Flu Virus binding to Receptor Cells – Credit CDC
Considering the recent spate of worrisome H5 and H7N9 bird flu news, I’m happy to report that at least two recently emerged avian viruses haven’t yet acquired one of the main traits that would allow them to become serious pandemic threats; the ability to bind preferentially to human receptor cells.
While our gaze has been focused primarily on H5N1 and H7N9, in the summer of 2013 Taiwan reported the first known human infection with an avian H6N1 virus, and a few months later mainland China reported the first three cases of H10N8 (two fatal).
While only four cases were recorded, they – along with H5N6, and the globe-trotting H5N8 avian virus and its descendents – have shown just how quickly new subtypes can emerge.
Luckily, turning up in a small handful of cases is a far cry from being ready for prime time.
Human adapted influenza viruses have an RBS - Receptor Binding Site (the area of its genetic sequence that allows it to attach to, and infect, host cells) that – like a key slipping into a padlock -`fit’ the receptor cells commonly found in the human upper respiratory tract; the alpha 2,6 receptor cell.
While avian adapted flu viruses, like the H5N1 virus, bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds.
Although there are some alpha 2,3 cells deep in the lungs of humans, for an influenza to be successful in a human host, most researchers believe it needs to able to bind to the a 2,6 receptor cell.
There are other requirements – some we know about, others we don’t – that determine how well a virus can infect, replicate, and transmit in humans. The ability to replicate at the lower temperatures found in the upper respiratory system is one of them.
But first, and foremost, the virus must be able to bind to human receptor cells.
And here, the news on these two viruses remains encouraging.
The journal Cell, Host & Microbe carries a pair of studies this week that look at the binding properties of these viruses, and both find they fall short. While behind a pay wall, we do have a press release from the The Scripps Research Institute (TSRI) which provides some welcome details.
Links to the studies, and excerpts from the press release, follow:
Netanel Tzarum, Robert P. de Vries, Xueyong Zhu, Wenli Yu, Ryan McBride, James C. Paulson, Ian A. Wilson
- The human H6N1 HA receptor binding site is distinct from other avian and human HAs
- The HA of a human H6N1 influenza virus retains avian receptor specificity
- The interactions of H6 HA with avian receptor analogs differ from other HAs
- Additional mutations are required to switch H6 HA to human receptor specificity
Heng Zhang, Robert P. de Vries, Netanel Tzarum, Xueyong Zhu, Wenli Yu, Ryan McBride, James C. Paulson, Ian A. Wilson
- Human influenza H10N8 HA has negligible binding to human-like receptors
- Human influenza H10N8 HA retains strong binding to avian-like receptors
- The human receptor orientation in H10 HA differs from most human HA complexes
- Mutations that switch specificity in pandemic viruses do not alter H10 specificity
While ostensibly good news, the press release from Scripps warns that both of these viruses bind differently than other avian viruses we’ve seen, and that our understanding of how these viruses mutate isn’t complete enough to warrant complacency.
But Great Versatility of Viruses Suggests Continued Caution
LA JOLLA, CA—March 11, 2015—Scientists at The Scripps Research Institute (TSRI) have analyzed a key protein from two influenza strains that recently began causing sporadic infections among people in China and Taiwan.
The analyses suggest that the flu viruses, variants of subtypes H10N8 and H6N1, have not acquired changes that would allow them to infect people easily and cause a much-feared pandemic.
Yet the studies also highlight the versatility that bird flu viruses apparently have in attaching to host cells.
“These bird flu viruses seem able to bind to receptors on host cells in different ways and thus can probably mutate in different ways to jump to humans—so we shouldn’t be complacent about our ability to predict the viral changes required to get a pandemic,” said Ian A. Wilson, Hansen Professor of Structural Biology and chair of TSRI’s Department of Integrative Structural and Computational Biology.
Difficult to Predict
How did such bird viruses end up causing infections of people? “We suspect that sporadic cases of human infection by a bird flu virus can occur, even without a change in the receptor specificity, if the dose of the viral exposure is high enough and/or it gets deep into the lungs, where there are some flu-virus receptors like those found in birds,” said Tzarum, a research associate in the Wilson laboratory who was first author of the H6N1 paper.
Flu viruses with these HAs thus remain essentially bird viruses, with limited ability to infect humans. Yet further mutations that would enable a switch in preference to human receptors—and a potential global pandemic—are still possible.
The new TSRI analyses also show that, at the atomic scale, these new bird flu HAs bind to host-cell receptors in ways not observed in studies of other bird flu viruses—implying that the mutations required for the switch to human receptors may be different for different strains and inherently hard to know in advance.
“There appear to be no general rules for this switch among bird flu viruses,” said Tzarum.
Determining whether a bird flu strain has truly jumped the species barrier will therefore continue to require detailed receptor-binding and structural studies like these, Wilson said.