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Lorena E. Brown
The Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Australia

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Original research article
Published: 14 July 2021 in Frontiers in Microbiology
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A segmented genome enables influenza virus to undergo reassortment when two viruses infect the same cell. Although reassortment is involved in the creation of pandemic influenza strains and is routinely used to produce influenza vaccines, our understanding of the factors that drive the emergence of dominant gene constellations during this process is incomplete. Recently, we defined a spectrum of interactions between the gene segments of the A/Udorn/307/72 (H3N2) (Udorn) strain that occur within virus particles, a major interaction being between the NA and PB1 gene segments. In addition, we showed that the Udorn PB1 is preferentially incorporated into reassortant viruses that express the Udorn NA. Here we use an influenza vaccine seed production model where eggs are coinfected with Udorn and the high yielding A/Puerto Rico/8/34 (H1N1) (PR8) virus and track viral genotypes through the reassortment process under antibody selective pressure to determine the impact of Udorn NA-PB1 co-selection. We discovered that 86% of the reassortants contained the PB1 from the Udorn parent after the initial co-infection and this bias towards Udorn PB1 was maintained after two further passages. Included in these were certain gene constellations containing Udorn HA, NA, and PB1 that confered low replicative fitness yet rapidly became dominant at the expense of more fit progeny, even when co-infection ratios of the two viruses favoured PR8. Fitness was not compromised, however, in the corresponding reassortants that also contained Udorn NP. Of particular note is the observation that relatively unfit reassortants could still fulfil the role of vaccine seed candidates as they provided high haemagglutinin (HA) antigen yields through co-production of non-infectious particles and/or by more HA molecules per virion. Our data illustrate the dynamics and complexity of reassortment and highlight how major gene segment interactions formed during packaging, in addition to antibody pressure, initially restrict the reassortant viruses that are formed.

ACS Style

Sanja Trifkovic; Brad Gilbertson; Emily Fairmaid; Joanna Cobbin; Steven Rockman; Lorena E. Brown. Gene Segment Interactions Can Drive the Emergence of Dominant Yet Suboptimal Gene Constellations During Influenza Virus Reassortment. Frontiers in Microbiology 2021, 12, 1 .

AMA Style

Sanja Trifkovic, Brad Gilbertson, Emily Fairmaid, Joanna Cobbin, Steven Rockman, Lorena E. Brown. Gene Segment Interactions Can Drive the Emergence of Dominant Yet Suboptimal Gene Constellations During Influenza Virus Reassortment. Frontiers in Microbiology. 2021; 12 ():1.

Chicago/Turabian Style

Sanja Trifkovic; Brad Gilbertson; Emily Fairmaid; Joanna Cobbin; Steven Rockman; Lorena E. Brown. 2021. "Gene Segment Interactions Can Drive the Emergence of Dominant Yet Suboptimal Gene Constellations During Influenza Virus Reassortment." Frontiers in Microbiology 12, no. : 1.

Review
Published: 24 May 2021 in Viruses
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Despite seasonal influenza vaccines having been routinely used for many decades, influenza A virus continues to pose a global threat to humans, causing high morbidity and mortality each year. The effectiveness of the vaccine is largely dependent on how well matched the vaccine strains are with the circulating influenza virus strains. Furthermore, low vaccine efficacy in naïve populations such as young children, or in the elderly, who possess weakened immune systems, indicates that influenza vaccines need to be more personalized to provide broader community protection. Advances in both vaccine technologies and our understanding of influenza virus infection and immunity have led to the design of a variety of alternate vaccine strategies to extend population protection against influenza, some of which are now in use. In this review, we summarize the progress in the field of influenza vaccines, including the advantages and disadvantages of different strategies, and discuss future prospects. We also highlight some of the challenges to be faced in the ongoing effort to control influenza through vaccination.

ACS Style

Toshiki Sekiya; Marumi Ohno; Naoki Nomura; Chimuka Handabile; Masashi Shingai; David Jackson; Lorena Brown; Hiroshi Kida. Selecting and Using the Appropriate Influenza Vaccine for Each Individual. Viruses 2021, 13, 971 .

AMA Style

Toshiki Sekiya, Marumi Ohno, Naoki Nomura, Chimuka Handabile, Masashi Shingai, David Jackson, Lorena Brown, Hiroshi Kida. Selecting and Using the Appropriate Influenza Vaccine for Each Individual. Viruses. 2021; 13 (6):971.

Chicago/Turabian Style

Toshiki Sekiya; Marumi Ohno; Naoki Nomura; Chimuka Handabile; Masashi Shingai; David Jackson; Lorena Brown; Hiroshi Kida. 2021. "Selecting and Using the Appropriate Influenza Vaccine for Each Individual." Viruses 13, no. 6: 971.

Journal article
Published: 08 March 2021 in JCI Insight
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The impact of respiratory virus infections on global health is felt not just during a pandemic, but endemic seasonal infections pose an equal and ongoing risk of severe disease. Moreover, vaccines and antiviral drugs are not always effective or available for many respiratory viruses. We investigated how induction of effective and appropriate antigen-independent innate immunity in the upper airways can prevent the spread of respiratory virus infection to the vulnerable lower airways. Activation of TLR2, when restricted to the nasal turbinates, resulted in prompt induction of innate immune–driven antiviral responses through action of cytokines, chemokines, and cellular activity in the upper but not the lower airways. We have defined how nasal epithelial cells and recruitment of macrophages work in concert and play pivotal roles to limit progression of influenza virus to the lungs and sustain protection for up to 7 days. These results reveal underlying mechanisms of how control of viral infection in the upper airways can occur and support the implementation of strategies that can activate TLR2 in nasal passages to provide rapid protection, especially for at-risk populations, against severe respiratory infection when vaccines and antiviral drugs are not always effective or available.

