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

Zaraket, Hassan; Baranovich, Tatiana; Kaplan, Bryan S.; Robert, Caroline; Song, Min Suk; Paulson, James C.; Rehg, Jerold E.; Bahl, Justin; Crumpton, Jeri Carol; Seiler, J.; Edmonson, Michael N.; Wu, Gang; Karlsson, Erik A.; Fabrizio, Thomas; Zhu, Hua; Guan, Yi; Husain, Matloob; Schultz‐Cherry, Stacey; Krauss, Scott; McBride, Ryan; Webster, Robert G.; Govorkova, Elena A.; Zhang, Jinghui; Russell, Charles J.; Webby, Richard J.

doi:10.1038/ncomms7553

Cited by 92 publications

(101 citation statements)

References 59 publications

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“…While mixed V627 and E627 genotypes were transmitted among chickens, only the V627 or K627 genotype was transmitted to four ferrets where chicken-to-ferret or ferret-to-ferret transmission of HK3263 was observed. This observation is in agreement with the recent report of a narrow transmission bottleneck for the H7N9 virus among ferrets (44). However, this narrow transmission bottleneck was not observed for SCk1772, as both E627 and K627 could be detected from one of the two ferrets infected by SCk1772.…”

Section: Discussionsupporting

confidence: 83%

Transmission of H7N9 Influenza Viruses with a Polymorphism at PB2 Residue 627 in Chickens and Ferrets

Luk

Leung

Sia

et al. 2015

J Virol

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Poultry exposure is a major risk factor for human H7N9 zoonotic infections, for which the mode of transmission remains unclear. We studied the transmission of genetically related poultry and human H7N9 influenza viruses differing by four amino acids, including the host determinant PB2 residue 627. A/Silkie chicken/HK/1772/2014 (SCk1772) and A/HK/3263/14 (HK3263) replicated to comparable titers in chickens, with superior oropharyngeal over cloacal shedding; both viruses transmitted efficiently among chickens via direct contact but inefficiently via the airborne route. Interspecies transmission via the airborne route was observed for ferrets exposed to the SCk1772-or HK3263-infected chickens, while low numbers of copies of influenza viral genome were detected in the air, predominantly at particle sizes larger than 4 m. In ferrets, the human isolate HK3263 replicated to higher titers and transmitted more efficiently via direct contact than SCk1772. We monitored "intrahost" and "interhost" adaptive changes at PB2 residue 627 during infection and transmission of the Sck1772 that carried E627 and HK3263 that carried V/K/E polymorphism at 60%, 20%, and 20%, respectively. For SCk1772, positive selection for K627 over E627 was observed in ferrets during the chicken-to-ferret or ferret-to-ferret transmission. For HK3263 that contained V/K/E polymorphism, mixed V627 and E627 genotypes were transmitted among chickens while either V627 or K627 was transmitted to ferrets with a narrow transmission bottleneck. Overall, our results suggest direct contact as the main mode for H7N9 transmission and identify the PB2-V627 genotype with uncompromised fitness and transmissibility in both avian and mammalian species. IMPORTANCEWe studied the modes of H7N9 transmission, as this information is crucial for developing effective control measures for prevention. Using chicken (SCk1772) and human (HK3263) H7N9 isolates that differed by four amino acids, including the host determinant PB2 residue 627, we observed that both viruses transmitted efficiently among chickens via direct contact but inefficiently via the airborne route. Chicken-to-ferret transmission via the airborne route was observed, along with the detection of viral genome in the air at low copy numbers. In ferrets, HK3263 transmitted more efficiently than SCk1772 via direct contact. During the transmission of SCk1772 that contained E and HK3263 that contained V/K/E polymorphism at PB2 residue 627, positive selections of E627 and K627 were observed in chickens and ferrets, respectively. In addition, PB2-V627 was transmitted and stably maintained in both avian and mammalian species. Our results support applying intervention strategies that minimize direct and indirect contact at the poultry markets during epidemics.

