Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance

Frise, Rebecca; Bradley, Konrad C.; Doremalen, Neeltje van; Galiano, Mónica; Elderfield, Ruth A.; Stilwell, Peter; Ashcroft, Jonathan W.; Fernández-Alonso, Mirian; Miah, Shahjahan; Lackenby, Angie; Roberts, Kim L.; Donnelly, Christl A.; Barclay, William

doi:10.1038/srep29793

Cited by 55 publications

(61 citation statements)

References 48 publications

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“…Although mice are a valid animal model for studying influenza virus pathogenicity, we cannot discard the possibility that mutations in NS1 affect virus transmission in humans. Therefore, future experiments to analyze virus transmission in more relevant animal transmission models, such as guinea pigs or ferrets (55,56), will be required to evaluate the roles of NS1 binding to CPSF30 and inhibition of host general gene expression in viral transmission.…”

Section: Discussionmentioning

confidence: 99%

Functional Evolution of Influenza Virus NS1 Protein in Currently Circulating Human 2009 Pandemic H1N1 Viruses

Clark

Nogales

Martínez-Sobrido

et al. 2017

J Virol

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In 2009, a novel H1N1 influenza virus emerged in humans, causing a global pandemic. It was previously shown that the NS1 protein from this human 2009 pandemic H1N1 (pH1N1) virus was an effective interferon (IFN) antagonist but could not inhibit general host gene expression, unlike other NS1 proteins from seasonal human H1N1 and H3N2 viruses. Here we show that the NS1 protein from currently circulating pH1N1 viruses has evolved to encode 6 amino acid changes (E55K, L90I, I123V, E125D, K131E, and N205S) with respect to the original protein. Notably, these 6 residue changes restore the ability of pH1N1 NS1 to inhibit general host gene expression, mainly by their ability to restore binding to the cellular factor CPSF30. This is the first report describing the ability of the pH1N1 NS1 protein to naturally acquire mutations that restore this function. Importantly, a recombinant pH1N1 virus containing these 6 amino acid changes in the NS1 protein (pH1N1/NSs-6mut) inhibited host IFN and proinflammatory responses to a greater extent than that with the parental virus (pH1N1/NS1-wt), yet virus titers were not significantly increased in cell cultures or in mouse lungs, and the disease was partially attenuated. The pH1N1/NSs-6mut virus grew similarly to pH1N1/NSs-wt in mouse lungs, but infection with pH1N1/NSs-6mut induced lower levels of proinflammatory cytokines, likely due to a general inhibition of gene expression mediated by the mutated NS1 protein. This lower level of inflammation induced by the pH1N1/NSs-6mut virus likely accounts for the attenuated disease phenotype and may represent a host-virus adaptation affecting influenza virus pathogenesis. Seasonal influenza A viruses (IAVs) are among the most common causes of respiratory infections in humans. In addition, occasional pandemics are caused when IAVs circulating in other species emerge in the human population. In 2009, a swine-origin H1N1 IAV (pH1N1) was transmitted to humans, infecting people then and up to the present. It was previously shown that the NS1 protein from the 2009 pandemic H1N1 (pH1N1) virus is not able to inhibit general gene expression. However, currently circulating pH1N1 viruses have evolved to encode 6 amino acid changes (E55K, L90I, I123V, E125D, K131E, and N205S) that allow the NS1 protein of contemporary pH1N1 strains to inhibit host gene expression, which correlates with its ability to interact with CPSF30. Infection with a recombinant pH1N1 virus encoding these 6 amino acid changes (pH1N1/NSs-6mut) induced lower levels of proinflammatory cytokines, resulting in viral attenuation This might represent an adaptation of pH1N1 virus to humans.

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Section: Discussionmentioning

confidence: 99%

Functional Evolution of Influenza Virus NS1 Protein in Currently Circulating Human 2009 Pandemic H1N1 Viruses

Clark

Nogales

Martínez-Sobrido

et al. 2017

J Virol

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“…Vertical bars represent confidence intervals equivalent to a cut-off of 2 log likelihood units. 13 in the explicit method. Evidence from simulated data suggests that the explicit method is probably more accurate in this range.…”

Section: Compound Method Inferred Haplotypesmentioning

confidence: 99%

“…A model of genetic drift may also be applied: smaller or larger changes in the composition of a viral population suggest that a larger or smaller number of viruses were transmitted (3,(8)(9)(10)(11). In some situations, engineered viruses with genetic markers have been used to directly evaluate transmission events (12,13) Recent studies of influenza transmission between human hosts have used metrics based upon changes in allele frequencies to evaluate the bottleneck at transmission (3,11,14,15). Such metrics have limitations; transmission is ultimately an event in which whole viruses, rather than independent alleles, are passed from one host to another.…”

