Abstract
Influenza is a major respiratory viral disease caused by infections from the influenza A virus (IAV) that persists across various seasonal outbreaks globally each year. Host immune response is a key factor determining disease severity of influenza infection, presenting an attractive target for the development of novel therapies for treatments. Among the multiple signal transduction pathways regulating the host immune activation and function in response to IAV infections, the mitogen-activated protein kinase (MAPK) pathways are important signalling axes, downstream of various pattern recognition receptors (PRRs), activated by IAVs that regulate various cellular processes in immune cells of both innate and adaptive immunity. Moreover, aberrant MAPK activation underpins overexuberant production of inflammatory mediators, promoting the development of the “cytokine storm”, a characteristic of severe respiratory viral diseases. Therefore, elucidation of the regulatory roles of MAPK in immune responses against IAVs is not only essential for understanding the pathogenesis of severe influenza, but also critical for developing MAPK-dependent therapies for treatment of respiratory viral diseases. In this review, we will summarise the current understanding of MAPK functions in both innate and adaptive immune response against IAVs and discuss their contributions towards the cytokine storm caused by highly pathogenic influenza viruses.
Highlights
Viruses are major contributors of infectious diseases, causing significant morbidity and mortality worldwide [1]
Pathogenic influenza A virus (IAV) (HPIAVs), such as H5N1, are capable of manipulating crucial host cell signalling, including mitogen-activated protein kinase (MAPK), to induce an overabundant expression of the inflammatory mediators. Such excessive and uncontrolled release of pro-inflammatory cytokines results in the generation of the cytokine storm that often leads to acute lung injuries and acute respiratory distress syndrome (ARDS), which is a common characteristic of severe respiratory viral diseases caused by Highly pathogenic IAVs (HPIAVs) or other viruses including Severe Acute Respiratory Syndrome (SARS)-CoVs [63]
Such excessive and uncontrolled release of pro-inflammatory cytokines, such as IL-1β, interleukin 6 (IL-6) and tumour necrotic factor α (TNFα), results in the generation of the cytokine storm that often leads to acute lung injuries and ARDS, which is a common characteristic of severe respiratory viral diseases caused by HPIAVs or other viruses including SARS-CoVs [63]
Summary
Viruses are major contributors of infectious diseases, causing significant morbidity and mortality worldwide [1]. Viruses are greatly dependent on host’s cellular machinery for virulence and survival Both innate and adaptive immunities have evolved and developed various ways to detect and eliminate virus and infected cells in response to viral infections. Surface viral proteins, such as the capsid and viral genomes, act as pathogen-associated molecular patterns (PAMPs), which are recognised by pathogen recognition receptors (PRRs) on immune cells [4]. In response to the selection pressure from the host immune response, the rapid yet error-prone replication of viruses allows them to constantly generate mutants that aid in the adaptation and evasion of host immunity [6] This is clearly demonstrated in the never-ending persistence of global infections caused by the influenza A virus (IAV) every year due to its high rates of mutation [7]
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