Histone H4 potentiates neutrophil inflammatory responses to influenza A virus: Down-modulation by H4 binding to C-reactive protein and Surfactant protein D

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.

COVID-19 Salivary Protein Profile: Unravelling Molecular Aspects of SARS-CoV-2 Infection

“…ORF1a and rep interact with histone H4 (H4). Histone H4 has the most potent antiviral activity among histones and has been shown to promote neutrophil activation and consequently the early phase of the innate immune response to influenza A virus [ 91 , 92 , 93 , 94 ]. This study shows a reduction in histone H4 in patients with COVID-19 (FC −14.47), which may prevent an effective elimination of the virus at an early stage of infection.…”

Histones: The critical players in innate immunity

“…Extracellular histone H4 is an activator of neutrophils, which continuously increases the concentration of intracellular calcium by affecting the membrane permeability of neutrophils, leading to respiratory burst response, adhesion, myeloperoxidase (MPO), and IL-8 release ( 63 , 64 ). Respiratory burst and degranulation responses depend primarily on the elevation of intracellular calcium from extracellular sources.…”

Determinantes no manejo clínico e terapêutico em pacientes graves com Sars-cov-2 em um hospital público do Distrito Federal

“…Os valores elevados de PCR encontrados em nosso trabalho está compatível com a literatura, pois trata-se de uma molécula que tem seu aumento no organismo quando existe inflamação ativa, como a causada por infecções (HSIEH et al, 2021), e suas marcações elevadas servem ao propósito de acompanhar a evolução do quadro infeccioso (CALDERÓN-PARRA et al, 2021), bem como marcador prognóstico de necessidade de internação (SHARIFPOUR et al, 2020). Estudo realizado na cidade de Atlanta, na Geórgia, no qual pacientes internados com infecção por SARS-CoV-2, com um mínimo de dois valores de PCR em sete dias desde a admissão foram monitorados até os seus respectivos desfechos, logo, confirmou-se que o valor mediano se correlaciona com a gravidade da patologia e é um preditor de mortalidade.…”