Maybe Not Quite The End
Posted by ajcann on January 15, 2008
This post is from regular guest blogger:
Ed Rybicki, Department of Molecular and Cell Biology, University of Cape Town, South Africa.
Given the current scare over H5N1 influenza virus in swans in the UK, it is possibly timely to recall that I wrote a little while ago in MicrobiologyBytes about how easy it appeared to be for the highly pathogenic H5N1 avian influenza virus to change receptor and therefore host specificity: all it apparently needed was substitutions at position 129 and 134 in the HA protein to change from binding avian-type sialic acid (SA) α2,3Gal(actose) receptors to the human-type SA α2,6Gal receptor. And the outlook was gloomy, and panic was close at hand.
Fortunately for us, it turns out that things are not so simple. According to a letter in the January 2008 issue of Nature Biotechnology, it is a characteristic structural topology, and not just the α2,6 linkage, that enables specific binding of HA to α2,6 sialylated glycans. The authors state:
…recognition of this topology may be critical for adaptation of HA to bind glycans in the upper respiratory tract of humans. An integrated biochemical, analytical and data mining approach demonstrates that HAs from the human-adapted H1N1 and H3N2 viruses, but not H5N1 (bird flu) viruses, specifically bind to long α2-6 sialylated glycans with this topology. This could explain why H5N1 viruses have not yet gained a foothold in the human population.
Apparently the critical shape in humans is umbrella-like, whereas the avian receptor is characteristically cone-like. Again from the paper:
The topology of α2-3 and α2-6 is governed by the glycosidic torsion angles of the trisaccharide motifs-Neu5Aca2-3Galb1-3/4GlcNAc and Neu5Aca2-6Galb1-4GlcNAc, respectively (Supplementary Fig. 3 online).
Ram Sasisekharan and colleagues showed that human-adapted viruses with mixed α2,3/α2,6 binding ability that bound the umbrella-type receptor were efficiently transmitted, whereas viruses with the same basic specificity that did not have HA binding specificity to “long” α2,6, were not.
This means that the perceived threat of H5N1 human adaptation and rapid spread has receded somewhat, as the virus HA needs considerably more adaptation than the simple mutations that were previously assumed to change the specificity. Furthermore, these findings also allow the possibility of using glycan arrays with long α2,6 molecules for the screening of H5N1 and other avian virus isolates for possible evolutionary adaptation to the appropriate receptor binding form. They close their paper with these encouraging words:
A sufficient understanding of the avian H5N1 HA mutations leading to long α2-6 binding specificity offers an opportunity for intervention through vaccine development to negate the eventuality of a H5N1 pandemic.
Now while I am happy that the threat may not be as imminent as I thought it was, I must point out that H5N1 flu is still one of the nastiest pandemic prospects facing humanity. The virus is established as an endemic pathogen worldwide, meaning it could break into the human population just about anywhere people keep domestic poultry. While the threat of mutation leading to rapid adaptation may be a lot less severe than we thought, there is still the possibility of
recombination / reassortment leading to a virulent, human-adapted virus - and we should recall that the flu pandemics of the 1950s and 1960s were due to reassortment between the prevailing H1N1 virus and a H2N2 type in 1957, and between a H3-containing virus and the prevailing H2N2 in 1968. And the contributing avian viruses were nowhere near as well distributed as H5N1 is now, nor as virulent …
So the apocalypse is still nigh - but possibly less nigh than we may have thought. However, as the inimitable Gregory House has observed, “It’s not paranoia if they’re really after you”. And I think they still are.
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Related:
January 15, 2008 at 6:55 am
Spread of avian flu by drinking water
There is a widespread link between avian flu and water, e.g. in Egypt to the Nile delta or Indonesia to residential districts of less prosperous humans with backyard flocks and without central water supply as in Vietnam: http://www.cdc.gov/ncidod/EID/vol12no12/06-0829.htm. See also the WHO webside: http://www.who.int/water_sanitation_health/emerging/h5n1background.pdf and http://www.umwelt-medizin-gesellschaft.de/ abstract in English “Influenza: Initial introduction of influenza viruses to the population via abiotic water supply versus biotic human viral respirated droplet shedding” and http://www.thelancet.com/journals/laninf/article/PIIS1473309907700294/abstract?iseop=true “Transmission of influenza A in human beings”.
Avian flu infections may increase in consequence to increase of virus circulation. Transmission of avian flu by direct contact to infected poultry is an unproved assumption from the WHO. Infected poultry can everywhere contaminate the drinking water. All humans have contact to drinking water. Special in cases of small water supplies this pathway can explain small clusters in households. In hot climates and the tropics flood-related influenza is typical after extreme weather and natural after floods. The virulence of the influenza virus depends on temperature and time. If young and fresh H5N1 contaminated water from low local wells, cisterns, tanks, rain barrels or rice fields is used for water supply the water temperature for infection may be higher (at 24°C the virulence of influenza viruses amount to 2 days) as in temperate climates (for “older” water from central water supplies cold water is decisive to virulence of viruses: at 7°C the virulence of influenza viruses amount to 14 days).
Human to human and contact transmission of influenza occur - but are overvalued immense. In the course of influenza epidemics in Germany, recognized clusters are rare, accounting for just 9 percent of cases e.g. in the 2005 season. In temperate climates the lethal H5N1 virus will be transferred to humans via cold drinking water, as with the birds in February and March 2006, strong seasonal at the time when drinking water has its temperature minimum.
The performance to eliminate viruses from the drinking water processing plants regularly does not meet the requirements of the WHO and the USA/USEPA. Conventional disinfection procedures are poor, because microorganisms in the water are not in suspension, but embedded in particles. Even ground water used for drinking water is not free from viruses.
In temperate climates strong seasonal waterborne infections like the norovirus, rotavirus, salmonella, campylobacter and - differing from the usual dogma - influenza are mainly triggered by drinking water, dependent on the water’s temperature (in Germany it is at a minimum in February and March and at a maximum in August). There is no evidence that influenza primarily is transmitted by saliva droplets. In temperate climates the strong interdependence between influenza infections and environmental temperatures can’t be explained by the primary biotic transmission by saliva droplets from human to human at temperatures of 37.5°C. There must be an abiotic vehicle like cold drinking water. There is no other appropriate abiotic vehicle. In Germany about 98 percent of inhabitants have a central public water supply with older and better protected water. Therefore, in Germany cold water is decisive to the virulence of viruses.
Dipl.-Ing. Wilfried Soddemann - Free Science Journalist - soddemann-aachen@t-online.de - http://www.dugi-ev.de/information.html - Epidemiological Analysis: http://www.dugi-ev.de/TW_INFEKTIONEN_H5N1_20071019.pdf
January 20, 2008 at 5:41 pm
While this is very interesting, and may well explain the puzzling epidemiology of influenza outbreaks - with pronounced winter peaks in temperate countries - I think that would be “epidemiology” or “infectivity” rather than “virulence”, in several places above.
And I would imagine it would explain things far better for countries with water than is less purified than is the norm in Germany?
Still, more surprising thaings have happened - like a recent statement that influenza virions can survive for far longer in the dried state than was previously believed, especially when in the presence of solutes as are found in saliva…go on, Google it for yourselves!