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Background
On Friday, April 24, 2009, news about a new and apparently severe form of influenza causing illness in Mexico and the United States spread around the globe. The virus apparently originates from pigs and is different from human influenza viruses. It has infected humans and possesses the capacity to transmit from human to human (H2H transmission), thus affording the potential of spreading quickly through the human population. At the same time, the new virus seems to be capable of causing severe disease. By Monday, April 27, 2009 more than 100 deaths have been reported in Mexico. Furthermore, additional suspect infections have been found globally, with several cases already confirmed to be caused by the new virus. At the time of this writing the magnitude of the threat is unclear. If the spread of the virus continues, we will have to prepare for the possibility of many people getting sick. It is also still unclear how severe the disease caused by this novel virus will be. If we are lucky infected people will not tend to get severely ill. At any rate, many countries are taking serious precautions and the media report thoroughly on this issue.
Figure 1: Micrograph of influenza viruses
(picture courtesy U.S. Centers for Disease Control & Prevention, Atlanta, USA)
Basis of the Disease – The Influenza Virus
To elucidate the origin of a new strain of the influenza virus, scientists resort to analyzing its genome sequence. The flu virus has an RNA genome with a length of between 10,000 and 15,000 nucleotides, which comes in eight separate pieces, or so-called segments. Each segment codes for one or more proteins of the virus. Two proteins that the virus carries on its surface are of particular importance for the capability of the virus to infect organisms: The hemagglutinin protein facilitates attachment of the virus to the cell that it is going to infect and entry into the host cell. Once it has entered a cell, the virus reprograms it to produce more virus particles. These particles eventually assemble, separate from the cell and can subsequently infect other cells. The separation is partly facilitated by another viral surface protein, the neuraminidase protein. The composition of these two proteins is thought to largely determine what tissues are infected in which organisms.
Influenza viruses are not all the same. They vary with respect to their genomes and corresponding proteins. Based on such differences human influenza viruses are classified into the types A, B and C. While viruses of the types B and C circulate at lower abundances, influenza A is responsible for most cases of the human flu. For the influenza A virus, the two proteins mentioned above exist in different variants (subtypes), that are enumerated as H1 to H16 for hemagglutinin and N1 to N9 for neuraminidase. The subtype of a viral strain is a composition of the subtypes of these surface proteins. H1N1 and H3N2 are the currently prevailing subtypes for the human influenza virus A. However, influenza A viruses also exist in other mammals, such as pigs, and in birds. H5N1 is the subtype of the bird flu virus that in recent years has caused much concern regarding the possibility of a species jump from birds to humans and emergence of a novel human adapted variant with the capability of H2H transmission. H1N1 is the subtype of both the Spanish flu pandemic of 1918 and of the novel flu virus responsible for the current outbreak. It is important to note that the subtype does not determine which organism is infected by the virus. The protein characteristics that determine infectiousness are more subtle than can be indicated by the subtype. Thus, there are different H1N1 strains infecting pigs, birds and humans, respectively, for instance.
Figure 2: Evolutionary tree of HA segments of influenza viruses
(picture courtesy U.S. Centers for Disease Control & Prevention, Atlanta, USA)
The fact that the genome of the influenza virus consists of eight separate segments makes this virus especially dangerous. Let us assume that a human is infected by a virus variant H that causes only mild symptoms. Let us further assume that this person gets infected by another viral variant P of an influenza virus originating from pigs. (Such infections can happen through close association of humans with pigs, such as in farm life). If now viruses of both types P and H make it into the same cell of the infected person, their genome segments can mix in this cell and create a new variant PH, a so-called reassortant virus. The variant PH may have the capacity for H2H transmission and at the same time may cause more severe disease in humans than the variant H. Reassortment can also happen – and indeed is known to happen frequently – in the cell of a pig simultaneously infected with more than one virus. This kind of viral lottery takes place wherever different infected species cohabitate. It seems that something like this has happened and that the corresponding virus is responsible for the current outbreak in Mexico since March of this year.
Where Does The New Flu Virus Come From?
The comparative analysis of the viral genome sequences of a newly occurring strain and of other circulating influenza strains can afford insight into the origin of the new viral variant. The scientists at the Influenza Division of the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia have computed evolutionary trees displaying the relative similarities of related segments from several viral strains. The figure shows such a tree for the hemagglutinin segment (figure icon insert and full figure in link). In the tree viral strains are identified by a sample code specifying the viral subtype, the region of origin and year of sampling. Sequences that are more similar to each other occur closer to each other in the tree. The interpretation of this particular tree is as follows: The two red sequences are from the new flu variant that spreads between humans. Very close to these two red sequences which are very similar to each other, are sequences from swine flu viruses from both North America and Eurasia (China) and also a sequence that is not from pigs but from a bird (Turkey). Apparently a reassortment event has occurred between quite different flu strains – something that has not been observed before. In contrast, the currently circulating human H1N1 strains (colored green) are much more distantly related to the new strain, as are other strains of swine flu that have resulted in individual human infections but no subsequent human to human spread (colored blue).
MPII helps facilitate genomic analyses of viral influenza strains
The basis for such an analysis is the availability of sequences for many influenza virus genomes. The Global Initiative on Sharing All Influenza Data (GISAID) is an international independent community of scientists that have come together to facilitate the access to such data for scientists world-wide. The only prerequisite for any scientist to join this community is to agree to a code of conduct for handling the provided data. This code of conduct is central to the success of the GISAID model and has helped to resolve previous hurdles to making such data globally accessible. The Computational Biology Department of the Max Planck Institute for Informatics (MPII) provides the portal to the GISAID site and the database. A special software module hosted by Kisters AG allows for tracking viral samples.
While the GISAID portal has received wide-spread attention through the current influenza outbreak, its original concept goes beyond facilitating support for scientific responses to short-term challenges. In the center of GISAID stands the idea of creating a world-wide scientific community that uses the provided data for increasing our understanding of influenza through computational approaches. Today’s version of the site provides the sequences themselves and basic tools for sequence alignment and the inference of evolutionary trees. These tools help to investigate the origin of newly arising strains. However, many more computational methods are required, including those that predict important phenotypic and clinical properties of the virus. Such properties include target species and tissues for a virus, levels of infectiousness, risk of epidemic spread, risk of a species jump etc. Furthermore, the development of new drugs and vaccines against influenza could be further supported by computational methods. Such tools, once they exist, will be linked to GISAID for easy use over the internet.
To develop such methods more than just viral sequence data is needed. Through community building GISAID in general, and MPII in particular, foster a systematic collection of data beyond the viral sequence information and the development of the respective tools.
In September 2008 and February 2009 the viral strains that are used for vaccine production for the coming influenza seasons in the Southern and Northern Hemisphere, respectively, have been selected using the GISAID data. The current flu outbreak is the third major test for the platform.
In the group of Alice McHardy, MPII is undertaking research on influenza.
| Created: | Uwe Brahm/MPII/DE, 04/28/2009 11:38 AM | Last modified: | Uwe Brahm/MPII/DE, 11/04/2009 07:17 PM |
