asymptomatic or mildly symptomatic and show typical clinical signs of common cold. Neutrophil extracellular traps (NETs) are webs of extracellular DNA that entrap bacteria and potentially viruses. Unfortunately, NET-degradation products (NDPs), such as histones, are toxic, and growing evidence suggests that NDPs contribute to organ damage in COVID-19. Maki Ishizuka and her group at the Children's Hospital of Philadelphia in Philadelphia had stated that platelet factor 4 (PF4), a platelet-specific chemokine, aggregates NETs, enhancing bacterial capture while protecting NETs from nuclease degradation, thereby limiting NDP release. Her aim was to look further into the effect of PF4 on NET-mediated entrapment of coronaviruses.
Using confocal microscopy and scanning electron microscopy, Ishizuka observed that the coronaviruses formed aggregates with PF4 and adhered to the NET surface in the presence of PF4. This suggests that PF4 binding enhances NET-mediated capture of coronaviruses. Thus, PF4 released by activated platelets may improve virion entrapment by NETs and limit infectivity, while treatment with PF4 infusions may provide additional clinical benefit by enhancing virion entrapment by NETs while also preventing NDP release. The future vision of research from Ishizuka is to assess whether antibodies that stabilize PF4 binding to NETs, currently being explored as a treatment strategy in bacterial sepsis, can improve NET entrapment of SARS-CoV-2 and can decrease disease severity in COVID-19.