Stochastic processes dominate the within and between host evolution of influenza virus

AbstractThe global evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define the dynamics of influenza A virus populations in human hosts through next generation sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected over 5 seasons from individuals in a prospective community-based cohort, they are broadly representative of natural human infections with seasonal viruses. We used viral sequence data from 35 serially sampled individuals to estimate a within host effective population size of 30-70 and an in vivo mutation rate of 4x10−5 per nucleotide per cellular infectious cycle. These estimates are consistent across several models and robust to the models' underlying assumptions. We also identified 43 epidemiologically linked and genetically validated transmission pairs. Maximum likelihood optimization of multiple transmission models estimates an effective transmission bottleneck of 1-2 distinct genomes. Our data suggest that positive selection of novel viral variants is inefficient at the level of the individual host and that genetic drift and other stochastic processes dominate the within and between host evolution of influenza A viruses.

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Stochastic processes constrain the within and between host evolution of influenza virus

eLife ◽

10.7554/elife.35962 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 81

Author(s):

John T McCrone ◽

Robert J Woods ◽

Emily T Martin ◽

Ryan E Malosh ◽

Arnold S Monto ◽

...

Keyword(s):

Influenza Virus ◽

Stochastic Processes ◽

Positive Selection ◽

Evolutionary Dynamics ◽

Sequence Data ◽

Influenza Viruses ◽

Single Nucleotide Variants ◽

Individual Host ◽

The Individual ◽

Host Evolution

The evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define influenza virus dynamics in human hosts through sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected from individuals in a prospective community-based cohort, they are broadly representative of natural infections with seasonal viruses. Consistent with a neutral model of evolution, sequence data from 49 serially sampled individuals illustrated the dynamic turnover of synonymous and nonsynonymous single nucleotide variants and provided little evidence for positive selection of antigenic variants. We also identified 43 genetically-validated transmission pairs in this cohort. Maximum likelihood optimization of multiple transmission models estimated an effective transmission bottleneck of 1–2 genomes. Our data suggest that positive selection is inefficient at the level of the individual host and that stochastic processes dominate the host-level evolution of influenza viruses.

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The effective population size and mutation rate of influenza A virus in acutely infected individuals

10.1101/2020.10.24.353748 ◽

2020 ◽

Author(s):

John T. McCrone ◽

Robert J. Woods ◽

Arnold S. Monto ◽

Emily T. Martin ◽

Adam S. Lauring

Keyword(s):

Population Size ◽

Effective Population Size ◽

Mutation Rate ◽

Influenza A ◽

Evolutionary Dynamics ◽

Sequence Data ◽

Influenza Viruses ◽

Influenza A Viruses ◽

Effective Population

AbstractThe global evolutionary dynamics of influenza viruses ultimately derive from processes that take place within and between infected individuals. Recent work suggests that within-host populations are dynamic, but an in vivo estimate of mutation rate and population size in naturally infected individuals remains elusive. Here we model the within-host dynamics of influenza A viruses using high depth of coverage sequence data from 200 acute infections in an outpatient, community setting. Using a Wright-Fisher model, we estimate a within-host effective population size of 32-72 and an in vivo mutation rate of 3.4×10−6 per nucleotide per generation.

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In vivo reassortment of influenza viruses.

Acta Biochimica Polonica ◽

10.18388/abp.2014_1860 ◽

2014 ◽

Vol 61 (3) ◽

Cited By ~ 5

Author(s):

Kinga Urbaniak ◽

Iwona Markowska-Daniel

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Influenza Pandemic ◽

Genetic Material ◽

Influenza Viruses ◽

Influenza A Viruses ◽

Individual Gene ◽

Different Strains ◽

The Individual

The genetic material of influenza A virus consists of eight negative-sense RNA segments. Under suitable conditions, the segmented structure of the viral genome allows an exchange of the individual gene segments between different strains, causing formation of new reassorted viruses. For reassortment to occur, co-infection with two or more influenza virus strains is necessary. The reassortment is an important evolutionary mechanism which can result in antigenic shifts that modify host range, pathology, and transmission of the influenza A viruses. In this process, the influenza virus strain with epidemic and/or pandemic potential can be created. Cases of this kind were in 1957 (Asian flu), 1968 (Hong Kong flu) and recently in 2009 (Mexico). Viruses containing genes of avian, swine, and/or human origin are widespread around the world, for example the triple reassortant H1N1 virus causing the 2009 influenza pandemic in 2009 that has become a seasonal virus. The aim of the study is to present the mechanism of reassortment and the results of experimental co-infection with different influenza viruses.