ACS Style

Georgia Deliyannis; Chinn Yi Wong; Hayley A. McQuilten; Annabell Bachem; Michele Clarke; Xiaoxiao Jia; Kylie Horrocks; Weiguang Zeng; Jason Girkin; Nichollas E. Scott; Sarah L. Londrigan; Patrick C. Reading; Nathan W. Bartlett; Katherine Kedzierska; Lorena E. Brown; Francesca Mercuri; Christophe Demaison; David C. Jackson; Brendon Y. Chua. TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs. JCI Insight 2021, 6, 1 .

AMA Style

Georgia Deliyannis, Chinn Yi Wong, Hayley A. McQuilten, Annabell Bachem, Michele Clarke, Xiaoxiao Jia, Kylie Horrocks, Weiguang Zeng, Jason Girkin, Nichollas E. Scott, Sarah L. Londrigan, Patrick C. Reading, Nathan W. Bartlett, Katherine Kedzierska, Lorena E. Brown, Francesca Mercuri, Christophe Demaison, David C. Jackson, Brendon Y. Chua. TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs. JCI Insight. 2021; 6 (5):1.

Chicago/Turabian Style

Georgia Deliyannis; Chinn Yi Wong; Hayley A. McQuilten; Annabell Bachem; Michele Clarke; Xiaoxiao Jia; Kylie Horrocks; Weiguang Zeng; Jason Girkin; Nichollas E. Scott; Sarah L. Londrigan; Patrick C. Reading; Nathan W. Bartlett; Katherine Kedzierska; Lorena E. Brown; Francesca Mercuri; Christophe Demaison; David C. Jackson; Brendon Y. Chua. 2021. "TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs." JCI Insight 6, no. 5: 1.

Preprint content
Published: 11 February 2021
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A segmented genome enables influenza virus to undergo reassortment when two viruses infect the same cell. Resulting reassorted progeny have a spectrum of gene constellations and potentially different phenotypes. Although reassortment is involved in the creation of pandemic influenza strains and is routinely used to produce influenza vaccines, our understanding of the factors that drive the emergence of dominant gene constellations during this process is incomplete. Using an influenza vaccine seed production model, reassortant genotypes were tracked through the reassortment process under antibody selective pressure. We discovered that certain gene constellations conferring low replicative fitness were selected at the expense of more fit progeny. Nevertheless, relatively unfit reassortants likely provide high hemagglutinin antigen yields through co-production of non-infectious particles and/or by more hemagglutinin molecules per virion. Our data illustrate the dynamics and complexity of reassortment and highlight how gene segment interactions formed during packaging, in addition to antibody pressure, restrict the final viruses that dominate.

ACS Style

Sanja Trifkovic; Brad Gilbertson; Emily Fairmaid; Joanna Cobbin; Steven Rockman; Lorena E. Brown. The role of gene segment interactions in driving the emergence of dominant gene constellations during influenza virus reassortment. 2021, 1 .

AMA Style

Sanja Trifkovic, Brad Gilbertson, Emily Fairmaid, Joanna Cobbin, Steven Rockman, Lorena E. Brown. The role of gene segment interactions in driving the emergence of dominant gene constellations during influenza virus reassortment. . 2021; ():1.

Chicago/Turabian Style

Sanja Trifkovic; Brad Gilbertson; Emily Fairmaid; Joanna Cobbin; Steven Rockman; Lorena E. Brown. 2021. "The role of gene segment interactions in driving the emergence of dominant gene constellations during influenza virus reassortment." , no. : 1.

Other
Published: 18 September 2020
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We report in-concert dynamics of 18 key immune parameters, related to clinical, genetic and virological factors, in patients hospitalized with influenza across different severity levels. Influenza disease was associated with correlated increases in IL6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells (cTfhs) correlated with peak antibody-secreting cells (ASC) and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differed from vaccination-induced B-cell responses. Influenza-specific CD8+/CD4+ T-cells increased early in disease and remained activated during patient recovery. Here, we describe the broadest to-date immune cellular networks underlying recovery from influenza infection, highly relevant to other infectious diseases.

ACS Style

Thi H.O. Nguyen; Marios Koutsakos; Carolien E. van de Sandt; Jeremy Chase Crawford; Liyen Loh; Sneha Sant; Ludivine Grzelak; Emma K. Allen; Tim Brahm; E. Bridie Clemens; Maria Auladell; Luca Hensen; Zhongfang Wang; Simone Nüssing; Xiaoxiao Jia; Patrick Günther; Adam K. Wheatley; Stephen J. Kent; Malet Aban; Yi-Mo Deng; Karen L. Laurie; Aeron C. Hurt; Stephanie Gras; Jamie Rossjohn; Jane Crowe; Jianqing Xu; David Jackson; Lorena E. Brown; Nicole La Gruta; Weisan Chen; Peter C. Doherty; Stephen J. Turner; Tom C. Kotsimbos; Paul G. Thomas; Allen C. Cheng; Katherine Kedzierska. In-concert immune dynamics during natural influenza virus infection and recovery in acute hospitalized patients. 2020, 1 .

