Antigenic drift of the pandemic 2009 A(H1N1) influenza virus in a ferret model
- Guarnaccia, Teagan, Carolan, Louise, Maurer-Stroh, Sebastian, Lee, Raphael, Job, Emma, Reading, Patrick, Petrie, Stephen, McCaw, James, McVernon, Jodie, Hurt, Aeron, Kelso, Anne, Mosse, Jennifer, Barr, Ian, Laurie, Karen
- Authors: Guarnaccia, Teagan , Carolan, Louise , Maurer-Stroh, Sebastian , Lee, Raphael , Job, Emma , Reading, Patrick , Petrie, Stephen , McCaw, James , McVernon, Jodie , Hurt, Aeron , Kelso, Anne , Mosse, Jennifer , Barr, Ian , Laurie, Karen
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS Pathogens Vol. 9, no. 5 (2013), p. 1-18
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- Description: Surveillance data indicate that most circulating A(H1N1)pdm09 influenza viruses have remained antigenically similar since they emerged in humans in 2009. However, antigenic drift is likely to occur in the future in response to increasing population immunity induced by infection or vaccination. In this study, sequential passaging of A(H1N1)pdm09 virus by contact transmission through two independent series of suboptimally vaccinated ferrets resulted in selection of variant viruses with an amino acid substitution (N156K, H1 numbering without signal peptide; N159K, H3 numbering without signal peptide; N173K, H1 numbering from first methionine) in a known antigenic site of the viral HA. The N156K HA variant replicated and transmitted efficiently between naïve ferrets and outgrew wildtype virus in vivo in ferrets in the presence and absence of immune pressure. In vitro, in a range of cell culture systems, the N156K variant rapidly adapted, acquiring additional mutations in the viral HA that also potentially affected antigenic properties. The N156K escape mutant was antigenically distinct from wildtype virus as shown by binding of HA-specific antibodies. Glycan binding assays demonstrated the N156K escape mutant had altered receptor binding preferences compared to wildtype virus, which was supported by computational modeling predictions. The N156K substitution, and culture adaptations, have been detected in human A(H1N1)pdm09 viruses with N156K preferentially reported in sequences from original clinical samples rather than cultured isolates. This study demonstrates the ability of the A(H1N1)pdm09 virus to undergo rapid antigenic change to evade a low level vaccine response, while remaining fit in a ferret transmission model of immunization and infection. Furthermore, the potential changes in receptor binding properties that accompany antigenic changes highlight the importance of routine characterization of clinical samples in human A(H1N1)pdm09 influenza surveillance.
- Authors: Guarnaccia, Teagan , Carolan, Louise , Maurer-Stroh, Sebastian , Lee, Raphael , Job, Emma , Reading, Patrick , Petrie, Stephen , McCaw, James , McVernon, Jodie , Hurt, Aeron , Kelso, Anne , Mosse, Jennifer , Barr, Ian , Laurie, Karen
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS Pathogens Vol. 9, no. 5 (2013), p. 1-18
- Full Text:
- Reviewed:
- Description: Surveillance data indicate that most circulating A(H1N1)pdm09 influenza viruses have remained antigenically similar since they emerged in humans in 2009. However, antigenic drift is likely to occur in the future in response to increasing population immunity induced by infection or vaccination. In this study, sequential passaging of A(H1N1)pdm09 virus by contact transmission through two independent series of suboptimally vaccinated ferrets resulted in selection of variant viruses with an amino acid substitution (N156K, H1 numbering without signal peptide; N159K, H3 numbering without signal peptide; N173K, H1 numbering from first methionine) in a known antigenic site of the viral HA. The N156K HA variant replicated and transmitted efficiently between naïve ferrets and outgrew wildtype virus in vivo in ferrets in the presence and absence of immune pressure. In vitro, in a range of cell culture systems, the N156K variant rapidly adapted, acquiring additional mutations in the viral HA that also potentially affected antigenic properties. The N156K escape mutant was antigenically distinct from wildtype virus as shown by binding of HA-specific antibodies. Glycan binding assays demonstrated the N156K escape mutant had altered receptor binding preferences compared to wildtype virus, which was supported by computational modeling predictions. The N156K substitution, and culture adaptations, have been detected in human A(H1N1)pdm09 viruses with N156K preferentially reported in sequences from original clinical samples rather than cultured isolates. This study demonstrates the ability of the A(H1N1)pdm09 virus to undergo rapid antigenic change to evade a low level vaccine response, while remaining fit in a ferret transmission model of immunization and infection. Furthermore, the potential changes in receptor binding properties that accompany antigenic changes highlight the importance of routine characterization of clinical samples in human A(H1N1)pdm09 influenza surveillance.