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Heterosubtypic Protection Conferred by the Human Monoclonal Antibody PN-SIA28 against Influenza A Virus Lethal Infections in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00118-15 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2647-2653 ◽

Cited By ~ 1

Author(s):

Miguel Retamal ◽

Yacine Abed ◽

Chantal Rhéaume ◽

Francesca Cappelletti ◽

Nicola Clementi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Body Weight ◽

Influenza Virus ◽

Influenza A ◽

Human Monoclonal Antibody ◽

Influenza A Viruses ◽

Virus Challenge ◽

Influenza A H1n1

ABSTRACTPN-SIA28 is a human monoclonal antibody (Hu-MAb) targeting highly conserved epitopes within the stem portion of the influenza virus hemagglutinin (HA) (N. Clementi, et al, PLoS One 6:e28001, 2011,http://dx.doi.org/10.1371/journal.pone.0028001). Previousin vitrostudies demonstrated PN-SIA28 neutralizing activities against phylogenetically divergent influenza A subtypes. In this study, the protective activity of PN-SIA28 was evaluated in mice inoculated with lethal influenza A/WSN/33 (H1N1), A/Quebec/144147/09 (H1N1)pdm09, and A/Victoria/3/75 (H3N2) viruses. At 24 h postinoculation (p.i.), animals received PN-SIA28 intraperitoneally (1 or 10 mg/kg of body weight) or 10 mg/kg of unrelated Hu-MAb (mock). Body weight loss and mortality rate (MR) were recorded for 14 days postinfection (p.i.). Lung viral titers (LVT) were determined at day 5 p.i. In A/WSN/33 (H1N1)-infected groups, all untreated and mock-receiving mice died, whereas MRs of 87.5% and 25% were observed in mice that received PN-SIA28 1 and 10 mg/kg, respectively. In influenza A(H1N1) pdm09-infected groups, an MR of 75% was recorded for untreated and mock-treated groups, whereas the PN-SIA28 1-mg/kg and 10-mg/kg groups had rates of 62.5% and 0%, respectively. In A/Victoria/3/75 (H3N2)-infected animals, untreated and mock-treated animals had MRs of 37.5% and 25%, respectively, and no mortalities were recorded after PN-SIA28 treatments. Accordingly, PN-SIA28 treatments significantly reduced weight losses and resulted in a ≥1-log reduction in LVT compared to the control in all infection groups. This study confirms that antibodies targeting highly conserved epitopes in the influenza HA stem region, like PN-SIA28, not only neutralize influenza A viruses of clinically relevant subtypesin vitrobut also, more importantly, protect from a lethal influenza virus challengein vivo.

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Within-host evolutionary dynamics of seasonal and pandemic human influenza A viruses in young children

eLife ◽

10.7554/elife.68917 ◽

2021 ◽

Vol 10 ◽

Author(s):

Alvin X Han ◽

Zandra C Felix Garza ◽

Matthijs RA Welkers ◽

René M Vigeveno ◽

Nhu Duong Tran ◽

...

Keyword(s):

Young Children ◽

Influenza A ◽

Evolutionary Dynamics ◽

De Novo ◽

Purifying Selection ◽

Influenza Viruses ◽

Human Influenza ◽

Influenza A Viruses ◽

Virus Diversity ◽

Host Evolution

The evolution of influenza viruses is fundamentally shaped by within-host processes. However, the within-host evolutionary dynamics of influenza viruses remain incompletely understood, in part because most studies have focused on infections in healthy adults based on single timepoint data. Here, we analysed the within-host evolution of 82 longitudinally-sampled individuals, mostly young children, infected with A/H1N1pdm09 or A/H3N2 viruses between 2007 and 2009. For A/H1N1pdm09 infections during the 2009 pandemic, nonsynonymous minority variants were more prevalent than synonymous ones. For A/H3N2 viruses in young children, early infection was dominated by purifying selection. As these infections progressed, nonsynonymous variants typically increased in frequency even when within-host virus titres decreased. Unlike the short-lived infections of adults where de novo within-host variants are rare, longer infections in young children allow for the maintenance of virus diversity via mutation-selection balance creating potentially important opportunities for within-host virus evolution.

