Mammalian adaptation of influenza A(H7N9) virus is limited by a narrow genetic bottleneck.

Hassan Zaraket¹ Tatiana Baranovich² Bryan S Kaplan² Robert Carter³ Min-Suk Song² James C Paulson⁴ Jerold E Rehg⁵ Justin Bahl⁶ Jeri C Crumpton² Jon Seiler² Michael Edmonson³ Gang Wu³ Erik Karlsson² Thomas Fabrizio² Huachen Zhu⁷ Yi Guan⁷ Matloob Husain⁸ Stacey Schultz-Cherry² Scott Krauss² Ryan McBride⁴ Robert G Webster² Elena A Govorkova² Jinghui Zhang³ Charles J Russell⁹ Richard J Webby⁹

Affiliations 9 institutions

1] Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA [2] Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, PO Box 11-0236 Riad El Solh, Beirut 1107 2020, Lebanon.
Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA.
Department of Computation Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA.
Departments of Cell and Molecular Biology and Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM-L71, La Jolla, California 92037, USA.
Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA.
School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston Texas 77030 USA.
Joint Influenza Research Center (Shantou University Medical College &Hong Kong University), Shantou University Medical College, Shantou, Guangdong 515031, PR China.
Department of Microbiology and Immunology, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
1] Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, USA [2] Department of Microbiology, Immunology &Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.

PMID25850788 DOI10.1038/ncomms7553 Year2015 Journal Nature communications Nat Commun Languageeng Statusepublish

Abstract

Human infection with avian influenza A(H7N9) virus is associated mainly with the exposure to infected poultry. The factors that allow interspecies transmission but limit human-to-human transmission are unknown. Here we show that A/Anhui/1/2013(H7N9) influenza virus infection of chickens (natural hosts) is asymptomatic and that it generates a high genetic diversity. In contrast, diversity is tightly restricted in infected ferrets, limiting further adaptation to a fully transmissible form. Airborne transmission in ferrets is accompanied by the mutations in PB1, NP and NA genes that reduce viral polymerase and neuraminidase activity. Therefore, while A(H7N9) virus can infect mammals, further adaptation appears to incur a fitness cost. Our results reveal that a tight genetic bottleneck during avian-to-mammalian transmission is a limiting factor in A(H7N9) influenza virus adaptation to mammals. This previously unrecognized biological mechanism limiting species jumps provides a measure of adaptive potential and may serve as a risk assessment tool for pandemic preparedness.

Supporting text Virus Host Location

Genetic Variation 127 Adaptation, Physiological 33 Animals 1948 Asymptomatic Infections 5 Chickens 146 Chlorocebus aethiops 70 Dogs 176 Ferrets 79 HEK293 Cells 61 Humans 1440 Influenza A Virus, H7N9 Subtype 87 Influenza in Birds 341 Influenza, Human 286 Madin Darby Canine Kidney Cells 36 Multiplex Polymerase Chain Reaction 2 Mutation 209 Neuraminidase 62 Nucleocapsid Proteins 15 Orthomyxoviridae Infections 228 Reverse Transcriptase Polymerase Chain Reaction 35 RNA, Viral 193 RNA-Binding Proteins 18 Vero Cells 55 Viral Core Proteins 6

Evidence records

4 total

Experimental Infection

3 records · 2 evidence types

Evidence type Host Range Experiment

2 records

OVE1987 Host Range Experiment

Key finding

A/Anhui/1/2013(H7N9) influenza virus infected both chickens and ferrets in controlled experiments, showing high genetic diversity in chickens but restricted diversity in ferrets.

Virus

Host

Location

Supporting text

Here we show that A/Anhui/1/2013(H7N9) influenza virus infection of chickens (natural hosts) is asymptomatic and that it generates a high genetic diversity. In contrast, diversity is tightly restricted in infected ferrets, limiting further adaptation to a fully transmissible form.

Method: experimental infection | genetic diversity analysis | sequencing
Experimental system: animal infection model

OVE1990 Host Range Experiment

Key finding

A(H7N9) influenza virus transmission from avian hosts to mammals is associated with a tight genetic bottleneck limiting adaptation in mammals.

Virus

Host

Location

Supporting text

Our results reveal that a tight genetic bottleneck during avian-to-mammalian transmission is a limiting factor in A(H7N9) influenza virus adaptation to mammals.

Method: infection of chickens | infection of ferrets | airborne transmission
Experimental system: experimental infection

Evidence type Experimental Transmission

1 records

OVE1988 Experimental Transmission

Key finding

Airborne transmission of A(H7N9) virus occurred between experimentally infected ferrets.

Virus

Host

Location

Supporting text

Airborne transmission in ferrets is accompanied by the mutations in PB1, NP and NA genes that reduce viral polymerase and neuraminidase activity. Therefore, while A(H7N9) virus can infect mammals, further adaptation appears to incur a fitness cost.

Method: ferret transmission experiment | genetic and phenotypic analysis of PB1, NP, and NA mutations
Experimental system: airborne transmission model in ferrets

Functional Mechanism

1 records · 1 evidence types

Evidence type Molecular Adaptation

1 records

OVE1989 Molecular Adaptation

Key finding

Airborne transmission of A(H7N9) virus in ferrets involved mutations in PB1, NP, and NA genes that reduced viral polymerase and neuraminidase activity, indicating limited mammalian adaptation.

Virus

Host

Location

Supporting text

Airborne transmission in ferrets is accompanied by the mutations in PB1, NP and NA genes that reduce viral polymerase and neuraminidase activity.

Genes or proteins: PB1 | NP | NA
Mechanism types: replication adaptation | transmission fitness

References

61 references

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