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Next-Generation Sequencing Analysis of the Within-Host Genetic Diversity of Influenza A(H1N1)pdm09 Viruses in the Upper and Lower Respiratory Tracts of Patients with Severe Influenza.

ABSTRACT: The influenza A(H1N1)pdm09 virus emerged in April 2009 with an unusual incidence of severe disease and mortality, and currently circulates as a seasonal influenza virus. Previous studies using consensus viral genome sequencing data have overlooked the viral genomic and phenotypic diversity. Next-generation sequencing (NGS) may instead be used to characterize viral populations in an unbiased manner and to measure within-host genetic diversity. In this study, we used NGS analysis to investigate the within-host genetic diversity of influenza A(H1N1)pdm09 virus in the upper and lower respiratory samples from nine patients who were admitted to the intensive care unit (ICU). A total of 47 amino acid substitution positions were found to differ between the upper and lower respiratory tract samples from all patients. However, the D222G/N substitution in hemagglutinin (HA) protein was the only amino acid substitution common to multiple patients. Furthermore, the substitution was detected only in the six samples from the lower respiratory tract. Therefore, it is important to investigate influenza A(H1N1)pdm09 virus populations using multiple paired samples from the upper and lower respiratory tract to avoid overlooking potentially important substitutions, especially in patients with severe disease.IMPORTANCE The D222G/N substitution in the hemagglutinin (HA) protein of influenza A(H1N1)pdm09 virus has been reported to be associated with disease severity and mortality in numerous previous studies. In the present study, 75% of lower respiratory samples contained heterogeneous influenza populations that carried different amino acids at position 222 of the HA protein, whereas all upper respiratory samples only contained the wild-type 222D. These results suggest the influenza A(H1N1)pdm09 virus has diversified inside the host owing to differences in tissue specificity. In this study, the within-host genetic diversity of influenza A(H1N1)pdm09 virus was investigated for the first time using next-generation sequencing analysis of the viral whole-genome in samples extracted from the upper and lower respiratory tracts of patients with severe disease.

SUBMITTER: Takayama I

PROVIDER: S-EPMC7845592 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledThe majority of currently circulating influenza A(H1N1) viruses are antigenically similar to the virus that caused the 2009 influenza pandemic. However, antigenic variants are expected to emerge as population immunity increases. Amino acid substitutions in the hemagglutinin protein can result in escape from neutralizing antibodies, affect viral fitness, and change receptor preference. In this study, we constructed mutants with substitutions in the hemagglutinin of A/Netherlands/602/09 in an attenuated backbone to explore amino acid changes that may contribute to emergence of antigenic variants in the human population. Our analysis revealed that single substitutions affecting the loop that consists of amino acid positions 151 to 159 located adjacent to the receptor binding site caused escape from ferret and human antibodies elicited after primary A(H1N1)pdm09 virus infection. The majority of these substitutions resulted in similar or increased replication efficiency in vitro compared to that of the virus carrying the wild-type hemagglutinin and did not result in a change of receptor preference. However, none of the substitutions was sufficient for escape from the antibodies in sera from individuals that experienced both seasonal and pandemic A(H1N1) virus infections. These results suggest that antibodies directed against epitopes on seasonal A(H1N1) viruses contribute to neutralization of A(H1N1)pdm09 antigenic variants, thereby limiting the number of possible substitutions that could lead to escape from population immunity.ImportanceInfluenza A viruses can cause significant morbidity and mortality in humans. Amino acid substitutions in the hemagglutinin protein can result in escape from antibody-mediated neutralization. This allows the virus to reinfect individuals that have acquired immunity to previously circulating strains through infection or vaccination. To date, the vast majority of A(H1N1)pdm09 strains remain antigenically similar to the virus that caused the 2009 influenza pandemic. However, antigenic variants are expected to emerge as a result of increasing population immunity. We show that single amino acid substitutions near the receptor binding site were sufficient to escape from antibodies specific for A(H1N1)pdm09 viruses but not from antibodies elicited in response to infections with seasonal A(H1N1) and A(H1N1)pdm09 viruses. This study identified substitutions in A(H1N1)pdm09 viruses that support escape from population immunity but also suggested that the number of potential escape variants is limited by previous exposure to seasonal A(H1N1) viruses.

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Next-Generation Sequencing Analysis of the Within-Host Genetic Diversity of Influenza A(H1N1)pdm09 Viruses in the Upper and Lower Respiratory Tracts of Patients with Severe Influenza.

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