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Interleukin-15 Is Critical in the Pathogenesis of Influenza A Virus-Induced Acute Lung Injury

Journal of Virology ◽

10.1128/jvi.02030-09 ◽

2010 ◽

Vol 84 (11) ◽

pp. 5574-5582 ◽

Cited By ~ 32

Author(s):

Risa Nakamura ◽

Naoyoshi Maeda ◽

Kensuke Shibata ◽

Hisakata Yamada ◽

Tetsuo Kase ◽

...

Keyword(s):

T Cells ◽

Influenza Virus ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Virus Infection ◽

Severe Pneumonia ◽

Influenza A Viruses ◽

Highly Pathogenic ◽

Interleukin 15

ABSTRACT Highly pathogenic influenza A viruses cause acute severe pneumonia to which the occurrence of “cytokine storm” has been proposed to contribute. Here we show that interleukin-15 (IL-15) knockout (KO) mice exhibited reduced mortality after infection with influenza virus A/FM/1/47 (H1N1, a mouse-adapted strain) albeit the viral titers of these mice showed no difference from those of control mice. There were significantly fewer antigen-specific CD44+ CD8+ T cells in the lungs of infected IL-15 KO mice, and adoptive transfer of the CD8+ T cells caused reduced survival of IL-15 KO mice following influenza virus infection. Mice deficient in β2-microglobulin by gene targeting and those depleted of CD8+ T cells by in vivo administration of anti-CD8 monoclonal antibody displayed a reduced mortality rate after infection. These results indicate that IL-15-dependent CD8+ T cells are at least partly responsible for the pathogenesis of acute pneumonia caused by influenza A virus.

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Comparison of Avian and Human Influenza A Viruses Reveals a Mutational Bias on the Viral Genomes

Journal of Virology ◽

10.1128/jvi.01414-06 ◽

2006 ◽

Vol 80 (23) ◽

pp. 11887-11891 ◽

Cited By ~ 86

Author(s):

Raul Rabadan ◽

Arnold J. Levine ◽

Harlan Robins

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Genomic Sequence ◽

Sequence Data ◽

H1n1 Influenza ◽

Mutational Bias ◽

Influenza A Viruses ◽

Viral Genomes ◽

Avian Influenza Virus H5n1 ◽

History Of

ABSTRACT In the last few years, the genomic sequence data for thousands of influenza A virus strains, including the 1918 pandemic strain, and hundreds of isolates of the avian influenza virus H5N1, which is causing an increasing number of human fatalities, have become publicly available. This large quantity of sequence data allows us to do comparative genomics with the human and avian versions of the virus. We find that the nucleotide compositions of influenza A viruses infecting the two hosts are sufficiently different that we can determine the host at almost 100% accuracy. This assignment works at the segment level, which allows us to construct the reassortment history of individual segments within each strain. We suggest that the different nucleotide compositions can be explained by a host-dependent mutation bias. To support this idea, we estimate the fixation rates for the different polymerase segments and the ratios of synonymous to nonsynonymous changes. Additionally, we provide evidence supporting the hypothesis that the H1N1 influenza virus entered the human population just prior to the 1918 outbreak, with an earliest bound of 1910.

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Contrasting the epidemiological and evolutionary dynamics of influenza spatial transmission

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2012.0199 ◽

2013 ◽

Vol 368 (1614) ◽

pp. 20120199 ◽

Cited By ~ 30

Author(s):

Cécile Viboud ◽

Martha I. Nelson ◽

Yi Tan ◽

Edward C. Holmes

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Large Scale ◽

Evolutionary Dynamics ◽

Spatial Scales ◽

Epidemiological Data ◽

Influenza Viruses ◽

Future Research ◽

Influenza A Viruses ◽

Molecular Studies

In the past decade, rapid increases in the availability of high-resolution molecular and epidemiological data, combined with developments in statistical and computational methods to simulate and infer migration patterns, have provided key insights into the spatial dynamics of influenza A viruses in humans. In this review, we contrast findings from epidemiological and molecular studies of influenza virus transmission at different spatial scales. We show that findings are broadly consistent in large-scale studies of inter-regional or inter-hemispheric spread in temperate regions, revealing intense epidemics associated with multiple viral introductions, followed by deep troughs driven by seasonal bottlenecks. However, aspects of the global transmission dynamics of influenza viruses are still debated, especially with respect to the existence of tropical source populations experiencing high levels of genetic diversity and the extent of prolonged viral persistence between epidemics. At the scale of a country or community, epidemiological studies have revealed spatially structured diffusion patterns in seasonal and pandemic outbreaks, which were not identified in molecular studies. We discuss the role of sampling issues in generating these conflicting results, and suggest strategies for future research that may help to fully integrate the epidemiological and evolutionary dynamics of influenza virus over space and time.

