Temporally structured metapopulation dynamics and persistence of influenza A H3N2 virus in humans

Abstract

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.

Fig. 1.

Temporally structured maximum clade credibility phylogenetic tree showing the mixing of H3N2 influenza A virus global populations. This tree is representative of Bayesian sampled trees used to determine geographic structuring at tree tips for isolates sampled in Australia (AU, yellow), Europe (EU, brown), Hong Kong (HK, red), Japan (JP, purple), New York (NY, blue), New Zealand (NZ, green), and Southeast Asia (SEA, pink). Gray bars indicate the northern temperate epidemic season. See SI Appendix, Fig. S3 for virus names.

Fig. 2.

Temporally structured phylogenetic and coalescent analysis of (A) phylogenies generated from all available sequence data of annual epidemics from viruses isolated in each location studied, and (B) Bayesian skyride analysis depicting fluctuating levels of relative genetic diversity from 2002 to 2006 of each location. The x axis indicates time from youngest sampled sequence to the lower 95% confidence interval (CI) of the tree-root height, and the y axis indicates relative genetic diversity (N_et) as estimated from the skyride coalescent analysis. Location of virus isolation is indicated by color (see legend to Fig. 1). See SI Appendix, Figs. S4, S5, S6, S7, S8, S9, and S10 for virus names and SI Appendix, Table S1 for sequence accession numbers.

Fig. 3.

Supported state transitions recovered from the combined independent Bayesian analyses after removal of burnin (n = 15,000 sampling events) for three randomized datasets (solid lines) indicating persistence of a virus metapopulation migrating between geographic regions. Dashed lines indicate state transitions that were supported in two of three randomized datasets. (A) Assumes no seasonality in Southeast Asia or Hong Kong; (B) assumes seasonality that corresponds to epidemics in temperate regions; and (C) groups the metapopulation into three epidemic zones. Location of virus isolation is indicated by color (see legend to Fig. 1).

Fig. 4.

Supported state transitions indicating migration events and directionality between discrete localities from 2003 to 2005 epidemic seasons visualized on a global map (Model 1, Fig. 3A). Geographic regions are indicated by color (see legend to Fig. 1).