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doi: 10.7554/eLife.16777.

Origins of the 2009 H1N1 influenza pandemic in swine in Mexico

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Origins of the 2009 H1N1 influenza pandemic in swine in Mexico

Ignacio Mena et al. Elife..

Abstract

Asia is considered an important source of influenza A virus (IAV) pandemics, owing to large, diverse viral reservoirs in poultry and swine. However, the zoonotic origins of the 2009 A/H1N1 influenza pandemic virus (pdmH1N1) remain unclear, due to conflicting evidence from swine and humans. There is strong evidence that the first human outbreak of pdmH1N1 occurred in Mexico in early 2009. However, no related swine viruses have been detected in Mexico or any part of the Americas, and to date the most closely related ancestor viruses were identified in Asian swine. Here, we use 58 new whole-genome sequences from IAVs collected in Mexican swine to establish that the swine virus responsible for the 2009 pandemic evolved in central Mexico. This finding highlights how the 2009 pandemic arose from a region not considered a pandemic risk, owing to an expansion of IAV diversity in swine resulting from long-distance live swine trade.

Keywords: 2009 pandemic; epidemiology; evolution; global health; infectious disease; influenza A virus; microbiology; phylogeography; swine; virus; zoonosis.

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Conflict of interest statement

The authors declare that no competing interests exist.