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Nanopore metagenomic sequencing of influenza virus directly from respiratory samples: diagnosis, drug resistance and nosocomial transmission

10.1101/2020.04.21.20073072 ◽

2020 ◽

Author(s):

Yifei Xu ◽

Kuiama Lewandowski ◽

Louise O Downs ◽

James Kavanagh ◽

Thomas Hender ◽

...

Keyword(s):

Drug Resistance ◽

Influenza Virus ◽

Influenza A ◽

Sequence Data ◽

Diagnostic Testing ◽

Nosocomial Transmission ◽

Molecular Diagnostic ◽

Metagenomic Sequencing ◽

Influenza A Viruses ◽

Genome Phylogeny

ABSTRACTBackgroundInfluenza virus presents a significant challenge to public health by causing seasonal epidemics and occasional pandemics. Nanopore metagenomic sequencing has the potential to be deployed for near-patient testing, providing rapid diagnosis of infection, rationalising antimicrobial therapy, and supporting interventions for infection control. This study aimed to evaluate the applicability of this sequencing approach as a routine laboratory test for influenza in clinical settings.MethodsWe conducted Nanopore metagenomic sequencing for 180 respiratory samples from a UK hospital during the 2018/19 influenza season, and compared results to routine molecular diagnostic testing. We investigated drug resistance, genetic diversity, and nosocomial transmission using influenza sequence data.ResultsMetagenomic sequencing was 83% (75/90) sensitive and 93% (84/90) specific for detecting influenza A viruses compared with the diagnostic standard (Cepheid Xpress/BioFire FilmArray Respiratory Panel). We identified a H3N2 genome with the oseltamivir resistant S331R mutation in the NA protein, potentially associated with the emergence of a distinct intra-subtype reassortant. Whole genome phylogeny refuted suspicions of a transmission cluster in the infectious diseases ward, but identified two other clusters that likely reflected nosocomial transmission, associated with a predominant strain circulating in the community. We also detected a range of other potentially pathogenic viruses and bacteria from the metagenome.ConclusionNanopore metagenomic sequencing can detect the emergence of novel variants and drug resistance, providing timely insights into antimicrobial stewardship and vaccine design. Generation of full genomes can contribute to the investigation and management of nosocomial outbreaks.

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The within-host evolutionary dynamics of seasonal and pandemic human influenza A viruses in young children

10.1101/2021.03.20.436248 ◽

2021 ◽

Author(s):

Alvin X. Han ◽

Zandra C. Felix Garza ◽

Matthijs R. A. Welkers ◽

Rene M. Vigeveno ◽

Nhu Duong Tran ◽

...

Keyword(s):

Young Children ◽

Influenza A ◽

Evolutionary Dynamics ◽

Average Duration ◽

Purifying Selection ◽

Influenza Viruses ◽

Human Influenza ◽

Influenza A Viruses ◽

Virus Diversity ◽

Host Evolution

The evolution of influenza viruses is fundamentally shaped by within-host processes. However, the within-host evolutionary dynamics of influenza viruses remain incompletely understood, in part because most studies have focused on within-host virus diversity of infections in otherwise healthy adults based on single timepoint data. Here, we analysed the within-host evolution of 82 longitudinally sampled individuals, mostly young children, infected with A/H3N2 or A/H1N1pdm09 viruses between 2007 and 2009. For A/H1N1pdm09 infections during the 2009 pandemic, nonsynonymous changes were common early in infection but decreased or remained constant throughout infection. For A/H3N2 viruses, early infection was dominated by purifying selection. However, as the A/H3N2 infections progressed for longer-than-average duration (up to 2 weeks) in relatively young or influenza naive individuals, nonsynonymous variants increased in frequencies even though within-host virus titres decreased, leading to the maintenance of virus diversity via mutation-selection balance and provide important opportunities for within-host virus evolution.

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