AMA Style

Thi H.O. Nguyen, Marios Koutsakos, Carolien E. van de Sandt, Jeremy Chase Crawford, Liyen Loh, Sneha Sant, Ludivine Grzelak, Emma K. Allen, Tim Brahm, E. Bridie Clemens, Maria Auladell, Luca Hensen, Zhongfang Wang, Simone Nüssing, Xiaoxiao Jia, Patrick Günther, Adam K. Wheatley, Stephen J. Kent, Malet Aban, Yi-Mo Deng, Karen L. Laurie, Aeron C. Hurt, Stephanie Gras, Jamie Rossjohn, Jane Crowe, Jianqing Xu, David Jackson, Lorena E. Brown, Nicole La Gruta, Weisan Chen, Peter C. Doherty, Stephen J. Turner, Tom C. Kotsimbos, Paul G. Thomas, Allen C. Cheng, Katherine Kedzierska. In-concert immune dynamics during natural influenza virus infection and recovery in acute hospitalized patients. . 2020; ():1.

Chicago/Turabian Style

Thi H.O. Nguyen; Marios Koutsakos; Carolien E. van de Sandt; Jeremy Chase Crawford; Liyen Loh; Sneha Sant; Ludivine Grzelak; Emma K. Allen; Tim Brahm; E. Bridie Clemens; Maria Auladell; Luca Hensen; Zhongfang Wang; Simone Nüssing; Xiaoxiao Jia; Patrick Günther; Adam K. Wheatley; Stephen J. Kent; Malet Aban; Yi-Mo Deng; Karen L. Laurie; Aeron C. Hurt; Stephanie Gras; Jamie Rossjohn; Jane Crowe; Jianqing Xu; David Jackson; Lorena E. Brown; Nicole La Gruta; Weisan Chen; Peter C. Doherty; Stephen J. Turner; Tom C. Kotsimbos; Paul G. Thomas; Allen C. Cheng; Katherine Kedzierska. 2020. "In-concert immune dynamics during natural influenza virus infection and recovery in acute hospitalized patients." , no. : 1.

Journal article
Published: 04 October 2019 in Viruses
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Circulating avian influenza viruses pose a significant threat, with human infections occurring infrequently but with potentially severe consequences. To examine the dynamics and locale of the adaptation process of avian influenza viruses when introduced to a mammalian host, we infected ferrets with H5N1 viruses. As expected, all ferrets infected with the human H5N1 isolate A/Vietnam/1203/2004 showed severe disease and virus replication outside the respiratory tract in multiple organs including the brain. In contrast infection of ferrets with the avian H5N1 virus A/Chicken/Laos/Xaythiani26/2006 showed a different collective pattern of infection; many ferrets developed and cleared a mild respiratory infection but a subset (25–50%), showed extended replication in the upper respiratory tract and developed infection in distal sites. Virus from these severely infected ferrets was commonly found in tissues that included liver and small intestine. In most instances the virus had acquired the common virulence substitution PB2 E627K but, in one case, a previously unidentified combination of two amino acid substitutions at PB2 S489P and NP V408I, which enhanced polymerase activity, was found. We noted that virus with high pathogenicity adaptations could be dominant in an extra-respiratory site without being equally represented in the nasal wash. Further ferret passage of these mutated viruses resulted in high pathogenicity in all ferrets. These findings illustrate the remarkable ability of avian influenza viruses that avoid clearance in the respiratory tract, to mutate towards a high pathogenicity phenotype during just a single passage in ferrets and also indicate a window of less than 5 days in which treatment may curtail systemic infection.

ACS Style

Jeffrey Butler; Deborah Middleton; Jessica Haining; Rachel Layton; Steven Rockman; Lorena E. Brown; Sandra Sapats. Insights into the Acquisition of Virulence of Avian Influenza Viruses during a Single Passage in Ferrets. Viruses 2019, 11, 915 .

AMA Style

Jeffrey Butler, Deborah Middleton, Jessica Haining, Rachel Layton, Steven Rockman, Lorena E. Brown, Sandra Sapats. Insights into the Acquisition of Virulence of Avian Influenza Viruses during a Single Passage in Ferrets. Viruses. 2019; 11 (10):915.

Chicago/Turabian Style

Jeffrey Butler; Deborah Middleton; Jessica Haining; Rachel Layton; Steven Rockman; Lorena E. Brown; Sandra Sapats. 2019. "Insights into the Acquisition of Virulence of Avian Influenza Viruses during a Single Passage in Ferrets." Viruses 11, no. 10: 915.

Journal article
Published: 20 August 2019 in Viruses
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Innate antiviral factors in saliva play a role in protection against respiratory infections. We tested the anti-influenza virus activities of saliva samples taken from human infants, 1–12 months old, with no history of prior exposure to influenza. In contrast to the inhibitory activity we observed in mouse and ferret saliva, the activity of human infant saliva was complex, with both sialic acid-dependent and independent components, the proportion of which differed between individuals. Taken as a whole, we showed that the major anti-influenza activity of infant saliva is acquired over the first year of life and is associated with sialic acid-containing molecules. The activity of sialic acid-independent inhibitors was lower overall, more variable between individuals, and less dependent on age. The results show that the saliva of very young infants can provide a degree of protection against influenza, which may be critical in the absence of adaptive immunity.

