br Introduction Influenza comprises a substantial portion of

Introduction Influenza comprises a substantial portion of morbidity and mortality caused by acute respiratory infections, which are the fourth leading cause of death and the second highest cause of years of life lost (Organization, 2014; Radin et al., 2012; Nair et al., 2011). Severe influenza diseases with high mortality have been frequently reported, especially in those patients infected with avian influenza (AI) A (H5N1, H5N6, H7N9 or H10N8) viruses or during a pandemic (Organization, 2015; Ortiz et al., 2013; Chen et al., 2014). Severe AI or pandemic patients present with rapidly progressive pneumonia, leading to acute respiratory distress syndrome or the complication of multiple organ failure (Gao et al., 2013a; Pan et al., 2016; Chen et al., 2014; Investigators et al., 2009). Respiratory distress is the most common cause of death in patients infected by these viruses (Liem et al., 2009; Gao et al., 2013a). Autopsy or postmortem biopsy studies showed that extensive diffuse alveolar damage is the most consistent finding, and the virus predominantly infected lung parenchyma in H5N1, H5N6, and H7N9 patients or fatal cases infected by influenza pandemic viruses (Guo et al., 2014; Gao et al., 2016; Shieh et al., 2010). In terms of therapy, other than lung protective ventilation for support for oxygenation, antiviral treatment is an important component to manage those patients infected with these viruses (Gao et al., 2013a; Yu et al., 2008; Zhang et al., 2009). However, influenza viruses mutate readily, and produce drug-resistant strains or unmanageable stains using vaccine (Govorkova et al., 2013; Hu et al., 2013; Shore et al., 2013). In addition, in case of lethal influenza infection, antiviral treatment is needed early to block virus replication and prevent triggering dysregulation of immune response, thereby abrogating the immunopathology (Wong et al., 2011). Once triggered, the immune-mediated tissue damage possibly presents limited sensitivity to antiviral agents (Yen et al., 2005; Govorkova et al., 2009). C-reactive protein (CRP), a pentraxin, is a marker of STI571 Supplier that has been extensively used in clinical practice. CRP is involved in the innate immune response by attaching to microorganisms and damaged cellular components via phosphocholine. This leads to complement activation and phagocytosis. Excessive host immune response including complement activation has been shown to play a critical role on pathogenesis of severe influenza infections (US, 2008; Gao et al., 2013b). Activation of the complement system has been implicated in the development of acute lung diseases induced by highly pathogenic influenza viruses (Garcia et al., 2013; Sun et al., 2013, 2015). Recent studies have brought up the idea of CRP to be not only a systemic marker of inflammation but also a mediator in inflammation faci (Thiele et al., 2015), and indicated that high levels of CRP is a high risk factor of fatality in H7N9 patients (Cheng et al., 2015; Wu et al., 2016). However, its exact physiological roles remain largely unknown, especially in severe influenza diseases. In this study, we characterized the role of CRP on pathogenesis of severe infections by influenza A (H5N1, H7N9 or H10N8) viruses, and indicated a candidate molecule for immunotherapy of severe influenza infection.
Materials and Methods
Results
Discussion Our data established an important role of CRP in the pathogenesis of avian influenza A (H5N1, H7N9 or H10N8) infections. Although highly pathogenic avian influenza virus infections have a different epidemiology, the most common cause of death is respiratory distress caused by severe alveolar damage in infected patients. Innate host response plays a key role in the pathogenesis of severe avian influenza diseases (Liu et al., 2016; Darwish et al., 2011; US, 2008). Previous studies suggested that anaphylatoxin C5a has been implicated in the pathogenesis of ARDS by mediating neutrophil attraction, aggregation, activation, and subsequently pulmonary endothelia damage (Wang et al., 2015; Tate and Repine, 1983; Sacks et al., 1978). Animal experiments showed that C5a inhibition can partially alleviate the pathogenicity of H5N1 or H7N9 infection (Sun et al., 2015, 2013). Our study showed that CRP correlated with complement activation in patients with severe avian influenza (H5N1, H7N9 or H10N8). The C5a deposition was extensive in lung tissues of fatal H5N1 cases. Globally, the biological role of CRP after binding to ligands is to trigger the complement pathway (Pepys and Hirschfield, 2003; Lelubre et al., 2013). CRP is recognized by complement protein C1q and potently activates the classic complement pathway, engaging C3, and the main molecule of adhesion of the complement system (Lelubre et al., 2013; Agrawal et al., 2001). CRP located upstream of immune mediation would be a better immune mediator than C5a when designing a candidate molecule for immunotherapy for severe avian influenza diseases.