Role of Hypercytokinemia/hyperchemokinemia in the Pathogenesis of Influenza

The influenza A virus is an RNA virus belonging to the family Orthomyxoviridae. Commonly referred to as the flu virus, influenza A virus is specific to avians and mammals. The virus is classified based on antibody responses in serum during various flu outbreaks. Some examples of these serotypes include H5N1, H1N1 and H3N2 which are classified by the HA (hemagglutinin) and the NA (neuraminidase) surface glycoproteins.The key target cells for influenza A virus are lung alveolar epithelial cells and alveolar macrophages, though virus dissemination does occur beyond the human respiratory tract and sometimes contributes to disease severity. In vitro and in vivo studies have indicated that high viral replication and cytokine dysregulation are key factors contributing to lung pathology.Cytokine dysregulation is characterized by the extreme production and secretion of a number of predominantly pro-inflammatory cytokines and chemokines which are detected in the lung as well as blood of those infected with influenza A virus. This phenomenon is referred to as a 'cytokine storm'. Studies show that H5N1 viruses induce markedly higher levels of secretion of these cytokines and chemokines than H1N1 or H3N2 viruses, possibly accounting for the devastating nature of H5N1 infections. Cytokines and chemokines involved in this cytokine storm include TNF-α, interferons (IFNs), IL-6, IL-1, CCL3 (MIP-1α), IP-10, CCL2 (MCP-1), CCL5 (RANTES) and IL-8. IFNs are important in regulating the expression of genes that are antiviral in function. IFNs are produced and secreted by macrophages and plasmacytoid dendritic cells. IL-1, IL-8, IL-6, CCL2 and CCL5 also induce pro-inflammatory responses such as leukocyte recruitment into the lung, which then sets off a cascade of inflammatory responses. IL-17 produced by T-cells (CD4, CD8 and γδ) may recruit neutrophils to the infected lung. It has been postulated that mutations of some viral genes (NS1, PB2, HA and NA) are responsible for the cytokine storm by increasing viral replication and facilitating systemic invasion of the host. An exaggerated inflammatory response has been cited as the cause of pulmonary edema, alveolar hemorrhage and acute respiratory distress syndrome, conditions associated with necrosis and tissue destruction. (Updated 09/04/2020)