ACS Style

Brad Gilbertson; Kathryn Edenborough; Jodie McVernon; Lorena E. Brown. Inhibition of Influenza A Virus by Human Infant Saliva. Viruses 2019, 11, 766 .

AMA Style

Brad Gilbertson, Kathryn Edenborough, Jodie McVernon, Lorena E. Brown. Inhibition of Influenza A Virus by Human Infant Saliva. Viruses. 2019; 11 (8):766.

Chicago/Turabian Style

Brad Gilbertson; Kathryn Edenborough; Jodie McVernon; Lorena E. Brown. 2019. "Inhibition of Influenza A Virus by Human Infant Saliva." Viruses 11, no. 8: 766.

Letter
Published: 22 July 2019 in Nature Microbiology
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Influenza A viruses (IAVs) constitute a major threat to human health. The IAV genome consists of eight single-stranded viral RNA segments contained in separate viral ribonucleoprotein (vRNP) complexes that are packaged together into a single virus particle. The structure of viral RNA is believed to play a role in assembling the different vRNPs into budding virions1–8 and in directing reassortment between IAVs9. Reassortment between established human IAVs and IAVs harboured in the animal reservoir can lead to the emergence of pandemic influenza strains to which there is little pre-existing immunity in the human population10,11. While previous studies have revealed the overall organization of the proteins within vRNPs, characterization of viral RNA structure using conventional structural methods is hampered by limited resolution and an inability to resolve dynamic components12,13. Here, we employ multiple high-throughput sequencing approaches to generate a global high-resolution structure of the IAV genome. We show that different IAV genome segments acquire distinct RNA conformations and form both intra- and intersegment RNA interactions inside influenza virions. We use our detailed map of IAV genome structure to provide direct evidence for how intersegment RNA interactions drive vRNP cosegregation during reassortment between different IAV strains. The work presented here is a roadmap both for the development of improved vaccine strains and for the creation of a framework to ‘risk assess’ reassortment potential to better predict the emergence of new pandemic influenza strains. A combination of secondary structure probing and RNA crosslinking sequencing approaches sheds lights on the RNA conformations and the intra- and intersegment interactions of the genome inside influenza A virions.

ACS Style

Bernadeta Dadonaite; Brad Gilbertson; Michael L. Knight; Sanja Trifkovic; Steven Rockman; Alain Laederach; Lorena E. Brown; Ervin Fodor; David L. V. Bauer. The structure of the influenza A virus genome. Nature Microbiology 2019, 4, 1781 -1789.

AMA Style

Bernadeta Dadonaite, Brad Gilbertson, Michael L. Knight, Sanja Trifkovic, Steven Rockman, Alain Laederach, Lorena E. Brown, Ervin Fodor, David L. V. Bauer. The structure of the influenza A virus genome. Nature Microbiology. 2019; 4 (11):1781-1789.

Chicago/Turabian Style

Bernadeta Dadonaite; Brad Gilbertson; Michael L. Knight; Sanja Trifkovic; Steven Rockman; Alain Laederach; Lorena E. Brown; Ervin Fodor; David L. V. Bauer. 2019. "The structure of the influenza A virus genome." Nature Microbiology 4, no. 11: 1781-1789.

Short report
Published: 21 December 2017 in Human Vaccines & Immunotherapeutics
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Live attenuated influenza vaccines (LAIV) induce CD8+ T lymphocyte responses that play an important role in killing virus-infected cells. Despite the relative conservation of internal influenza A proteins, the epitopes recognized by T cells can undergo drift under immune pressure. The internal proteins of Russian LAIVs are derived from the master donor virus A/Leningrad/134/17/57 (Len/17) isolated 60 years ago and as such, some CD8+ T cell epitopes may vary between the vaccine and circulating wild-type strains. To partially overcome this issue, the nucleoprotein (NP) gene of wild-type virus can be incorporated into LAIV reassortant virus, along with the HA and NA genes. The present study compares the human CD8+ T cell memory responses to H3N2 LAIVs with the Len/17 or the wild-type NP using an in vitro model.

ACS Style

D. Korenkov; T. H. O. Nguyen; I. Isakova-Sivak; T. Smolonogina; L. E. Brown; K. Kedzierska; L. Rudenko. Live Attenuated Influenza Vaccines engineered to express the nucleoprotein of a recent isolate stimulate human influenza CD8+ T cells more relevant to current infections. Human Vaccines & Immunotherapeutics 2017, 14, 941 -946.

AMA Style

D. Korenkov, T. H. O. Nguyen, I. Isakova-Sivak, T. Smolonogina, L. E. Brown, K. Kedzierska, L. Rudenko. Live Attenuated Influenza Vaccines engineered to express the nucleoprotein of a recent isolate stimulate human influenza CD8+ T cells more relevant to current infections. Human Vaccines & Immunotherapeutics. 2017; 14 (4):941-946.

