Effects of Receptor Specificity and Conformational Stability of Influenza A Virus Hemagglutinin on Infection and Activation of Different Cell Types in Human PBMCs
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...
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|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-a, CCL5, RIG-I, and IL-6. Elevated levels of IFN-a
mRNA were accompanied by elevated IFN-a 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.
|Gefördert durch den Open-Access-Publikationsfonds der UB Marburg.