Today’s title refers to the perhaps unexpected origins of the recent swine ’flu outbreak, that apparently comes not from the widespread intermingling of wildfowl and table ducks in Asia but via as yet uncertain processes in the western hemisphere. In the previous blog, I summarised some of the issues of swine flu as I saw them. Meanwhile, the e-print scientific literature is starting to become populated with some epidemiological and related analyses (I thank Fiona Tomley of our Institute for Animal Health for drawing my attention to some of them). The general consensus remains that the present outbreak is of a strain that is not excessively virulent, but that during the northern summer (southern winter) a reservoir of infection (in pigs, birds and humans) will build up and the likelihood of mutations or reassortment events producing something considerably nastier will increase significantly. However, all of the uncertainties are very considerable at this stage, since the numbers of cases – and especially fatalities – are (happily) still small. Of 11 known human cases of the (probably related) ‘triple reassortment’ swine flu in the US from 2005-9, analysed via routine surveillance, all recovered. By May 5, 642 cases had been confirmed in the USA. Ferguson and colleagues have estimated R0, the basic reproduction number, of the strain as being between 1.2 and 1.6, the lower end being considered more likely from genetic and other evidence, and with the percentage of fatalities being perhaps around 0.4% (significantly more than ‘Hong Kong’ and ‘Asian’ flu but much less than the strain involved in the ‘Spanish’ flu pandemic), but the exact numbers are sufficiently small to make uncertainties very large, and the analysis is necessarily based on many assumptions about transmissibility and its homogeneity.
Irvine and Brown point out that we still do not know whether the strain of the present pandemic actually originated directly in pigs, and if so of what origin! They state, “It is not known if the particular genotype of H1N1 virus that appears putatively to have originated in Mexico is circulating in North American pigs, but its close similarity to other strains of swine influenza known to be circulating in the region (sharing 6 of 8 gene segments) has led to the assumption that this novel H1N1 strain is derived from pigs”, and “Based on current evidence from surveillance programmes in several European countries, the variant of H1N1 virus recently isolated in human beings has never been reported, and therefore does not appear to be present in the European pig population.” Certainly the situation in European and American pigs seems quite different, so plans based on a unitary model of transmission (and, when numbers of cases merit improving them, any unitary models themselves) are probably inappropriate.
Equally, it remains unclear as to why the strain circulating on North America appears to be much more virulent in Mexico than in e.g. the USA. Differences in the genetic makeup of the relevant human populations are likely a major contributor, but it could as easily be the interaction of the virus with jalapeño peppers or (more plausibly) the host nutritional status generally (which can even influence viral mutation rates) or iron status where, for instance, high iron levels can enhance virulence and virus-induced pathogenesis, iron chelation can reduce it, while increased HO-1 (haem oxygenase 1) levels are protective in mice. Note of course that statistical or experimental bias can be a powerful factor in these kinds of analysis, and there is real danger of excess stratification or ‘data dredging’ when numbers are small. As we acquire more genetic knowledge of these host populations, as well as of the viral sequences, we may get useful clues as to the biochemical bases of human resistance and susceptibility. Some possibilities are known already, e.g. MxA (=Mx1 in mice).
Many of these wide-ranging and complex problems may usefully be attacked by the tools of Science Wikinomics, as has happened in a project using a collaborative environment on the SARS coronoavirus. As is probably by now well known, the pattern of searches at Google (and presumably at other search engines) can reveal the location of potential outbreaks well in advance of their detection by biochemical assays in central locations, a useful and powerful example of Web 2.0 trends and of data-driven science. Readers may also be interested in following events via sites like the CDC flu site, flutrackers, Medical News Today, the NCBI flu resource (paper) and the NIAID Influenza Resource, our NHS, the VLA swine flu site, the WHO flu site and Wikipedia.
And as to the origin of the title of this blog, the original quote, with apologies to the late Ken Kesey, its author (and participant in Jack Kerouac’s “On the road”), is of course “…one flew east, one flew west, One flew over the cuckoo’s nest”.
