Abstract
The amino acid substitution of aspartic acid to glycine in hemagglutinin (HA) in position 222 (HA-D222G) as well as HA-222D/G polymorphism of pandemic (H1N1) 2009 influenza viruses (A(H1N1)pdm09) were frequently reported in severe influenza in humans and mice. Their impact on viral pathogenicity and the course of influenza has been discussed controversially and the underlying mechanism remained unclarified. In the present study, BALB/c mice, infected with the once mouse lung- and cell-passaged A(H1N1)pdm09 isolate A/Jena/5258/09 (mpJena/5258), developed severe pneumonia. From day 2 to 3 or 4 post infection (p.i.) symptoms (body weight loss and clinical score) continuously worsened. After a short disease stagnation or even recovery phase in most mice, severity of disease further increased on days 6 and 7 p.i. Thereafter, surviving mice recovered. A 45 times higher virus titer maximum in the lung than in the trachea on day 2 p.i. and significantly higher tracheal virus titers compared to lung on day 6 p.i. indicated changes in the organ tropism during infection. Sequence analysis revealed an HA-222D/G polymorphism. HA-D222 and HA-G222 variants co-circulated in lung and trachea. Whereas, HA-D222 variant predominated in the lung, HA-G222 became the major variant in the trachea after day 4 p.i. This was accompanied by lower neutralizing antibody titers and broader receptor recognition including terminal sialic acid α-2,3-linked galactose, which is abundant on mouse trachea epithelial cells. Plaque-purified HA-G222-mpJena/5258 virus induced severe influenza with maximum symptom on day 6 p.i. These results demonstrated for the first time that HA-222D/G quasispecies of A(H1N1)pdm09 caused severe biphasic influenza because of fast viral intra-host evolution, which enabled partial antibody escape and minor changes in receptor binding.
Highlights
In 2009, a new pandemic (H1N1) influenza virus (A(H1N1)pdm09) emerged in Mexico and spread around the world, causing the first pandemic since decades [1]
Amino acid substitution of aspartic acid to glycine at position 222 (D222G; H1 numbering) in the hemagglutinin (HA-D222G) was supposed to be associated with severe influenza and fatality in humans [7,8,9,10,11], this substitution was detected in virus isolates from patients with mild influenza [12,13]
Using mpJena/5258 as example, the kinetics of replication of A(H1N1)pdm09 variants with HA-222D/G polymorphism was modeled for the first time in vivo
Summary
In 2009, a new pandemic (H1N1) influenza virus (A(H1N1)pdm09) emerged in Mexico and spread around the world, causing the first pandemic since decades [1]. Amino acid substitution of aspartic acid to glycine at position 222 (D222G; H1 numbering) in the hemagglutinin (HA-D222G) was supposed to be associated with severe influenza and fatality in humans [7,8,9,10,11], this substitution was detected in virus isolates from patients with mild influenza [12,13]. The amino acid substitution of HA-D222G was detected during the adaptation of A(H1N1)pdm viruses to mice [17,18,19,20]. It was described by many as a virulence increasing determinant [15,19,20,21], but not confirmed by all [22]. Despite frequent description of the amino acid substitution HA-D222G and HA-222D/G polymorphism, the impact of these quasispecies on the course of influenza was discussed rather controversially until now
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