Chicago/Turabian Style

D. Korenkov; T. H. O. Nguyen; I. Isakova-Sivak; T. Smolonogina; L. E. Brown; K. Kedzierska; L. Rudenko. 2017. "Live Attenuated Influenza Vaccines engineered to express the nucleoprotein of a recent isolate stimulate human influenza CD8+ T cells more relevant to current infections." Human Vaccines & Immunotherapeutics 14, no. 4: 941-946.

Research article
Published: 08 September 2017 in PLOS ONE
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TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically-derived TNF.

ACS Style

Kylie Quinn; Wan-Ting Kan; Katherine A. Watson; Brian J. Liddicoat; Natasha G. Swan; Hayley McQuilten; Alice Denton; Jasmine Li; Weisan Chen; Lorena Brown; David Jackson; Patrick Reading; Peter C. Doherty; Katherine Kedzierska; Lukasz Kedzierski; Stephen J. Turner; Nicole L. La Gruta. Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude. PLOS ONE 2017, 12, e0184732 .

AMA Style

Kylie Quinn, Wan-Ting Kan, Katherine A. Watson, Brian J. Liddicoat, Natasha G. Swan, Hayley McQuilten, Alice Denton, Jasmine Li, Weisan Chen, Lorena Brown, David Jackson, Patrick Reading, Peter C. Doherty, Katherine Kedzierska, Lukasz Kedzierski, Stephen J. Turner, Nicole L. La Gruta. Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude. PLOS ONE. 2017; 12 (9):e0184732.

Chicago/Turabian Style

Kylie Quinn; Wan-Ting Kan; Katherine A. Watson; Brian J. Liddicoat; Natasha G. Swan; Hayley McQuilten; Alice Denton; Jasmine Li; Weisan Chen; Lorena Brown; David Jackson; Patrick Reading; Peter C. Doherty; Katherine Kedzierska; Lukasz Kedzierski; Stephen J. Turner; Nicole L. La Gruta. 2017. "Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude." PLOS ONE 12, no. 9: e0184732.

Short report
Published: 22 August 2017 in Virology Journal
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Influenza A virus (IAV) PB1-F2 protein has been linked to viral virulence. Strains of the H3N2 subtype historically express full-length PB1-F2 proteins but during the 2010–2011 influenza seasons, nearly half of the circulating H3N2 IAVs encoded truncated PB1-F2 protein. Using a panel of reverse engineered H3N2 IAVs differing only in the origin of the PB1 gene segment, we found that only the virus encoding the avian-derived 1968 PB1 gene matching the human pandemic strain enhanced cellular infiltrate into the alveolar spaces of infected mice. We linked this phenomenon to expression of full-length PB1-F2 protein encompassing critical “inflammatory” residues.

ACS Style

Julie McAuley; Yi-Mo Deng; Brad Gilbertson; Charley MacKenzie-Kludas; Ian Barr; Lorena Brown. Rapid evolution of the PB1-F2 virulence protein expressed by human seasonal H3N2 influenza viruses reduces inflammatory responses to infection. Virology Journal 2017, 14, 1 -6.

AMA Style

Julie McAuley, Yi-Mo Deng, Brad Gilbertson, Charley MacKenzie-Kludas, Ian Barr, Lorena Brown. Rapid evolution of the PB1-F2 virulence protein expressed by human seasonal H3N2 influenza viruses reduces inflammatory responses to infection. Virology Journal. 2017; 14 (1):1-6.

Chicago/Turabian Style

Julie McAuley; Yi-Mo Deng; Brad Gilbertson; Charley MacKenzie-Kludas; Ian Barr; Lorena Brown. 2017. "Rapid evolution of the PB1-F2 virulence protein expressed by human seasonal H3N2 influenza viruses reduces inflammatory responses to infection." Virology Journal 14, no. 1: 1-6.

Journal article
Published: 15 July 2017 in Journal of Virology
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It is possible to model the progression of influenza virus from the upper respiratory tract to the lower respiratory tract in the mouse using viral inoculum delivered in a restricted manner to the nose. In this model, infection with the A/Udorn/307/72 (Udorn) strain of virus results ultimately in high viral titers in both the trachea and lungs. In contrast, the A/Puerto Rico/8/34 (PR8) strain causes an infection that is almost entirely limited to the nasal passages. The factors that govern the progression of virus down the respiratory tract are not well understood. Here, we show that, while PR8 virus grows to high titers in the nose, an inhibitor present in the saliva blocks further progression of infection to the trachea and lungs and renders an otherwise lethal dose of virus completely asymptomatic. In vitro , the salivary inhibitor was capable of potent neutralization of PR8 virus and an additional 20 strains of type A virus and two type B strains that were tested. The exceptions were Udorn virus and the closely related H3N2 strains A/Port Chalmers/1/73 and A/Victoria/3/75. Characterization of the salivary inhibitor showed it to be independent of sialic acid and other carbohydrates for its function. This and other biochemical properties, together with its virus strain specificity and in vivo function, indicate that the mouse salivary inhibitor is a previously undescribed innate inhibitory molecule that may have evolved to provide pulmonary protection of the species from fatal influenza virus infection. IMPORTANCE Influenza A virus occasionally jumps from aquatic birds, its natural host, into mammals to cause outbreaks of varying severity, including pandemics in humans. Despite the laboratory mouse being used as a model to study influenza virus pathogenesis, natural outbreaks of influenza have not been reported in the species. Here, we shed light on one mechanism that might allow mice to be protected from influenza in the wild. We show that virus deposited in the mouse upper respiratory tract will not progress to the lower respiratory tract due to the presence of a potent inhibitor of the virus in saliva. Containing inhibitor-sensitive virus to the upper respiratory tract renders an otherwise lethal infection subclinical. This knowledge sheds light on how natural inhibitors may have evolved to improve survival in this species.