Section: Introductionmentioning

confidence: 99%

Inferring transmission bottleneck size from viral sequence data using a novel haplotype reconstruction method

Ghafari

Lumby

Weissman

et al. 2020

Preprint

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The transmission bottleneck is defined as the number of viral particles transmitted from one host to another. Genome sequence data has been used to evaluate the size of the transmission bottleneck between humans infected with the influenza virus, however, the methods used to make these estimates have some limitations. Specifically, approaches using viral allele frequency data may not fully capture a process which involves the transmission of entire viral genomes. Here we set out a novel approach for inferring viral transmission bottlenecks; our method combines haplotype reconstruction, a method for inferring the composition of genomes in a viral population, with two maximum likelihood methods for bottleneck inference, tailored for small and large bottleneck sizes respectively. Our method allows for rapid calculation, and performs well when applied to data from simulated transmission events, being robust to errors in the haplotype reconstruction process. Applied to data from a previous household transmission study of influenza A infection we confirm the result that the majority of transmission events involve a small number of viruses, albeit with slightly looser bottlenecks being inferred, with between 1 and 13 particles transmitted in the majority of cases. While influenza A transmission involves a tight population bottleneck, the bottleneck is not so tight as to universally prevent the transmission of within-host viral diversity.

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“…The shared susceptibility to influenza infection is based on similarity in respiratory tract physiology, where a predominance of α2,6‐linked sialic acid (SA) receptors in the upper respiratory tract of ferrets mimics that of humans, unlike α2,3‐SA prevalent in other species such as mice. Ferrets are an extremely valuable model for studies on influenza pathogenesis and both direct and aerosol transmission . Critically, ferrets are a susceptible host for highly pathogenic avian strains of influenza with pandemic potential, such as H5N1 and H7N9, although disease severity in infected ferrets is somewhat variable .…”

Section: Ferrets As An Influenza Pathogenesis and Transmission Modelmentioning

confidence: 99%

Improving immunological insights into the ferret model of human viral infectious disease

Wong

Layton

Wheatley

et al. 2019

Influenza Resp Viruses

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Influenza Other Respi Viruses. 2019;13:535-546. | 535 wileyonlinelibrary.com/journal/irv 1 | INTRODUC TI ON Animal models have proved critical in developing concepts of immunity to infection. Non-human primates (NHP) are a highly humanrelevant disease model for infectious agents due to high genetic conservation between humans and NHP. 1-3 However, significant cost and ethical issues often necessitate the use of smaller animal models for both basic and translational research. Mice (Mus musculus) are a favoured small animal model due to widespread availability, incisive transgenic models, comprehensive genomic information 4 and readily available reagents. However, for many viruses, alternative animal models better recapitulate human physiology and disease. Ferrets (Mustela putorius furo) have been employed to study the pathogenesis of a variety of human pathogens, including human and avian influenzas, coronaviruses including severe acute respiratory syndrome (SARS-CoV), 5-14 human respiratory syncytial virus (HRSV), 15-20 human metapneumovirus (HMPV), 21 Ebola virus 22-28 and henipavirus (Nipah virus and Hendra virus). 29-34 While ferretscan be productively infected with many of these viruses, a lack of some tools to interrogate ferret immunological responses to infection limits insights that might impact the development of vaccines and/or therapeutics. Here, we review recent insights gained from ferret models of human respiratory diseases, with a major focus on influenza, and highlight several knowledge gaps whose closure will greatly enhance the informational gain from ferret models to advance development of human vaccines and therapeutics. AbstractFerrets are a well-established model for studying both the pathogenesis and transmission of human respiratory viruses and evaluation of antiviral vaccines. Advanced immunological studies would add substantial value to the ferret models of disease but are hindered by the low number of ferret-reactive reagents available for flow cytometry and immunohistochemistry. Nevertheless, progress has been made to understand immune responses in the ferret model with a limited set of ferret-specific reagents and assays. This review examines current immunological insights gained from the ferret model across relevant human respiratory diseases, with a focus on influenza viruses. We highlight key knowledge gaps that need to be bridged to advance the utility of ferrets for immunological studies. K E Y W O R D S ferret, immunology, influenza How to cite this article: Wong J, Layton D, Wheatley AK, Kent SJ. Improving immunological insights into the ferret model of human viral infectious disease. Influenza Other Respi Viruses. 2019;13:535-546. https ://doi.

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Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance

Cited by 55 publications

References 48 publications

Functional Evolution of Influenza Virus NS1 Protein in Currently Circulating Human 2009 Pandemic H1N1 Viruses

Functional Evolution of Influenza Virus NS1 Protein in Currently Circulating Human 2009 Pandemic H1N1 Viruses

Inferring transmission bottleneck size from viral sequence data using a novel haplotype reconstruction method

Improving immunological insights into the ferret model of human viral infectious disease

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