- Carolan, Louise, Rockman, Steve, Borg, Kathryn, Guarnaccia, Teagan, Reading, Patrick, Mosse, Jennifer, Kelso, Anne, Barr, Ian, Laurie, Karen
- Authors: Carolan, Louise , Rockman, Steve , Borg, Kathryn , Guarnaccia, Teagan , Reading, Patrick , Mosse, Jennifer , Kelso, Anne , Barr, Ian , Laurie, Karen
- Date: 2016
- Type: Text , Journal article
- Relation: Journal of Virology Vol. 90, no. 6 (2016), p. 2838-2848
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- Description: The burden of infection with seasonal influenza viruses is significant. Each year is typically characterized by the dominance of one (sub)type or lineage of influenza A or B virus, respectively. The incidence of disease varies annually, and while this may be attributed to a particular virus strain or subtype, the impacts of prior immunity, population differences, and variations in clinical assessment are also important. To improve our understanding of the impacts of seasonal influenza viruses, we directly compared clinical symptoms, virus shedding, and expression of cytokines, chemokines, and immune mediators in the upper respiratory tract (URT) of ferrets infected with contemporary A(H1N1)pdm09, A(H3N2), or influenza B virus. Gene expression in the lower respiratory tract (LRT) was also assessed. Clinical symptoms were minimal. Overall cytokine/chemokine profiles in the URT were consistent in pattern and magnitude between animals infected with influenza A and B viruses, and peak expression levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-12p40, alpha interferon (IFN-α), IFN-β, and tumor necrosis factor alpha (TNF-α) mRNAs correlated with peak levels of viral shedding. MCP1 and IFN-γ were expressed after the virus peak. Granzymes A and B and IL-10 reached peak expression as the virus was cleared and seroconversion was detected. Cytokine/chemokine gene expression in the LRT following A(H1N1)pdm09 virus infection reflected the observations seen for the URT but was delayed 2 or 3 days, as was virus replication. These data indicate that disease severities and localized immune responses following infection with seasonal influenza A and B viruses are similar, suggesting that other factors are likely to modulate the incidence and impact of seasonal influenza. © 2016, American Society for Microbiology.
Interval between infections and viral hierarchy are determinants of viral interference following influenza virus infection in a ferret model
- Laurie, Karen, Guarnaccia, Teagan, Carolan, Louise, Yan, Aada, Aban, Malet, Petrie, Stephen, Cao, Pengxing, Heffernan, Jane, McVernon, Jodie, Mosse, Jennifer, Kelso, Anne, McCaw, James, Barr, Ian
- Authors: Laurie, Karen , Guarnaccia, Teagan , Carolan, Louise , Yan, Aada , Aban, Malet , Petrie, Stephen , Cao, Pengxing , Heffernan, Jane , McVernon, Jodie , Mosse, Jennifer , Kelso, Anne , McCaw, James , Barr, Ian
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Infectious Diseases Vol. 212, no. 10 (2015), p. 1701-1710
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- Description: Background. Epidemiological studies suggest that, following infection with influenza virus, there is a short period during which a host experiences a lower susceptibility to infection with other influenza viruses. This viral interference appears to be independent of any antigenic similarities between the viruses. We used the ferret model of human influenza to systematically investigate viral interference. Methods. Ferrets were first infected then challenged 1-14 days later with pairs of influenza A(H1N1)pdm09, influenza A(H3N2), and influenza B viruses circulating in 2009 and 2010. Results. Viral interference was observed when the interval between initiation of primary infection and subsequent challenge was <1 week. This effect was virus specific and occurred between antigenically related and unrelated viruses. Coinfections occurred when 1 or 3 days separated infections. Ongoing shedding from the primary virus infection was associated with viral interference after the secondary challenge. Conclusions. The interval between infections and the sequential combination of viruses were important determinants of viral interference. The influenza viruses in this study appear to have an ordered hierarchy according to their ability to block or delay infection, which may contribute to the dominance of different viruses often seen in an influenza season.