ACS Style

Karen Ivinson; Georgia Deliyannis; Leanne McNabb; Lara Grollo; Brad Gilbertson; David Jackson; Lorena E. Brown. Salivary Blockade Protects the Lower Respiratory Tract of Mice from Lethal Influenza Virus Infection. Journal of Virology 2017, 91, e00624-17 .

AMA Style

Karen Ivinson, Georgia Deliyannis, Leanne McNabb, Lara Grollo, Brad Gilbertson, David Jackson, Lorena E. Brown. Salivary Blockade Protects the Lower Respiratory Tract of Mice from Lethal Influenza Virus Infection. Journal of Virology. 2017; 91 (14):e00624-17.

Chicago/Turabian Style

Karen Ivinson; Georgia Deliyannis; Leanne McNabb; Lara Grollo; Brad Gilbertson; David Jackson; Lorena E. Brown. 2017. "Salivary Blockade Protects the Lower Respiratory Tract of Mice from Lethal Influenza Virus Infection." Journal of Virology 91, no. 14: e00624-17.

Article
Published: 15 July 2017 in Journal of Virology
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We previously identified a novel inhibitor of influenza virus in mouse saliva that halts the progression of susceptible viruses from the upper to the lower respiratory tract of mice in vivo and neutralizes viral infectivity in MDCK cells. Here, we investigated the viral target of the salivary inhibitor by using reverse genetics to create hybrid viruses with some surface proteins derived from an inhibitor-sensitive strain and others from an inhibitor-resistant strain. These viruses demonstrated that the origin of the viral neuraminidase (NA), but not the hemagglutinin or matrix protein, was the determinant of susceptibility to the inhibitor. Comparison of the NA sequences of a panel of H3N2 viruses with differing sensitivities to the salivary inhibitor revealed that surface residues 368 to 370 (N2 numbering) outside the active site played a key role in resistance. Resistant viruses contained an EDS motif at this location, and mutation to either EES or KDS, found in highly susceptible strains, significantly increased in vitro susceptibility to the inhibitor and reduced the ability of the virus to progress to the lungs when the viral inoculum was initially confined to the upper respiratory tract. In the presence of saliva, viral strains with a susceptible NA could not be efficiently released from the surfaces of infected MDCK cells and had reduced enzymatic activity based on their ability to cleave substrate in vitro . This work indicates that the mouse has evolved an innate inhibitor similar in function, though not in mechanism, to what humans have created synthetically as an antiviral drug for influenza virus. IMPORTANCE Despite widespread use of experimental pulmonary infection of the laboratory mouse to study influenza virus infection and pathogenesis, to our knowledge, mice do not naturally succumb to influenza. Here, we show that mice produce their own natural form of neuraminidase inhibitor in saliva that stops the virus from reaching the lungs, providing a possible mechanism through which the species may not experience severe influenza virus infection in the wild. We show that the murine salivary inhibitor targets the outer surface of the influenza virus neuraminidase, possibly occluding entry to the enzymatic site rather than binding within the active site like commercially available neuraminidase inhibitors. This knowledge sheds light on how the natural inhibitors of particular species combat infection.

ACS Style

Brad Gilbertson; Wy Ching Ng; Simon Crawford; Jenny L. McKimm-Breschkin; Lorena E. Brown. Mouse Saliva Inhibits Transit of Influenza Virus to the Lower Respiratory Tract by Efficiently Blocking Influenza Virus Neuraminidase Activity. Journal of Virology 2017, 91, e00145-17 .

AMA Style

Brad Gilbertson, Wy Ching Ng, Simon Crawford, Jenny L. McKimm-Breschkin, Lorena E. Brown. Mouse Saliva Inhibits Transit of Influenza Virus to the Lower Respiratory Tract by Efficiently Blocking Influenza Virus Neuraminidase Activity. Journal of Virology. 2017; 91 (14):e00145-17.

Chicago/Turabian Style

Brad Gilbertson; Wy Ching Ng; Simon Crawford; Jenny L. McKimm-Breschkin; Lorena E. Brown. 2017. "Mouse Saliva Inhibits Transit of Influenza Virus to the Lower Respiratory Tract by Efficiently Blocking Influenza Virus Neuraminidase Activity." Journal of Virology 91, no. 14: e00145-17.

Journal article
Published: 22 March 2017 in Mucosal Immunology
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Cell surface mucin (cs-mucin) glycoproteins are constitutively expressed at the surface of respiratory epithelia where pathogens such as influenza A virus (IAV) gain entry into cells. Different members of the cs-mucin family each express a large and heavily glycosylated extracellular domain that towers above other receptors on the epithelial cell surface, a transmembrane domain that enables shedding of the extracellular domain, and a cytoplasmic tail capable of triggering signaling cascades. We hypothesized that IAV can interact with the terminal sialic acids presented on the extracellular domain of cs-mucins, resulting in modulation of infection efficiency. Utilizing human lung epithelial cells, we found that IAV associates with the cs-mucin MUC1 but not MUC13 or MUC16. Overexpression of MUC1 by epithelial cells or the addition of sialylated synthetic MUC1 constructs, reduced IAV infection in vitro. In addition, Muc1−/− mice infected with IAV exhibited enhanced morbidity and mortality, as well as greater inflammatory mediator responses compared to wild type mice. This study implicates the cs-mucin MUC1 as a critical and dynamic component of the innate host response that limits the severity of influenza and provides the foundation for exploration of MUC1 in resolving inflammatory disease.

