Abstract
Neutrophils participate in the early phase of the innate response to uncomplicated influenza A virus (IAV) infection but also are a major component in later stages of severe IAV or COVID 19 infection where neutrophil extracellular traps (NETs) and associated cell free histones are highly pro-inflammatory. It is likely that IAV interacts with histones during infection. We show that histone H4 binds to IAV and aggregates viral particles. In addition, histone H4 markedly potentiates IAV induced neutrophil respiratory burst responses. Prior studies have shown reactive oxidants to be detrimental during severe IAV infection. C reactive protein (CRP) and surfactant protein D (SP-D) rise during IAV infection. We now show that both of these innate immune proteins bind to histone H4 and significantly down regulate respiratory burst and other responses to histone H4. Isolated constructs composed only of the neck and carbohydrate recognition domain of SP-D also bind to histone H4 and partially limit neutrophil responses to it. These studies indicate that complexes formed of histones and IAV are a potent neutrophil activating stimulus. This finding could account for excess inflammation during IAV or other severe viral infections. The ability of CRP and SP-D to bind to histone H4 may be part of a protective response against excessive inflammation in vivo.
Highlights
Influenza A viruses continue to pose a major threat to human health
The confocal image shows that histone H4 was detected interacting with Philippines 82/H3N2 (Phil82) influenza A virus (IAV) strain in IAV stimulated neutrophil extracellular traps (NETs) (Fig 1A)
Phil82, PR8 or Cal09 IAV strains were labeled with Alexa and were allowed to bind to plates coated with histone H4 as described in methods (Fig 1B)
Summary
Influenza A viruses continue to pose a major threat to human health. While most people recovery from IAV infection without major complications, some subjects suffer severe morbidity and mortality due to viral pneumonia, bacterial superinfection or exacerbation of underlying cardiac disease. Of major concern has been the possible emergence of radically new IAV strains from avian or porcine sources causing a pandemic. The mortality rate from human infection with avian IAV is very high and prior pandemics have varied in severity with the 1918 pandemic carrying the highest mortality rate. We are in the grips of the novel SARs-COV2 pandemic which bears some similarities to prior IAV pandemics but with a mortality rate exceeding that of seasonal IAV or even of most IAV pandemics excluding that.
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