Vet Microbiol . Mutations in PB2 and HA are crucial for the increased virulence and transmissibility of H1N1 swine influenza virus in mammalian models

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Vet Microbiol


. 2021 Dec 21;265:109314.
doi: 10.1016/j.vetmic.2021.109314. Online ahead of print.
Mutations in PB2 and HA are crucial for the increased virulence and transmissibility of H1N1 swine influenza virus in mammalian models


Junyi Hu ¹ , Zhe Hu ¹ , Yandi Wei ¹ , Ming Zhang ² , Senlin Wang ¹ , Qi Tong ¹ , Honglei Sun ¹ , Juan Pu ¹ , Jinhua Liu ¹ , Yipeng Sun ³



Affiliations

• PMID: 34963076
• DOI: 10.1016/j.vetmic.2021.109314

Abstract

Genetic analyses indicated that the pandemic H1N1/2009 influenza virus originated from a swine influenza virus (SIV). However, SIVs bearing the same constellation of genetic features as H1N1/2009 have not been isolated. Understanding the adaptation of SIVs with such genotypes in a new host may provide clues regarding the emergence of pandemic strains such as H1N1/2009. In this study, an artificial SIV with the H1N1/2009 genotype (rH1N1) was sequentially passaged in mice through two independent series, yielding multiple mouse-adapted mutants with high genetic diversity and increased virulence. These experiments were meant to mimic genetic bottlenecks during adaptation of wild viruses with rH1N1 genotypes in a new host. Molecular substitutions in the mouse-adapted variants mainly occurred in genes encoding surface proteins (hemagglutinin [HA] and neuraminidase [NA]) and polymerase proteins (polymerase basic 2 [PB2], polymerase basic 1 [PB1], polymerase acid [PA] proteins and nucleoprotein [NP]). The PB2_D309N and HA_L425M substitutions were detected at high frequencies in both passage lines and enhanced the replication and pathogenicity of rH1N1 in mice. Moreover, these substitutions also enabled direct transmission of rH1N1 in other mammals such as guinea pigs. PB2_D309N showed enhanced polymerase activity and HA_L425M showed increased stability compared with the wild-type proteins. Our findings indicate that if SIVs with H1N1/2009 genotypes emerge in pigs, they could undergo rapid adaptive changes during infection of a new host, especially in the PB2 and HA genes. These changes may facilitate the emergence of pandemic strains such as H1N1/2009.

Keywords: Mutation; Replication; Swine influenza virus; Transmission.