- Authors: Laurie, Karen , Guarnaccia, Teagan , Carolan, Louise , Yan, Aada , Aban, Malet , Petrie, Stephen , Cao, Pengxing , Heffernan, Jane , McVernon, Jodie , Mosse, Jennifer , Kelso, Anne , McCaw, James , Barr, Ian
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Infectious Diseases Vol. 212, no. 10 (2015), p. 1701-1710
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- Description: Background. Epidemiological studies suggest that, following infection with influenza virus, there is a short period during which a host experiences a lower susceptibility to infection with other influenza viruses. This viral interference appears to be independent of any antigenic similarities between the viruses. We used the ferret model of human influenza to systematically investigate viral interference. Methods. Ferrets were first infected then challenged 1-14 days later with pairs of influenza A(H1N1)pdm09, influenza A(H3N2), and influenza B viruses circulating in 2009 and 2010. Results. Viral interference was observed when the interval between initiation of primary infection and subsequent challenge was <1 week. This effect was virus specific and occurred between antigenically related and unrelated viruses. Coinfections occurred when 1 or 3 days separated infections. Ongoing shedding from the primary virus infection was associated with viral interference after the secondary challenge. Conclusions. The interval between infections and the sequential combination of viruses were important determinants of viral interference. The influenza viruses in this study appear to have an ordered hierarchy according to their ability to block or delay infection, which may contribute to the dominance of different viruses often seen in an influenza season.
- Chan, Kok Fei, Carolan, Louise, Druce, Julian, Chappell, Keith, Watterson, Daniel, Young, Paul, Korenkov, Daniil, Subbarao, Kanta, Barr, Ian, Laurie, Karen, Reading, Patrick
- Authors: Chan, Kok Fei , Carolan, Louise , Druce, Julian , Chappell, Keith , Watterson, Daniel , Young, Paul , Korenkov, Daniil , Subbarao, Kanta , Barr, Ian , Laurie, Karen , Reading, Patrick
- Date: 2018
- Type: Text , Journal article
- Relation: Journal of Virology Vol. 92, no. 4 (2018), p.
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- Description: Small-animal models have been used to obtain many insights regarding the pathogenesis and immune responses induced following infection with human respiratory syncytial virus (hRSV). Among those described to date, infections in cotton rats, mice, guinea pigs, chinchillas, and Syrian hamsters with hRSV strains Long and/or A2 have been well characterized, although clinical isolates have also been examined. Ferrets are also susceptible to hRSV infection, but the pathogenesis and immune responses elicited following infection have not been well characterized. Here, we describe the infection of adult ferrets with hRSV Long or A2 via the intranasal route and characterized virus replication, as well as cytokine induction, in the upper and lower airways. Virus replication and cytokine induction during the acute phase of infection (days 0 to 15 postinfection) were similar between the two strains, and both elicited high levels of F glycoprotein-specific binding and neutralizing antibodies following virus clearance (days 16 to 22 postinfection). Importantly, we demonstrate transmission from experimentally infected donor ferrets to cohoused naive recipients and have characterized virus replication and cytokine induction in the upper airways of infected contact animals. Together, these studies provide a direct comparison of the pathogenesis of hRSV Long and A2 in ferrets and highlight the potential of this animal model to study serological responses and examine interventions that limit transmission of hRSV. Ferrets have been widely used to study pathogenesis, immunity, and transmission following human influenza virus infections however, far less is known regarding the utility of the ferret model to study hRSV infections. Following intranasal infection of adult ferrets with the well-characterized Long or A2 strain of hRSV, we report virus replication and cytokine induction in the upper and lower airways, as well as the development of virus-specific humoral responses. Importantly, we demonstrate transmission of hRSV from experimentally infected donor ferrets to cohoused naive recipients. Together, these findings significantly enhance our understanding of the utility of the ferret as a small-animal model to investigate aspects of hRSV pathogenesis and immunity.
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