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

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.

SUBMITTER: Zaraket H

PROVIDER: S-EPMC4403340 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Zaraket Hassan H Baranovich Tatiana T Kaplan Bryan S BS Carter Robert R Song Min-Suk MS Paulson James C JC Rehg Jerold E JE Bahl Justin J Crumpton Jeri C JC Seiler Jon J Edmonson Michael M Wu Gang G Karlsson Erik E Fabrizio Thomas T Zhu Huachen H Guan Yi Y Husain Matloob M Schultz-Cherry Stacey S Krauss Scott S McBride Ryan R Webster Robert G RG Govorkova Elena A EA Zhang Jinghui J Russell Charles J CJ Webby Richard J RJ

Nature communications 20150408

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. Airborn ...[more]

PMID: 25850788

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Project description:Knowledge of influenza virus evolution at the point of transmission and at the intrahost level remains limited, particularly for human hosts. Here, we analyze a unique viral data set of next-generation sequencing (NGS) samples generated from a human influenza challenge study wherein 17 healthy subjects were inoculated with cell- and egg-passaged virus. Nasal wash samples collected from 7 of these subjects were successfully deep sequenced. From these, we characterized changes in the subjects' viral populations during infection and identified differences between the virus in these samples and the viral stock used to inoculate the subjects. We first calculated pairwise genetic distances between the subjects' nasal wash samples, the viral stock, and the influenza virus A/Wisconsin/67/2005 (H3N2) reference strain used to generate the stock virus. These distances revealed that considerable viral evolution occurred at various points in the human challenge study. Further quantitative analyses indicated that (i) the viral stock contained genetic variants that originated and likely were selected for during the passaging process, (ii) direct intranasal inoculation with the viral stock resulted in a selective bottleneck that reduced nonsynonymous genetic diversity in the viral hemagglutinin and nucleoprotein, and (iii) intrahost viral evolution continued over the course of infection. These intrahost evolutionary dynamics were dominated by purifying selection. Our findings indicate that rapid viral evolution can occur during acute influenza infection in otherwise healthy human hosts when the founding population size of the virus is large, as is the case with direct intranasal inoculation.Influenza viruses circulating among humans are known to rapidly evolve over time. However, little is known about how influenza virus evolves across single transmission events and over the course of a single infection. To address these issues, we analyze influenza virus sequences from a human challenge experiment that initiated infection with a cell- and egg-passaged viral stock, which appeared to have adapted during its preparation. We find that the subjects' viral populations differ genetically from the viral stock, with subjects' viral populations having lower representation of the amino-acid-changing variants that arose during viral preparation. We also find that most of the viral evolution occurring over single infections is characterized by further decreases in the frequencies of these amino-acid-changing variants and that only limited intrahost genetic diversification through new mutations is apparent. Our findings indicate that influenza virus populations can undergo rapid genetic changes during acute human infections.

Project description:UnlabelledOn 30 March 2013, a novel avian influenza A H7N9 virus causing severe human respiratory infections was identified in China. Preliminary sequence analyses have shown that the virus is a reassortant of H7N9 and H9N2 avian influenza viruses. In this study, we conducted enhanced surveillance for H7N9 virus in Guangdong, China, from April to August 2013. We isolated two H7N9 viral strains from environmental samples associated with poultry markets and one from a clinical patient. Sequence analyses showed that the Guangdong H7N9 virus isolated from April to May shared high sequence similarity with other strains from eastern China. The A/Guangdong/1/2013 (H7N9) virus isolated from the Guangdong patient on 10 August 2013 was divergent from previously sequenced H7N9 viruses and more closely related to local circulating H9N2 viruses in the NS and NP genes. Phylogenetic analyses revealed that four internal genes of the A/Guangdong/1/2013 (H7N9) virus-the NS, NP, PB1, and PB2 genes-were in clusters different from those for H7N9 viruses identified previously in other provinces of China. The discovery presented here suggests that continuing reassortment led to the emergence of the A/Guangdong/1/2013 (H7N9) virus as a novel H7N9 virus in Guangdong, China, and that viral adaptation to avian and human hosts must be assessed.ImportanceIn this study, we isolated and characterized the avian influenza A H7N9 virus in Guangdong, China, from April to August 2013. We show that the viruses isolated from Guangdong environmental samples and chickens from April to May 2013 were highly similar to other H7N9 strains found in eastern China. The H7N9 virus isolated from the clinical patient in Guangdong in August 2013 was divergent from previously identified H7N9 viruses, with the NS and NP genes originating from recent H9N2 viruses circulating in the province. This study provides direct evidence that continuing reassortment occurred and led to the emergence of a novel H7N9 influenza virus in Guangdong, China. These results also shed light on how the H7N9 virus evolved, which is critically important for future monitoring and tracing of viral transmission.

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

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

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