Swine Influenza A Viruses and the Tangled Relationship with Humans

Abstract

Influenza A viruses (IAVs) are the causative agents of one of the most important viral respiratory diseases in pigs and humans. Human and swine IAV are prone to interspecies transmission, leading to regular incursions from human to pig and vice versa. This bidirectional transmission of IAV has heavily influenced the evolutionary history of IAV in both species. Transmission of distinct human seasonal lineages to pigs, followed by sustained within-host transmission and rapid adaptation and evolution, represent a considerable challenge for pig health and production. Consequently, although only subtypes of H1N1, H1N2, and H3N2 are endemic in swine around the world, extensive diversity can be found in the hemagglutinin (HA) and neuraminidase (NA) genes, as well as the remaining six genes. We review the complicated global epidemiology of IAV in swine and the inextricably entangled implications for public health and influenza pandemic planning.

Figure 1.

Phylogeny of H1 and H3 influenza A virus hemagglutinin genetic lineages of contemporary influenza A virus in global swine. The best-known tree was inferred using maximum likelihood methods for 637 H1 swine hemagglutinin gene sequences showing the three major lineages collected globally from 2016 to September 2019, and from the United States from March 2019 to September 2019: 1A classical swine lineage; 1B human seasonal lineage; and 1C Eurasian avian lineage (A). For the H3 HA, there were 335 swine HA genes collected globally from 2016 to September 2019 and from the United States from March 2019 to September 2019 (B). “Other” designations in H1 and H3 represent reference human or swine HA genes that have yet to be classified within the global nomenclature system, or lack current evidence of sustained transmission. Branch color represents geographic groups and include North America with data from Canada, Mexico, and United States; Central and South America with data from Argentina, Brazil, and Chile; Europe with data from Belgium, Czech Republic, Denmark, England, France, Germany, Italy, and Spain; East Asia with data from China, Japan, and South Korea; Southeast Asia with data from Thailand and Vietnam; North Asia with data from Russia; and the Pacific with data from Australia. Each tree is midpoint-rooted for clarity; all branch lengths are drawn to scale; and the scale bar indicates the number of nucleotide substitutions per site.

Figure 2.

The major N1 and N2 neuraminidase genetic lineages and geographic distribution of contemporary influenza A virus in global swine. (A) The best-known tree was inferred using maximum likelihood methods for 255 swine N1 NA sequences collected globally from 2016 to September 2019 and from the United States from March 2019 to September 2019; and (B) 552 swine N2 NA sequences collected globally from 2016 to September 2019, and from the United States from March 2019 to September 2019. Branch color represents geographic groups and include North America with data from Canada and United States; Central and South America with data from Argentina, Brazil, and Chile; Europe with data from Czech Republic, France, Germany, Italy, and Spain; East Asia with data from China, Japan, and South Korea; Southeast Asia with data from Thailand and Vietnam; North Asia with data from Russia; and the Pacific with data from Australia. The lineage of N1 NA is indicated by solid black lines on the right of the tree in A. The decade of introduction of human seasonal N2 NA gene into swine populations is indicated by solid black lines on the right of the tree in B (e.g., the 1970s includes the introduction in Europe, the 2000s includes the 2002 lineage in North American swine, etc.); the trees are midpoint-rooted for clarity; branch lengths are drawn to scale; and the scale bars indicate the number of nucleotide substitutions per site.

Figure 3.

H1 and H3 influenza A virus hemagglutinin phylogenetic lineages of contemporary influenza A virus in global swine. The trees were inferred using maximum likelihood methods for randomly subsampled HA gene sequences, maintaining proportional representation of swine clades detected in the United States from March 2019 to September 2019 and from remaining global countries from 2016 to September 2019. (A) The 1A classical swine lineage; (B) 1B human seasonal lineage; (C) 1C Eurasian avian lineage; and (D) H3 swine lineages. Branch color represents swine genetic clade; reported human variant strain names are colored in orange; candidate vaccine virus strains are indicated by a red star; H1 and H3 human seasonal vaccine strains by a red square; and strains tested by hemagglutination inhibition assays as antigen or antisera by a black triangle. The trees are midpoint-rooted for clarity; branch lengths are drawn to scale; and the scale bars indicate the number of nucleotide substitutions per site.

Figure 3.

H1 and H3 influenza A virus hemagglutinin phylogenetic lineages of contemporary influenza A virus in global swine. The trees were inferred using maximum likelihood methods for randomly subsampled HA gene sequences, maintaining proportional representation of swine clades detected in the United States from March 2019 to September 2019 and from remaining global countries from 2016 to September 2019. (A) The 1A classical swine lineage; (B) 1B human seasonal lineage; (C) 1C Eurasian avian lineage; and (D) H3 swine lineages. Branch color represents swine genetic clade; reported human variant strain names are colored in orange; candidate vaccine virus strains are indicated by a red star; H1 and H3 human seasonal vaccine strains by a red square; and strains tested by hemagglutination inhibition assays as antigen or antisera by a black triangle. The trees are midpoint-rooted for clarity; branch lengths are drawn to scale; and the scale bars indicate the number of nucleotide substitutions per site.

Figure 3.

H1 and H3 influenza A virus hemagglutinin phylogenetic lineages of contemporary influenza A virus in global swine. The trees were inferred using maximum likelihood methods for randomly subsampled HA gene sequences, maintaining proportional representation of swine clades detected in the United States from March 2019 to September 2019 and from remaining global countries from 2016 to September 2019. (A) The 1A classical swine lineage; (B) 1B human seasonal lineage; (C) 1C Eurasian avian lineage; and (D) H3 swine lineages. Branch color represents swine genetic clade; reported human variant strain names are colored in orange; candidate vaccine virus strains are indicated by a red star; H1 and H3 human seasonal vaccine strains by a red square; and strains tested by hemagglutination inhibition assays as antigen or antisera by a black triangle. The trees are midpoint-rooted for clarity; branch lengths are drawn to scale; and the scale bars indicate the number of nucleotide substitutions per site.

Figure 3.

H1 and H3 influenza A virus hemagglutinin phylogenetic lineages of contemporary influenza A virus in global swine. The trees were inferred using maximum likelihood methods for randomly subsampled HA gene sequences, maintaining proportional representation of swine clades detected in the United States from March 2019 to September 2019 and from remaining global countries from 2016 to September 2019. (A) The 1A classical swine lineage; (B) 1B human seasonal lineage; (C) 1C Eurasian avian lineage; and (D) H3 swine lineages. Branch color represents swine genetic clade; reported human variant strain names are colored in orange; candidate vaccine virus strains are indicated by a red star; H1 and H3 human seasonal vaccine strains by a red square; and strains tested by hemagglutination inhibition assays as antigen or antisera by a black triangle. The trees are midpoint-rooted for clarity; branch lengths are drawn to scale; and the scale bars indicate the number of nucleotide substitutions per site.