ACS Style

J L McAuley; L Corcilius; Hyon Xhi Tan; R J Payne; Michael McGuckin; Lorena Brown. The cell surface mucin MUC1 limits the severity of influenza A virus infection. Mucosal Immunology 2017, 10, 1581 -1593.

AMA Style

J L McAuley, L Corcilius, Hyon Xhi Tan, R J Payne, Michael McGuckin, Lorena Brown. The cell surface mucin MUC1 limits the severity of influenza A virus infection. Mucosal Immunology. 2017; 10 (6):1581-1593.

Chicago/Turabian Style

J L McAuley; L Corcilius; Hyon Xhi Tan; R J Payne; Michael McGuckin; Lorena Brown. 2017. "The cell surface mucin MUC1 limits the severity of influenza A virus infection." Mucosal Immunology 10, no. 6: 1581-1593.

Journal article
Published: 02 November 2016 in The Journal of Immunology
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G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. G-CSF– and G-CSF receptor–deficient mice are profoundly protected in several models of rheumatoid arthritis, and Ab blockade of G-CSF also protects against disease. To further investigate the actions of blocking G-CSF/G-CSF receptor signaling in inflammatory disease, and as a prelude to human studies of the same approach, we developed a neutralizing mAb to the murine G-CSF receptor, which potently antagonizes binding of murine G-CSF and thereby inhibits STAT3 phosphorylation and G-CSF receptor signaling. Anti–G-CSF receptor rapidly halted the progression of established disease in collagen Ab-induced arthritis in mice. Neutrophil accumulation in joints was inhibited, without rendering animals neutropenic, suggesting an effect of G-CSF receptor blockade on neutrophil homing to inflammatory sites. Consistent with this, neutrophils in the blood and arthritic joints of anti–G-CSF receptor–treated mice showed alterations in cell adhesion receptors, with reduced CXCR2 and increased CD62L expression. Furthermore, blocking neutrophil trafficking with anti–G-CSF receptor suppressed local production of proinflammatory cytokines (IL-1β, IL-6) and chemokines (KC, MCP-1) known to drive tissue damage. Differential gene expression analysis of joint neutrophils showed a switch away from an inflammatory phenotype following anti–G-CSF receptor therapy in collagen Ab-induced arthritis. Importantly, G-CSF receptor blockade did not adversely affect viral clearance during influenza infection in mice. To our knowledge, we describe for the first time the effect of G-CSF receptor blockade in a therapeutic model of inflammatory joint disease and provide support for pursuing this therapeutic approach in treating neutrophil-associated inflammatory diseases.

ACS Style

Ian K. Campbell; David Leong; Kirsten M. Edwards; Veronika Rayzman; Milica Ng; Gabrielle L. Goldberg; Nicholas J. Wilson; Karen Scalzo-Inguanti; Charley MacKenzie-Kludas; Kate E. Lawlor; Ian P. Wicks; Lorena Brown; Adriana Baz Morelli; Con Panousis; Michael J. Wilson; Andrew D. Nash; Brent S. McKenzie; Arna E. Andrews. Therapeutic Targeting of the G-CSF Receptor Reduces Neutrophil Trafficking and Joint Inflammation in Antibody-Mediated Inflammatory Arthritis. The Journal of Immunology 2016, 197, 4392 -4402.

AMA Style

Ian K. Campbell, David Leong, Kirsten M. Edwards, Veronika Rayzman, Milica Ng, Gabrielle L. Goldberg, Nicholas J. Wilson, Karen Scalzo-Inguanti, Charley MacKenzie-Kludas, Kate E. Lawlor, Ian P. Wicks, Lorena Brown, Adriana Baz Morelli, Con Panousis, Michael J. Wilson, Andrew D. Nash, Brent S. McKenzie, Arna E. Andrews. Therapeutic Targeting of the G-CSF Receptor Reduces Neutrophil Trafficking and Joint Inflammation in Antibody-Mediated Inflammatory Arthritis. The Journal of Immunology. 2016; 197 (11):4392-4402.

Chicago/Turabian Style

Ian K. Campbell; David Leong; Kirsten M. Edwards; Veronika Rayzman; Milica Ng; Gabrielle L. Goldberg; Nicholas J. Wilson; Karen Scalzo-Inguanti; Charley MacKenzie-Kludas; Kate E. Lawlor; Ian P. Wicks; Lorena Brown; Adriana Baz Morelli; Con Panousis; Michael J. Wilson; Andrew D. Nash; Brent S. McKenzie; Arna E. Andrews. 2016. "Therapeutic Targeting of the G-CSF Receptor Reduces Neutrophil Trafficking and Joint Inflammation in Antibody-Mediated Inflammatory Arthritis." The Journal of Immunology 197, no. 11: 4392-4402.

