Influenza A virus is a respiratory pathogen that seasonally causes approximately 200,000 hospitalizations every year in US alone and affects human health worldwide extensively [1]. Seasonal viruses circulating in the human population cause annual epidemics with about 500,000 deaths per year. Furthermore, novel strains of influenza A virus without pre-existing immunity could cause a global pandemic with a high fatality rate; the 2009 H1N1 pandemic caused 151,700–575,400 deaths in its first year of circulation. [2, 3]
Viral pneumonia is the main complication in response to influenza infection, with or without secondary bacterial infections [4-6]. Our focus is on primary viral pneumonia, which can lead to acute respiratory distress …show more content…
NETs are released from neutrophils by a mechanism called NETosis. NETosis is a complex process and a type of cell death different from both necrosis and apoptosis [22, 23]. The precise mechanism of NETosis differs as per the stimulus and causes morphological changes within the cell ultimately leading to cell death [24]. The mechanism(s) of NETs release is poorly understood. During NETosis, chromatin undergoes decondensation, mediated by NE and MPO enzymes. NE degrades the linker histone H1 as well as core histones leading to chromatin decondensation; which is independently enhanced by MPO [25, 26]. Also, the core histones H3 and H4 undergo citrullination (protein modification), converting arginine residues to citrulline [27, 28]. This process is catalyzed by peptidylarginine deiminase 4 (PAD4) that is localized in the nucleus of neutrophils. It was shown that neutrophils isolated from PAD4-knockout mice lost their ability to release NET and histone hypercitrullination was not detectable [29]. Consequently, nuclear membrane ruptures, chromatin expands, mixes with the toxic granular factors and finally releases NETs studded with histones, due to rupture of cell membrane [30]. Narasaraju et al. [14] for the first time …show more content…
lead to the development of ARDS [35]. Several studies in both humans and animal-models have shown a correlation between excessive neutrophil response and severity of disease in various inflammatory, and trauma-related lung injuries [33, 36]. The activation and transmigration of neutrophils is viewed as the hallmark event in progression of ARDS [37]. Recently studies on influenza pneumonia have shown excessive recruitment and activation of neutrophils in the alveolar space in response to chemokines produced by epithelial cells, macrophages and even neutrophils [14]. Increased concentrations of cytokines and chemokines promote NETs release. Excessive accumulation and activity of neutrophils and ensuing tissue damage consequently increase the levels of circulating histones. As described above there are multiple proposed mechanisms through which extracellular histones expedite development of