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Section: Discussionsupporting

confidence: 83%

Transmission of H7N9 Influenza Viruses with a Polymorphism at PB2 Residue 627 in Chickens and Ferrets

Luk

Leung

Sia

et al. 2015

J Virol

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“…HA activation pH values were measured by syncytium assay as described previously (48). Vero cells were infected at an MOI of 3 for 1 h. Sixteen hours postinfection (hpi), HA-expressing cells were incubated for 15 min with 5 g/ml TPCK-treated trypsin (Worthington Biochemical, NJ) and treated with pH-adjusted PBS buffers for 5 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Influenza Virus Overcomes Cellular Blocks To Productively Replicate, Impacting Macrophage Function

Marvin

Russier

Huerta

et al. 2017

J Virol

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Whether influenza virus replication in macrophages is productive or abortive has been a topic of debate. Utilizing a panel of 28 distinct human, avian, and swine influenza viruses, we found that only a small subset can overcome cellular blocks to productively replicate in murine and primary human macrophages. Murine macrophages have two cellular blocks. The first block is during viral entry, where virions with relatively acid-stable hemagglutinin (HA) proteins are rendered incapable of pH-induced triggering for membrane fusion, resulting in lysosomal degradation. The second block is downstream of viral replication but upstream of late protein synthesis. In contrast, primary human macrophages only have one cellular block that occurs after late protein synthesis. To determine the impact of abortive replication at different stages of the viral life cycle or productive replication on macrophage function, we assessed cytotoxicity, nitric oxide or reactive oxygen species production, and phagocytosis. Intriguingly, productive viral replication decreased phagocytosis of IgG-opsonized bioparticles and Fc receptor CD16 and CD32 surface levels, a function, to our knowledge, never before reported for an RNA virus. These data suggest that replication in macrophages affects cellular function and plays an important role in pathogenesis during infection in vivo.IMPORTANCE Macrophages are a critical first line of defense against respiratory pathogens. Thus, understanding how viruses evade or exploit macrophage function will provide greater insight into viral pathogenicity and antiviral responses. We previously showed that only a subset of highly pathogenic avian (HPAI) H5N1 influenza virus strains could productively replicate in murine macrophages through a hemagglutinin (HA)-mediated mechanism. These studies expand upon this work and demonstrate that productive replication is not specific to unique HPAI H5N1 viruses; an H1N1 strain (A/WSN/33) can also replicate in macrophages. Importantly, we identify two cellular blocks limiting replication that can be overcome by an avian-like pH of activation for nuclear entry and a yet-to-be-identified mechanism(s) to overcome a postnuclear entry block. Overcoming these blocks reduces the cell's ability to phagocytose IgG-opsonized bioparticles by decreasing Fc receptor surface levels, a mechanism previously thought to occur during bacterial and DNA viral infections.KEYWORDS influenza, macrophage, replication M acrophages are one of the first lines of defense against infection. They are poised to secrete large amounts of cytokines, orchestrate the adaptive immune system, and clear infected and dying cells to aid in recovery (1). Further, alveolar macrophages are essential in preventing respiratory failure after infection (2) and for preventing bacterial superinfections during influenza infection (3). However, such responses must be tightly regulated, as excessive cytokine levels contribute to immunopathology and disease severity during infection (4-6).

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“…[73][74][75] for influenza), the ability to map symptoms back onto pathogen load will likely not work in general. Returning to influenza as our example, analyses of data from ferret infection studies showed that different influenza strains can generate similar viral loads but contrasting transmission potential [76,77]. Because the ferrets, in this study, were housed in cages with presumably little change in contact behaviour between different study groups, differences in transmission are not attributable to differences in host contact behaviour or viral load, but instead must be attributed to other features, such as qualitative differences in the virus [78] or differences in host infectiousness mediated by symptoms (e.g.…”

Section: Host Infectiousnessmentioning

confidence: 99%

Crossing the scale from within-host infection dynamics to between-host transmission fitness: a discussion of current assumptions and knowledge

Handel

Rohani

2015

Phil. Trans. R. Soc. B

109

181

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The progression of an infection within a host determines the ability of a pathogen to transmit to new hosts and to maintain itself in the population. While the general connection between the infection dynamics within a host and the population-level transmission dynamics of pathogens is widely acknowledged, a comprehensive and quantitative understanding that would allow full integration of the two scales is still lacking. Here, we provide a brief discussion of both models and data that have attempted to provide quantitative mappings from within-host infection dynamics to transmission fitness. We present a conceptual framework and provide examples of studies that have taken first steps towards development of a quantitative framework that scales from within-host infections to population-level fitness of different pathogens. We hope to illustrate some general themes, summarize some of the recent advances and—maybe most importantly—discuss gaps in our ability to bridge these scales, and to stimulate future research on this important topic.

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

Cited by 92 publications

References 59 publications

Transmission of H7N9 Influenza Viruses with a Polymorphism at PB2 Residue 627 in Chickens and Ferrets

Transmission of H7N9 Influenza Viruses with a Polymorphism at PB2 Residue 627 in Chickens and Ferrets

Influenza Virus Overcomes Cellular Blocks To Productively Replicate, Impacting Macrophage Function

Crossing the scale from within-host infection dynamics to between-host transmission fitness: a discussion of current assumptions and knowledge

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