Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to-mammal transmission through respiratory droplets. From surveillance data, we found that two of these substitutions are common in A/H5N1 viruses, and thus, some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals. We used a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors, combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas in which more data are needed for assessing, and potentially averting, this threat.
"Public health concerns have mostly centered on the potential of contemporary avian influenza subtype viruses to mutate or reassort with other influenza subtypes to a form that could become transmissible among humans. As a result, multiple studies have been performed to assess the molecular determinants of avian H5, H7 and H9 virus adaptation, pathogenicity and transmissibility in mammalian hosts (Maines et al., 2006; Salomon et al., 2006; Chen et al., 2012; Russell et al., 2012; Herfst et al., 2012; Sorrell et al., 2009). However, relatively less attention has been given to H2 subtype viruses largely due to their sporadic isolation and low pathogenicity in both avian and mammalian species (Pappas et al., 2010; Jones et al., 2014). "
[Show abstract][Hide abstract] ABSTRACT: After their disappearance from the human population in 1968, influenza H2 viruses have continued to circulate in the natural avian reservoir. The isolation of this virus subtype from multiple bird species as well as swine highlights the need to better understand the potential of these viruses to spread and cause disease in humans. Here we analyzed the virulence, transmissibility and receptor-binding preference of two avian influenza H2 viruses (H2N2 and H2N3) and compared them to a swine H2N3 (A/swine/Missouri/2124514/2006 [swMO]), and a human H2N2 (A/England/10/1967 [Eng/67]) virus using the ferret model as a mammalian host. Both avian H2 viruses possessed the capacity to spread efficiently between cohoused ferrets, and the swine (swMO) and human (Eng/67) viruses transmitted to naïve ferrets by respiratory droplets. Further characterization of the swMO hemagglutinin (HA) by x-ray crystallography and glycan microarray array identified receptor-specific adaptive mutations. As influenza virus quasispecies dynamics during transmission have not been well characterized, we sequenced nasal washes collected during transmission studies to better understand experimental adaptation of H2 HA. The avian H2 viruses isolated from ferret nasal washes contained mutations in the HA1, including a Gln226Leu substitution, which is a mutation associated with α2,6 sialic acid (human-like) binding preference. These results suggest that the molecular structure of HA in viruses of the H2 subtype continue to have the potential to adapt to a mammalian host and become transmissible, after acquiring additional genetic markers.
"Two of these 4 mutations (N158D and N224K) have lost their glycosylation sequons (Imai et al., 2012). Furthermore, the substitutions of the glycosylation sequon on HA have drifted in and out of the avian virus population over time, which might have been caused by little selective pressure (Russell et al., 2012). In addition, additional glycans in the globular head of HA resulted in substantially attenuated infection in H1N1 virus (Kim et al., 2013; Medina et al., 2013). "
"Transmission from human to human occurs sporadically, usually during care of patients (Ungchusak et al., 2005; Wang et al., 2008; WHO, 2008). But as shown in a ferret model only few mutations of the H5N1 virus are necessary to acquire airborne transmission (Herfst et al., 2012; Imai et al., 2012; Russell et al., 2012) and the segmented genome additionally favours reassortment and the production of a virus that can cause a human pandemic. These findings emphasise the urgent need for improved easy to perform and sensitive diagnostic tests for emergency diagnosis to timely initiate anti-viral therapy. "
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