The complexities of flu in the summer time - where does it go?

Publishing in the journal, PNAS, (free paper here) a group of researchers have uncovered the secrets to the success of influenza viruses in the human population. Using extensive genetic analysis from isolates collected across the world they were able to - for the first time - understand the global dynamics of flu evolution as it makes its way from country to country and year on year.

By building large phylogenetic trees and mapping these on to each country, the group show that rather than staying put in each region every year, influenza makes its way around the world, never staying in one place too long. This they call a 'temporally structured metapopulation', and it is this which is the key to the virus's success by allowing it a continuous presence within our population. These results go contrary with what has been put forward for flu in the past, but where does the virus hide out?

Every year, more temperate zones like Europe, the United States and Australia experience large epidemics of influenza with millions of people affected killing up to half a million people each year.  influenza responsible for the deaths of millions of people each year. In fact we are just beginning to feel it now; starting from November right through until March, the Northern Hemisphere will be assaulted by this virus. Conversely, from May until around September, the Southern Hemisphere will get it. This behavior is probably controlled by climatic and behavioral factors, but what factors, we don't know.  A major question in understanding influenza (and other seasonal pathogens) epidemiology and evolution is, how does the virus move around throughout the year, and where does it go to during our summers?

Two theories have predominated our understanding of the glabal movements of flu: the earliest, suggesting that virus persisted locally - perhaps replicating to low levels or maybe lying dormant within each person only to be re-activated when the environment was right, i.e it was cold.

The other, more recently hypothesized theory, being that flu rather than causing annual epidemics in tropical countries, affected these populations continuously throughout the year (which it does do) and as Autumn/Winter drew up in the temperate regions of the world, the virus would 'seed' into the likes of Europe or Australia. These both would give rise to the observed kinds of epidemics in the different regions. Although the first theory was officially disproved here, the second has become the prevailing thinking. This is pretty important when every year we have t try to predict which strains of flu are going to be introduced into a particular region, based on this theory, we should focus on South-East Asia (tropical regions). But is this correct?

This paper sought to test this 'source-sink' theory through using large data sets of highly surveillanced flu isolates - specifically the common H3N2 strains - from right across the world. 105 full-length genomes were used from Hong Kong as well as a total of 1,266 influenza hemagluttinin (HA) sequences, grouped according to area of isolation: Europe, New York, South-East Asia, Japan, Australia, New Zealand and Hong Kong, thus giving a large scale picture of how flu evolves.

Check out the abstract: (my emphasis)

Populations of seasonal influenza virus experience strong annual bottlenecks that pose a considerable extinction risk. It has been suggested that an influenza source population located in tropical Southeast or East Asia seeds annual temperate epidemics. Here we investigate the seasonal dynamics and migration patterns of influenza A H3N2 virus by analysis of virus samples obtained from 2003 to 2006 from Australia, Europe, Japan, New York, New Zealand, Southeast Asia, and newly sequenced viruses from Hong Kong. In contrast to annual temperate epidemics, relatively low levels of relative genetic diversity and no seasonal fluctuations characterized virus populations in tropical Southeast Asia and Hong Kong. Bayesian phylogeographic analysis using discrete temporal and spatial characters reveal high rates of viral migration between urban centers tested. Although the virus population that migrated between Southeast Asia and Hong Kong persisted through time, this was dependent on virus input from temperate regions and these tropical regions did not maintain a source for annual H3N2 influenza epidemics. We further show that multiple lineages may seed annual influenza epidemics, and that each region may function as a potential source population. We therefore propose that the global persistence of H3N2 influenza A virus is the result of a migrating metapopulation in which multiple different localities may seed seasonal epidemics in temperate regions in a given year. Such complex global migration dynamics may confound control efforts and contribute to the emergence and spread of antigenic variants and drug-resistant viruses.

They note a number of important points:

"Phylogenetic analysis of the HA1 domain showed viruses isolated from the same year and region tended to cluster together, but with frequent mixing with those from other regions." - influenza viruses are continuously being brought into any particular region, although they are not always successful in gaining dominance. One virus usually gets there first.

"....the extensive seasonal outbreaks in these regions generated numerous lineages but very few persist locally through time. For example, most lineages went extinct at the end of the New York 2001–2002 seasonal epidemic, except for individual viruses that were detected in New York 2002–2003." - the viruses which do get there don't hang around for long. In those locations they go extinct Probably due to build up of immune population or environment/behavioral change. See below. 

Flu virus evolution in temperate (yellow) and 'tropical' (pink). Note that in temperate region, only a couple of viruses survive each season, while in tropical regions, many more are continuously found.

"In contrast, multiple lineages cocirculated in both Hong Kong and Southeast Asia, often with a common ancestor that existed 1 to 2 y before virus sampling, thereby providing evidence of some long-term persistence" - this is different in 'tropical' regions. These viruses hang around more often here, albeit at low levels. Is this the case against build up of immunity? Maybe the multiple lineages allow the viruses to get around this. Maybe the climate factors are different here. See above.

Flu genetic diversity year by year in temperate (green/yellow) and tropical (pink) regions.

 

"strong seasonal periodicity in relative genetic diversity in temperate zones, with major fluctuations through time. Southeast Asia and Hong Kong we observe lower levels of relative genetic diversity of influenza than in temperate regions" - this is what you expect given the numbers of cases in each region.See above.

"There are two possible explanations for this pattern: either virus populations are smaller in Hong Kong and Southeast Asia or viruses are repeatedly introduced into Hong Kong and Southeast Asia (where they are not sustained) from other geographic regions experiencing epidemics. Our phylogenetic analysis strongly supports common ancestry of viruses isolated in Hong Kong and Southeast Asia with viruses from other regions. This linkage supports a model of repeated introductions rather than local circulation". Their conclusions based on the data arguing against the source-sink model of South-East Asia.

An example of the complex movement of infuenza around the world in 2005. Temperate zones seed other temperate zones, and even South-East Asian 'tropical' regions.

'Our results showed frequent two-way migration between temperate and tropical Asian regions, as well as direct viral movement between temperate regions. Critically, each model supported populations of viruses migrating between regions with no persistence in Southeast Asia or Hong Kong' - yup, viruses move around the world, (temperate-temperate, temperate - tropical etc). See above.

"no single location seeded every annual epidemic in other locations; rather, multiple geographic regions occupied sections of the tree backbone" - its more complicated than we once thought, influenza viruses don't have to pass through Asia.

"However, our results do show strong support for viral migration to multiple regions each year. For example, viruses from Europe (2003), Japan and Southeast Asia (2004), and Hong Kong (2005) each migrated to two or more other region"

These results highlight the complexity of virus transmission around the world relying on major transportation networks.  It also shows that with reference to developing annual vaccine strains, we shouldn't only focus on South-East Asia but we should also be looking into whats happening in the temperate zones. This should lead to further research on other flu strains over much longer periods of time and with greater resolution on specific cities in each region.  

Bahl J, Nelson MI, Chan KH, Chen R, Vijaykrishna D, Halpin RA, Stockwell TB, Lin X, Wentworth DE, Ghedin E, Guan Y, Peiris JS, Riley S, Rambaut A, Holmes EC, & Smith GJ (2011). Temporally structured metapopulation dynamics and persistence of influenza A H3N2 virus in humans. Proceedings of the National Academy of Sciences of the United States of America, 108 (48), 19359-64 PMID: 22084096