Abstract
Humans can be infected by zoonotic avian, pandemic and seasonal influenza A viruses (IAVs), which differ by receptor specificity and conformational stability of their envelope glycoprotein hemagglutinin (HA). It was shown that receptor specificity of the HA determines the tropism of IAVs to human airway epithelial cells, the primary target of IAVs in humans. Less is known about potential effects of the HA properties on viral attachment, infection and activation of human immune cells. To address this question, we studied the infection of total human peripheral blood mononuclear cells (PBMCs) and subpopulations of human PBMCs with well characterized recombinant IAVs differing by the HA and the neuraminidase (NA) but sharing all other viral proteins. Monocytes and all subpopulations of lymphocytes were significantly less susceptible to infection by IAVs with avian-like receptor specificity as compared to human-like IAVs, whereas plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells were equally susceptible to IAVs with avian-like and human-like receptor specificity. This tropism correlated with the surface expression of 2-3-linked sialic acids (avian-type receptors) and 2-6-linked sialic acids (human-type receptors). Despite a reduced infectivity of avian-like IAVs for PBMCs, these viruses were not less efficient than human-like IAVs in terms of cell activation as judged by the induction of cellular mRNA of IFN-α, CCL5, RIG-I, and IL-6. Elevated levels of IFN-α mRNA were accompanied by elevated IFN-α protein secretion in primary human pDC. We found that high basal expression in monocytes of antiviral interferon-induced transmembrane protein 3 (IFITM3) limited viral infection in these cells. siRNA-mediated knockdown of IFITM3 in monocytes demonstrated that viral sensitivity to inhibition by IFITM3 correlated with the conformational stability of the HA. Our study provides new insights into the role of host- and strain-specific differences of HA in the interaction of IAVs with human immune cells and advances current understanding of the mechanisms of viral cell tropism, pathogenesis and markers of virulence.
Highlights
Influenza A viruses (IAVs) are a major concern for human health and health care system
To characterize how receptor specificity and membrane fusion activity of the HA affects tropism of IAVs to human immune cells and response of the cells to IAV infection we used a panel of three 2:6 recombinant IAVs that shared six gene segments of Puerto Rico/8/1934 (PR8) and that contained the HAs of A/Vietnam/1203/2004 (H5N1), A/Hong Kong/1/1968 (H3N2), and A/Memphis/14/1996 (H1N1), as representative HAs of zoonotic avian, pandemic and seasonal IAVs infecting humans, respectively
IAVs infecting humans can differ by receptor binding specificity and conformational stability of their surface glycoprotein HA
Summary
Influenza A viruses (IAVs) are a major concern for human health and health care system. From wild aquatic birds, which are the natural reservoir, IAVs can occasionally transmit to different avian and mammalian species such as domestic birds and pigs. Circulation and adaptation in these intermediate hosts can lead to transmission to humans. Zoonotic IAVs (e.g. H5N1 and H7N9) usually do not transmit among humans, they often cause severe and fatal diseases characterized by an aberrant immune reaction. Pandemic viruses continue to circulate and evolve in the human population causing seasonal influenza outbreaks [for recent reviews on ecology, evolution and pathogenicity of IAVs, see refs [1–5]]. Humans can be infected by avian-origin zoonotic, pandemic and seasonal IAVs, which differ by their level of adaptation to human host and have distinguishable characteristics
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