- Akaike, T., Noguchi, Y., Ijiri, S., Setoguchi, K., Suga, M., Zheng, Y. M., Dietzschold, B. & Maeda, H. (1996). Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proc Natl Acad Sci U S A 93, 2448-53. Free full text
- Bao, Y., Bolotov, P., Dernovoy, D., Kiryutin, B., Zaslavsky, L., Tatusova, T., Ostell, J. & Lipman, D. (2008). The influenza virus resource at the National Center for Biotechnology Information. J Virol 82, 596-601. Free full text
- Beck, M. A., Handy, J. & Levander, O. A. (2004). Host nutritional status: the neglected virulence factor. Trends Microbiol 12, 417-23
- Broadhurst, D. & Kell, D. B. (2006). Statistical strategies for avoiding false discoveries in metabolomics and related experiments. Metabolomics 2, 171-196
- Chung, S. W., Hall, S. R. & Perrella, M. A. (2009). Role of haem oxygenase-1 in microbial host defence. Cell Microbiol 11, 199-207
- Fraser, C., Donnelly, C. A., Cauchemez, S., Hanage, W. P., Van Kerkhove, M. D., Hollingsworth, T. D., Griffin, J., Baggaley, R. F., Jenkins, H. E., Lyons, E. J., Jombart, T., Hinsley, W. R., Grassly, N. C., Balloux, F., Ghani, A. C., Ferguson, N. M., Rambaut, A., Pybus, O. G., Lopez-Gatell, H., Apluche-Aranda, C. M., Chapela, I. B., Zavala, E. P., Guevara, D. M., Checchi, F., Garcia, E., Hugonnet, S. & Roth, C. (2009). Pandemic potential of a strain of influenza A (H1N1) : early findings. Science e-print
- Ginsberg, J., Mohebbi, M. H., Patel, R. S., Brammer, L., Smolinski, M. S. & Brilliant, L. (2009). Detecting influenza epidemics using search engine query data. Nature 457, 1012-1014
- Hashiba, T., Suzuki, M., Nagashima, Y., Suzuki, S., Inoue, S., Tsuburai, T., Matsuse, T. & Ishigatubo, Y. (2001). Adenovirus-mediated transfer of heme oxygenase-1 cDNA attenuates severe lung injury induced by the influenza virus in mice. Gene Ther 8, 1499-507
- Irvine, R. M. & Brown, I. H. (2009). Novel H1N1 influenza in people: global spread from an animal source? Vet Rec 164, 577-8
- Kell, D. B. (2009). Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Medical Genomics 2, 2. Free full text
- Kell, D. B. & Oliver, S. G. (2004). Here is the evidence, now what is the hypothesis? The complementary roles of inductive and hypothesis-driven science in the post-genomic era. Bioessays 26, 99-105
- Kolatkar, A., Kennedy, K., Halabuk, D., Kunken, J., Marrinucci, D., Bethel, K., Guzman, R., Huckaby, T. & Kuhn, P. (2008). C-ME: a 3D community-based, real-time collaboration tool for scientific research and training. PLoS ONE 3, e1621. Free full text
- Nelson, H. K., Shi, Q., Van Dael, P., Schiffrin, E. J., Blum, S., Barclay, D., Levander, O. A. & Beck, M. A. (2001). Host nutritional selenium status as a driving force for influenza virus mutations. FASEB J 15, 1846-8
- Nelson, M. I., Viboud, C., Simonsen, L., Bennett, R. T., Griesemer, S. B., St George, K., Taylor, J., Spiro, D. J., Sengamalay, N. A., Ghedin, E., Taubenberger, J. K. & Holmes, E. C. (2008). Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918. PLoS Pathog 4, e1000012. Free full text
- Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. (2009). Emergence of a Novel Swine-Origin Influenza A (H1N1) Virus in Humans. N Engl J Med. Free full text
- Pavlovic, J., Zürcher, T., Haller, O. & Staeheli, P. (1990). Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol 64, 3370-5
- Rinaldi, A. (2009). Science wikinomics. Mass networking through the web creates new forms of scientific collaboration. EMBO Rep 10, 439-43
- Shinde, V., Bridges, C. B., Uyeki, T. M., Shu, B., Balish, A., Xu, X., Lindstrom, S., Gubareva, L. V., Deyde, V., Garten, R. J., Harris, M., Gerber, S., Vagoski, S., Smith, F., Pascoe, N., Martin, K., Dufficy, D., Ritger, K., Conover, C., Quinlisk, P., Klimov, A., Bresee, J. S. & Finelli, L. (2009). Triple-reassortant swine influenza A (H1) in humans in the United States, 2005-2009. N Engl J Med. E=print. Free full text
- Vidal, S. M., Malo, D., Marquis, J. F. & Gros, P. (2008). Forward genetic dissection of immunity to infection in the mouse. Annu Rev Immunol 26, 81-132
- Visseren, F. L., Verkerk, M. S., van der Bruggen, T., Marx, J. J., van Asbeck, B. S. & Diepersloot, R. J. (2002). Iron chelation and hydroxyl radical scavenging reduce the inflammatory response of endothelial cells after infection with Chlamydia pneumoniae or influenza A. Eur J Clin Invest 32 Suppl 1, 84-90
- Weinberg, E. D. (2008). Iron availability and infection. Biochim Biophys Acta., eprint
Related posts (based on tags and chronology):
It ain’t necessarily sow; the origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic
15 June 2009
If pigs had wings; what we know and what we don’t know about swine flu and bird flu
14 May 2009
When genetics meets the environment…the case of the missing heritability
22 December 2008
03 September 2012
Unilever, Institutes, TSB and Foo
06 February 2012