Abstract
The interaction of the hemagglutinin (HA) of the influenza A viruses (IAV) with the cell surface is a key factor for entry of the virus and productive infection of the cell. This glycoprotein has affinity for sialic acids (SA), and different strains present specificity for SA bound through α2,3 or α2,6 linkages to the underlying sugar chain, which is usually related with host and cell tropism. Nucleic acid recognizing receptors (mainly RIG-I and Toll-like receptors) are the most extensively studied pattern recognition receptors for IAV. However, due to the ability of the HA of avian, swine, or human influenza viruses to bind differently linked SA and also to the high levels and variability of glycosylations of their major virion glycoprotein components, HA and NA, IAV interacting proteins on the cell surface could also play an important role in initiating different signaling pathways to elicit the immune response in infected cells. But, at present, these processes are not well understood. In this mini-review we discuss how the interactions of IAV with cell surface receptors on immune cells might be important for the induction of specific innate immune responses and as a result, for pathogenicity in humans.
Highlights
Influenza viruses are an important threat to human health and global economy, causing an annual average of 36,000 deaths and over 200,000 hospitalizations during the 1990s (CDC, 2010)
The main roles of the HA are to mediate the interaction of the viral particle with the cell components on the surface and to promote the fusion of the viral and endosomal membranes, leading to the release of the Abbreviations: C-type lectins receptors (CLRs), C-type lectin receptors; DCs, dendritic cells; Dendritic cell-specific intercellular adhesion molecule-3grabbing non-integrin (DC-SIGN), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; EGFR, epidermal growth factor receptor; HA, hemagglutinin; High pathogenic avian influenza viruses (HPAIV), high pathogenic influenza avian viruses; influenza A viruses (IAV), influenza A virus; NA, neuraminidase; NLRs, Nod-like receptors; PI3K, phosphatidylinositol 3-kinases; PRRs, pattern recognition receptors; RLRs, RIG-I-like receptors; RNP, ribonucleoprotein; RTK, receptor tyrosine kinases; SA, sialic acids; TLRs, Toll-like receptors
In order to elucidate if differences in receptor specificity of the IAV are important for this hyper-induction of pro-inflammatory cytokines, we recently reported that recombinant viruses bearing the HA and NA from a HPAIV H5N1, which differed only in two amino-acids that were shown to modify receptor specificity, induced different cytokine profiles in human DCs, macrophages, and primary bronchial–epithelial cells (Ramos et al, 2011)
Summary
Due to the ability of the HA of avian, swine, or human influenza viruses to bind differently linked SA and to the high levels and variability of glycosylations of their major virion glycoprotein components, HA and NA, IAV interacting proteins on the cell surface could play an important role in initiating different signaling pathways to elicit the immune response in infected cells. At present, these processes are not well understood. In this mini-review we discuss how the interactions of IAV with cell surface receptors on immune cells might be important for the induction of specific innate immune responses and as a result, for pathogenicity in humans
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