Abstract
Influenza A virus (IAV) infection is a global public health burden causing up to 650,000 deaths per year. Yearly vaccination programmes and anti-viral drugs currently have limited benefits; therefore, research into IAV is fundamental. Leukocyte trafficking is a crucial process which orchestrates the immune response to infection to protect the host. It involves several homing molecules and receptors on both blood vessels and leukocytes. A key mediator of this process is the transmembrane glycoprotein L-selectin, which binds to vascular addressins on blood vessel endothelial cells. L-selectin classically mediates homing of naïve and central memory lymphocytes to lymph nodes via high endothelial venules (HEVs). Recent studies have found that L-selectin is essential for homing of activated CD8+ T cells to influenza-infected lungs and reduction in virus load. A disintegrin and metalloproteinase 17 (ADAM17) is the primary regulator of cell surface levels of L-selectin. Understanding the mechanisms that regulate these two proteins are central to comprehending recruitment of T cells to sites of IAV infection. This review summarises the immune response to IAV infection in humans and mice and discusses the roles of L-selectin and ADAM17 in T lymphocyte homing during IAV infection.
Highlights
The immune response to influenza A virus (IAV) infection requires a multitude of cells from both the innate and adaptive immune system to orchestrate protection to the host
This underpins the clearance of IAV, as cells must traffic to the correct tissues and organs to effectively eradicate the infection
The mechanisms behind the protective effects seen by blocking L-selectin shedding and/or A disintegrin and metalloproteinase 17 (ADAM17) function are still to be fully elucidated
Summary
Influenza virus enters the host through the respiratory tract. The haemagglutinin (HA) glycoprotein on the virion surface has receptor binding and membrane fusion capabilities to allow entry into host cells. As well as AMs, a range of immune cells such as monocytes, dendritic cells, neutrophils, natural killer (NK) cells, eosinophils and B cells are found to be directly infected by IAV in humans [9,10,11,12,13], and mice [14,15,16] Some studies suggest this can be abortive infection, whereby the cells infected do not produce functional IAV virions [13,15]. H5N1 viral RNAs have been found in peripheral blood and rectum of patients who died of the virus [18], as well as detectable virus in multiple organs including the brain, spleen and intestine of H5N1 infected ferrets [19] Further complications such as myocarditis, stroke, encephalitis, acute kidney injury (AKI) and rhabdomyolysis among others, have been documented in severe influenza cases [20]. It is currently unclear whether these complications are a direct effect of virus on the organs themselves, or whether it is a secondary effect caused by a heightened immune response [20]
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