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. 2009 Jul 24;325(5939):484-7.
doi: 10.1126/science.1177238. Epub 2009 Jul 2.

Transmission and pathogenesis of swine-origin 2009 A(H1N1) influenza viruses in ferrets and mice

Taronna R Maines  1 , Akila Jayaraman, Jessica A Belser, Debra A Wadford, Claudia Pappas, Hui Zeng, Kortney M Gustin, Melissa B Pearce, Karthik Viswanathan, Zachary H Shriver, Rahul Raman, Nancy J Cox, Ram Sasisekharan, Jacqueline M Katz, Terrence M Tumpey
Affiliations

Transmission and pathogenesis of swine-origin 2009 A(H1N1) influenza viruses in ferrets and mice

Taronna R Maines et al. Science. .

Abstract

Recent reports of mild to severe influenza-like illness in humans caused by a novel swine-origin 2009 A(H1N1) influenza virus underscore the need to better understand the pathogenesis and transmission of these viruses in mammals. In this study, selected 2009 A(H1N1) influenza isolates were assessed for their ability to cause disease in mice and ferrets and compared with a contemporary seasonal H1N1 virus for their ability to transmit to naïve ferrets through respiratory droplets. In contrast to seasonal influenza H1N1 virus, 2009 A(H1N1) influenza viruses caused increased morbidity, replicated to higher titers in lung tissue, and were recovered from the intestinal tract of intranasally inoculated ferrets. The 2009 A(H1N1) influenza viruses exhibited less efficient respiratory droplet transmission in ferrets in comparison with the highly transmissible phenotype of a seasonal H1N1 virus. Transmission of the 2009 A(H1N1) influenza viruses was further corroborated by characterizing the binding specificity of the viral hemagglutinin to the sialylated glycan receptors (in the human host) by use of dose-dependent direct receptor-binding and human lung tissue-binding assays.

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Figures

Figure 1
Figure 1. Dose dependent direct receptor binding of CA/04 HA
A streptavidin plate array comprising representative biotinylated α2–3 and α2–6 sialylated glycans were used for the assay. The biotinylated glycans include 3’SLN, 6’SLN, 3’SLN-LN, 6’SLN-LN and 3’SLN-LN-LN. LN corresponds to lactosamine (Galβ1–4GlcNAc) and 3’SLN and 6’SLN respectively correspond to Neu5Ac α2–3 and Neu5Ac α2–6 linked to LN. The assay was carried out as described previously (18) for an entire range of HA concentration from 0.01 – 40 µg/ml by pre-complexing HA: primary antibody: secondary antibody in the ratio 4:2:1 to enhance the multivalent presentation of HA. The binding signals for HA concentrations below 1 µg/ml were at background level and hence there concentrations are not shown on the x-axis. The y-axis shows the normalized binding signal as a percentage of the maximum value.
Figure 2
Figure 2. Human tissue binding of CA/04 HA
Shown in the top is the binding of CA/04 HA at 20 µg/ml concentration to apical surface (white arrow) of human tracheal tissue sections (green as against propidium iodide staining in red). The binding of the recombinantly expressed HA to the human tissues was carried out as described previously (19) by precomplexing HA: primary antibody:secondary antibody in the ratio 4:2:1 to enhance multivalent presentation of HA. Note the binding of HA to the apical surface of tracheal tissue which is known to predominantly express α2–6 sialylated glycans (19). Shown in the bottom is the minimal binding of HA at 20 µg/ml concentration to the alveolar tissue section. The sialic acid specific binding of HA to the tracheal tissue section was confirmed by blocking of HA binding to the tissue section pre-treated with 0.2 U of Sialidase A (recombinantly expressed in Arthrobacter ureafaciens).
Figure 3
Figure 3. Structural model of CA/04 HA bound to α2–6 oligosaccharide
The contacts of CA/04 HA with an α2–6 oligosaccharide (Neu5Ac α2–6Galβ1–4GlcNAcβ1–3Galβ1–4Glc) were analyzed by constructing a structural model as described previously (20). Shown in the figure is the cartoon representation of the glycan binding site of CA/04 HA where the side chains of the key amino acids are shown in stick representation (colored by atom carbon: gray; oxygen: red; nitrogen:blue). The α2–6 oligosaccharide is shown as a stick representation (colored by atom carbon: green; oxygen: red; nitrogen:blue) and labeled blue starting from non-reducing end Neu5Ac-1 to reducing end Glc-5. The potential destabilization of the interaction network due to the Ile219/Glu227 combination is highlighted in red dotted circle.
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