Friday, August 04, 2017

Cell: Avian-to-Human Receptor-Binding Adaptation by Influenza A Virus Hemagglutinin H4

Credit Cell Reports


As far as novel flu subtypes are concerned, H5 and H7 avian influenza viruses are viewed as posing the greatest pandemic threats (see Updating the CDC's IRAT (Influenza Risk Assessment Tool) Rankings - in part due to their observed severity in human hosts. 
While likely to have less of an impact should they erupt, there are other novel flu threats on the CDC's watch list (currently n=14), including swine variant H3N2v, canine H3N2, avian H7N7, avian H9N2, and most recently added - avian H7N8 [A/turkey/Indiana/1573-2/2016].
But going even further afield - particularly in places like China - there are many other novel viruses raising pandemic concerns.

Nearly five years ago, in Seroprevalence Study: Avian Flu In Chinese Pigs, we looked at research that found low levels of H3, H4, and H6 subtypes of avian influenza in Chinese pigs. The following year the study Epidemic Status of Swine Influenza Virus in China documented the presence of avian H3N8, H4N8, H5N1, H6N6, and H9N2 in Chinese pigs.
Since pigs possess both avian-like (SAα2,3Gal) and human-like (SAα2,6Gal) receptor cells in their respiratory tract, swine may constitute a `bridge' between avian and human strains.  
Not only can viruses evolve in pigs via host adaptation, pigs are also excellent `mixing vessels', providing an environment where two or more flu viruses can swap genetic material, and create a new hybrid or `reassorted' virus.

For these reasons - and because the last pandemic emerged from swine - we keep a close watch on novel influenza viruses circulating in pigs, as well as birds.  A few recent blogs include:
Journal AEM : US Feral Swine Were Exposed To Both Avian & Swine Influenza A Viruses
CDC FluView: 11 H3N2v Swine Flu Cases Reported In Ohio

PNAS: The Pandemic Potential Of Eurasian Avian-like H1N1 (EAH1N1) Swine Influenza

Today we've a new report in Cell Reports that finds that avian H4N6 viruses can adapt to human receptor cells when in a swine host.  First the link, abstract, and some excerpts . . . then I'll return with a bit more.

Avian-to-Human Receptor-Binding Adaptation by Influenza A Virus Hemagglutinin H4

Hao Song, Jianxun Qi, Haixia Xiao, Yuhai Bi, Wei Zhang, Ying Xu, Fei Wang, Yi Shi, George F. Gao8, 

Open Access

DOI: |


    •Structures of H4 hemagglutinin and its complex with avian or human receptor analogs
    •The substitutions in Q226L and G228S switch specificity from avian to human receptor binding
    •Structural basis for the switch from avian to human receptor binding by H4
    •H4 virus has the potential to cause human pandemics


Low-pathogenicity avian influenza viruses (LPAIVs) have caused a global concern to public health since the first novel LPAIV H7N9 outbreak occurred. The receptor-binding properties of the viral hemagglutinin are one key factor for efficient transmission and infection in humans.
Recent evidence shows that H4 subtype viruses have been widely circulating in domestic poultry and human asymptomatic infections might have occurred. Here, we evaluated the receptor-binding properties of two representative isolates, avian H4N6 (containing Q226 and G228) and swine H4N6 (containing L226 and S228), and found that the avian isolate preferentially binds to avian receptors, whereas the swine isolate preferentially binds to human receptors.
The Q226L and G228S substitutions are pivotal for the receptor-binding switch, which resulted in similar human receptor-binding features to the pandemic H2 and H3, implying that H4 has the potential to cause human infections. This early-warning study calls for future extensive surveillance.
Since the first H4 strain was isolated from a duck in the former Czechoslovakia in 1956, the H4 LPAIV has been discovered to be widely circulating in wild and domestic avian species in Asian, European, and North American countries (Bui et al., 2012, Donis et al., 1989, Kang et al., 2013, Liang et al., 2015, Teng et al., 2012, Wu et al., 2015, Yuan et al., 2015).
In recent years, multiple genotypes of H4 viruses have been shown to be co-circulating in the live poultry markets of Central, Eastern, and Southern China, and complex reassortment events between H4 subtype viruses and other subtype viruses (e.g., H3 subtype virus) have actively occurred in domestic ducks (Deng et al., 2013, Liang et al., 2015, Shi et al., 2016, Wu et al., 2015, Yuan et al., 2015).

H4 subtype viruses can replicate in mice without prior adaptation and transmit between guinea pigs via direct contact (Kang et al., 2013, Liang et al., 2015). Strikingly, some H4 strains can cause severe respiratory disease in mice, which eventually results in death (Bui et al., 2012).
 Aside from avian species, H4 viruses have been naturally isolated from mammalian animals including seals and pigs (Hinshaw et al., 1984, Hu et al., 2012, Karasin et al., 2000). Importantly, two H4N6 LPIAV strains isolated from pigs in Canada in 1999 possess Q226L and G228S substitutions in their HA sequences, implying the adaptation for human receptor preference (Bateman et al., 2008, Karasin et al., 2000). In addition, seroepidemiological studies reveal that poultry-exposed populations, including poultry farmers, workers, and veterinarians, are at a greater risk of infection with zoonotic IAVs, including H4 viruses (Kayali et al., 2010, Kayali et al., 2011, Ortiz et al., 2007).
These results clearly implicate the potential threat posed by H4 viruses to public health. Therefore, early-warning study of H4 subtype human receptor-binding property is highly appreciated.
         (Continue . . . )

LPAI (low path) H4 and H6 viruses are particularly common in waterfowl, and while they appear to be only mildly pathogenic (at worst) in humans (see Evidence of infection with H4 and H11 avian influenza viruses among Lebanese chicken growers), that could change over time. 
Until 2013 we'd never seen a serious human infection with avian H6 (see Taiwan CDC: Epidemiological Analysis Of Human H6N1 Infection), but after the virus was discovered circulating in Taiwan's dog population, and a 2015 study found  Adaptation Of H6N1 From Avian To Human Receptor-Binding that virus is now viewed with more respect.
The above mentioned epidemiological analysis warned that a (emphasis mine)  unique clade of H6N1 viruses with a G228S substitution of haemagglutinin have circulated persistently in poultry in Taiwan. These viruses continue to evolve and accumulate changes, increasing the potential risk of human-to-human transmission.” 
Last month, in Three Mutations That Switch H7N9 To Human-type Receptor Specificity, G228S and Q226L were both called out at being instrumental in changing H7N9 into a more humanized virus.
Due to their present low pathogenicity in both humans and birds, H4 viruses would seem a pretty poor pandemic candidate. But the discovery of these two key amino acid changes in a swine isolate H4N6 virus is a reminder that Nature's Laboratory is open 24/7, and that even for relatively obscure viruses like H4N6, evolution never stops.