The ability of pandemic influenza virus hemagglutinins to induce lower respiratory pathology is associated with decreased surfactant protein D binding

Abstract

Pandemic influenza viral infections have been associated with viral pneumonia. Chimeric influenza viruses with the hemagglutinin segment of the 1918, 1957, 1968 or 2009 pandemic influenza viruses in the context of a seasonal H1N1 influenza genome were constructed to analyze the role of hemagglutinin (HA) in pathogenesis and cell tropism in a mouse model. We also explored whether there was an association between the ability of lung surfactant protein D (SP-D) to bind to the HA and the ability of the corresponding chimeric virus to infect bronchiolar and alveolar epithelial cells of the lower respiratory tract. Viruses expressing the hemagglutinin of pandemic viruses were associated with significant pathology in the lower respiratory tract, including acute inflammation, and showed low binding activity for SP-D. In contrast, the virus expressing the HA of a seasonal influenza strain induced only mild disease with little lung pathology in infected mice and exhibited strong in vitro binding to SP-D.

Mutations flanking the carbohydrate binding site of surfactant protein D confer antiviral activity for pandemic influenza A viruses

“…We also show that D325AϩR343V can inhibit infectivity of a viral strain containing the HA of the 1918 H1N1. Previous studies showed that wild-type, native SP-D does not inhibit this strain in vitro or in vivo (21). The 1918 HA has high homology with the 2009 HA (including having the same glycan attachment sites) (23).…”

“…After thawing, the viral stocks contained ϳ5 ϫ 10 8 infectious focusforming units/ml. The California 2009 H1N1 pandemic strain (Cal09) and the New York 2001 H1N1 (NY01) seasonal strains were prepared by reverse genetics as described (21,27). Additional strains related to the 2009 pandemic strain were developed by reverse genetics, including a strain containing only the HA gene of the pandemic Mexico 2009 H1N1 combined with the other seven genes of NY01 (Mex 1:7) and an additional strain containing the HA and neuraminidase (NA) of Mexico 2009 (Mex 2:6).…”

“…The plaque reduction neutralization assay was performed as previously described (21). MDCK cells were seeded into 24-well plates and grown to confluency.…”

“…SP-D is the predominant mediator of antiviral activity against seasonal strains of IAV in human bronchoalveolar lavage (15), and mice lacking SP-D have significantly greater viral replication and illness from certain seasonal strains of IAV (18). Notably, pandemic IAV strains (including that in 2009), or recombinant viral strains containing just the hemagglutinin (HA) of a pandemic strain along with the other segments of a seasonal virus, are resistant to native SP-D (19,21). Pandemic and avian strains in general have limited glycosylation on their HA head regions, which likely accounts for their resistance to inhibition by SP-D. Resistance of pandemic viral strains to inhibition by SP-D or the related collectin, mannose-binding lectin (MBL) (27), is likely one factor in their increased pathogenicity (13).…”

Influenza Virus Hemagglutinin Glycoproteins with Different N-Glycan Patterns Activate Dendritic Cells In Vitro

“…The extents of glycosylation and the HA patterns determine the sensitivity of viruses to lectin-mediated innate defenses. In addition, pandemic pH1N1 and avian H5N1 and H7N9 viruses were resistant to soluble C-type lectin surfactant protein D in host cells, and this resulted in decreased antiviral activities in mice and significant pathology in the mouse lower respiratory tract (33,34). Another report indicated that the macrophage MR recognized the same spectrum of monosaccharides as the collectins do and served as a major endocytic receptor in the infectious entry of influenza virus into murine macrophages (35).…”