Figures

Figure 1.
Figure 1.. Live swine production in Mexico.
Each Mexican state is shaded according to the density of pigs (the number of pigs per square kilometer, light green = lower and dark blue = higher). The six Mexican states where influenza viruses were collected for this study are indicated, and the number of pigs in the state is provided below the state’s name. Source data from Mexico’s Secretariat of Agriculture, Livestock, Rural Development, Fisheries and Food (SAGARPA) is available in Figure 1—source data 1.DOI:http://dx.doi.org/10.7554/eLife.16777.003
Figure 2.
Figure 2.. Genetic diversity of IAVs in Mexican swine, 2010–2014.
Twelve genotypes were identified by surveillance in Mexican swien herds during 2010–2014. Each oval represents one of the eight segments of the viral genome. The surface antigens HA and NA are listed first, followed by the six internal gene segments. The shading of each oval corresonds to the genetic lineage of IAVs found in humans and swine globally. The number of swIAVs with a given genotype is indicated for each region in Mexico : Sonora (northern Mexico), Jalisco/Aguascalientes/Guanajuato (central-west Mexico), Puebla (central-east Mexico), and Yucatan (eastern Mexico). The genotype and additional characteristics of each of the 58 swIAVs collected and sequenced from Mexico for this study are provided in Figure 2—source data 1.DOI:http://dx.doi.org/10.7554/eLife.16777.005
Figure 3.
Figure 3.. Evolutionary relationships between swIAVs collected in Mexico and pdmH1N1.
Time-scaled Bayesian MCC trees inferred for the eight segments of the IAV genome, for the lineages found in pdmH1N1: TRIG (PB2, PB1, PA, NP, and NS), classical (H1), and avian-like Eurasian (N1 and MP). Trees include the 58 swIAVs collected in Mexico for this study, representative pdmH1N1 viruses, and other related swIAVs collected globally. The color of each branch indicates the most probable location state. For clarity, the pdmH1N1 clade is depicted as a triangle, the color of which represents the inferred location state of the node representing the inferred common ancestor of pdmH1N1 and the most closely related swIAVs (indicated by an open circle). Posterior probabilities are provided for key nodes. More detailed phylogenies including tip labels are provided in Figure 3—source data 1. along with trees inferred for lineages not shown here. Similar phylogenies inferred using maximum likelihood methods are provided in Figure 3—source data 2. Similar phylogenies that use genotype instead of geographic location as a trait are provided in Figure 3—source data 3. Nine Mexican swIAVs were excluded from the phylogenetic analysis because they were outliers in root-to-tip divergence (Figure 3—figure supplement 1). More detailed phylogenies of the pdmH1N1 viruses reveal multiple independent introductions from humans into swine in Mexico (Figure 3—source data 4).DOI:http://dx.doi.org/10.7554/eLife.16777.007
Figure 3—figure supplement 1.
Figure 3—figure supplement 1.. Mexican swIAVs excluded from the phylogenetic analysis.
A residual analysis was used to identify outliers from the linear regression line describing the relationship between the date of collection and genetic distances of sequences in our analysis. Nine swIAVs from Mexico were identified as outliers and removed from our analysis. These viruses were collected in 2010 but are closely related to reference triple reassortant viruses from 1998–1999.DOI:http://dx.doi.org/10.7554/eLife.16777.012
Figure 4.
Figure 4.. Heat-maps of IAV gene flow between locations.
'Markov jump' counts measure the number of inferred transitions, modeled by a continuous-time Markov chain process, that occur along the branches of the phylogeny, providing a measure of gene flow. The intensity of the color (red = high; white = low) reflects the number of Markov jump counts from a swine population in a location of origin (y-axis) to swine in one of six Mexican states (destination, x-axis; asymmetrical, summarized across all lineages and segments), and between human populations in Mexico, the United States, and globally during the early spatial dissemination of pdmH1N1 in humans during March–May 2009. Asterisks indicate the geographical source (y-axis) of the highest number of Markov jump counts for a particular destination (x-axis). Similar spatial linkages were observed using a Bayes factor (BF) test (Figure 4—figure supplement 1). A phylogenetic tree depicting the evolutionary relationships between human pdmH1N1 viruses is provided in Figure 4—figure supplement 2. Source data for both heat-maps is provided in Figure 4—source data 1.DOI:http://dx.doi.org/10.7554/eLife.16777.013
Figure 4—figure supplement 1.
Figure 4—figure supplement 1.. Supported rates of viral migration.
Bayes factor (BF) test for significant non-zero rates of swIAV migration in Mexico. Rates supported by a BF greater than 5 are indicated. The color of the line represents the relative strength of support for a rate; red lines indicate strong support and pale yellow lines indicate weaker support. For the 5 TRIG segments (PB2, PB1, PA, NP, and NS), the average BF is provided. The direction of viral flow is indicated by the line’s gradient, with the white end indicating the source location. The dotted lines indicate that rates between Asia and Mexico likely arise from gaps in sampling in Eurasian swine prior to 1995, and are unlikely to represent actual viral movements from Asia to Mexico.DOI:http://dx.doi.org/10.7554/eLife.16777.015
Figure 4—figure supplement 2.
Figure 4—figure supplement 2.. Phylogeography of pdmH1N1 in humans.
Evolutionary relationships between pdmH1N1 viruses collected in humans globally during March 1, 2009–May 31, 2009, inferred for 422 concatenated genome sequences. The color of each branch indicates the most probable location state: red = Asia; orange = Canada; yellow = Europe; light green = Mexico, for which the state of location was not known; green = Mexico City, Mexico; greenish blue = San Luis Potosi, Mexico; light blue = Veracruz, Mexico; blue = South America; bluish purple = Northeastern United States, including New York; purple = Midwestern United States, including Wisconsin; pink = Southern United States, including Texas; and coral = Western United States, including California. Select spatial clusters are labeled. Posterior probabilities >80 are provided for key nodes.DOI:http://dx.doi.org/10.7554/eLife.16777.016
Figure 5.
Figure 5.. Import of live swine and IAVs into Mexico.
The value of live swine imported into Mexico (USD, y-axis, left) from all countries during 1969–2010 is presented in the background in pink, based on trade data reported to the Food and Agricultural Organization (FAO) of the United Nationals, available in Figure 5—source data 1. Each horizontal line represents an introduction of an IAV segment into Mexican swine, the timing of which is inferred from the MCC trees. The shading of each line indicates the inferred location of origin of an introduction, consistent with Figure 3: dark pink = USA/Canadian swine, black = Eurasian swine, grey = humans. The length of the line indicates uncertainty in the timing of an introduction. Triangles represent clades resulting from onward transmission in Mexico and extend forward as far as the most recently sampled virus. The shading of each triangle indicates the destination location, consistent with Figure 3: dark purple = Yucatan, dark blue = Sonora, light blue = Puebla, and green = Jalisco, Aguascalientes, and Guanajuato (central-west Mexico). Lines without triangles represent singletons. A similar figure annotated with the segment associated with each introduction is provided in Figure 5—figure supplement 1.DOI:http://dx.doi.org/10.7554/eLife.16777.017
Figure 5—figure supplement 1.
Figure 5—figure supplement 1.. Similar to Figure 5, but annotated with the segment associated with each introduction.
DOI:http://dx.doi.org/10.7554/eLife.16777.019
Figure 6.
Figure 6.. Sources of live swine imports into Mexico.
Total imports of live swine into Mexico (USD) during 1996–2012 from nine reported trade partners: United States, Canada, Ireland, United Kingdom, Denmark, Spain, Guatemala, Guyana, and Peru. The shade of the line indicates the volume of imports (red = high, purple = low). The shading countries is for purposes of clarity only. Trade data is available from the UN Commodity Statistics Database (Figure 6—source data 1).DOI:http://dx.doi.org/10.7554/eLife.16777.020
Figure 7.
Figure 7.. Timing and location of swine ancestors of pdmH1N1.
The color of each dot represents the inferred location of the node representing the common ancestor of pdmH1N1 viruses and the most closely related swine ivurses (indicated by open circles on the MCC trees in Figure 3), for a posterior distribution of ~2000 trees inferred for each segment. A high proportion of blue dots indicates a higher proportion of trees with Mexico as the inferred location state. The x-axis indicates the tMRCA of the same node, again for each tree. The 95% HPD is provided in brackets. Older tMRCAs are associated with longer phylogenetic branch lengths and gaps in sampling.DOI:http://dx.doi.org/10.7554/eLife.16777.022
Figure 8.
Figure 8.. Origins of pdmH1N1.
Summary of the migration and reassortment events leading to the emergence of pdmH1N1 precursor viruses in central-west Mexican swine. Segments from classical and Eurasian viruses for which there is no evidence of onward transmission in central-west Mexican swine are indicated with short horizontal lines.DOI:http://dx.doi.org/10.7554/eLife.16777.024
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