Journal article
Published: 20 August 2016 in Viruses
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The influenza A virus genome comprises eight negative-sense viral RNAs (vRNAs) that form individual ribonucleoprotein (RNP) complexes. In order to incorporate a complete set of each of these vRNAs, the virus uses a selective packaging mechanism that facilitates co-packaging of specific gene segments but whose molecular basis is still not fully understood. Recently, we used a competitive transfection model where plasmids encoding the A/Puerto Rico/8/34 (PR8) and A/Udorn/307/72 (Udorn) PB1 gene segments were competed to show that the Udorn PB1 gene segment is preferentially co-packaged into progeny virions with the Udorn NA gene segment. Here we created chimeric PB1 genes combining both Udorn and PR8 PB1 sequences to further define the location within the Udorn PB1 gene that drives co-segregation of these genes and show that nucleotides 1776–2070 of the PB1 gene are crucial for preferential selection. In vitro assays examining specific interactions between Udorn NA vRNA and purified vRNAs transcribed from chimeric PB1 genes also supported the importance of this region in the PB1-NA interaction. Hence, this work identifies an association between viral genes that are co-selected during packaging. It also reveals a region potentially important in the RNP-RNP interactions within the supramolecular complex that is predicted to form prior to budding to allow one of each segment to be packaged in the viral progeny. Our study lays the foundation to understand the co-selection of specific genes, which may be critical to the emergence of new viruses with pandemic potential.

ACS Style

Brad Gilbertson; Tian Zheng; Marie Gerber; Anne Printz-Schweigert; Chi Ong; Roland Marquet; Catherine Isel; Steven Rockman; Lorena Brown. Influenza NA and PB1 Gene Segments Interact during the Formation of Viral Progeny: Localization of the Binding Region within the PB1 Gene. Viruses 2016, 8, 238 .

AMA Style

Brad Gilbertson, Tian Zheng, Marie Gerber, Anne Printz-Schweigert, Chi Ong, Roland Marquet, Catherine Isel, Steven Rockman, Lorena Brown. Influenza NA and PB1 Gene Segments Interact during the Formation of Viral Progeny: Localization of the Binding Region within the PB1 Gene. Viruses. 2016; 8 (8):238.

Chicago/Turabian Style

Brad Gilbertson; Tian Zheng; Marie Gerber; Anne Printz-Schweigert; Chi Ong; Roland Marquet; Catherine Isel; Steven Rockman; Lorena Brown. 2016. "Influenza NA and PB1 Gene Segments Interact during the Formation of Viral Progeny: Localization of the Binding Region within the PB1 Gene." Viruses 8, no. 8: 238.

Journal article
Published: 15 February 2016 in Journal of Virology
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Although avian H5N1 influenza virus has yet to develop the capacity for human-to-human spread, the severity of the rare cases of human infection has warranted intensive follow-up of potentially exposed individuals that may require antiviral prophylaxis. For countries where antiviral drugs are limited, the World Health Organization (WHO) has developed a risk categorization for different levels of exposure to environmental, poultry, or human sources of infection. While these take into account the infection source, they do not account for the likely mode of virus entry that the individual may have experienced from that source and how this could affect the disease outcome. Knowledge of the kinetics and spread of virus after natural routes of exposure may further inform the risk of infection, as well as the likely disease severity. Using the ferret model of H5N1 infection, we compared the commonly used but artificial inoculation method that saturates the total respiratory tract (TRT) with virus to upper respiratory tract (URT) and oral routes of delivery, those likely to be encountered by humans in nature. We show that there was no statistically significant difference in survival rate with the different routes of infection, but the disease characteristics were somewhat different. Following URT infection, viral spread to systemic organs was comparatively delayed and more focal than after TRT infection. By both routes, severe disease was associated with early viremia and central nervous system infection. After oral exposure to the virus, mild infections were common suggesting consumption of virus-contaminated liquids may be associated with seroconversion in the absence of severe disease. IMPORTANCE Risks for human H5N1 infection include direct contact with infected birds and frequenting contaminated environments. We used H5N1 ferret infection models to show that breathing in the virus was more likely to produce clinical infection than swallowing contaminated liquid. We also showed that virus could spread from the respiratory tract to the brain, which was associated with end-stage disease, and very early viremia provided a marker for this. With upper respiratory tract exposure, infection of the brain was common but hard to detect, suggesting that human neurological infections might be typically undetected at autopsy. However, viral spread to systemic sites was slower after exposure to virus by this route than when virus was additionally delivered to the lungs, providing a better therapeutic window. In addition to exposure history, early parameters of infection, such as viremia, could help prioritize antiviral treatments for patients most at risk of succumbing to infection.

ACS Style

Kathryn Edenborough; Suzanne Lowther; Karen Laurie; Manabu Yamada; Fenella Long; John Bingham; Jean Payne; Jennifer Harper; Jessica Haining; Rachel Arkinstall; Brad Gilbertson; Deborah Middleton; Lorena E. Brown. Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes. Journal of Virology 2016, 90, 1888 -1897.

AMA Style

Kathryn Edenborough, Suzanne Lowther, Karen Laurie, Manabu Yamada, Fenella Long, John Bingham, Jean Payne, Jennifer Harper, Jessica Haining, Rachel Arkinstall, Brad Gilbertson, Deborah Middleton, Lorena E. Brown. Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes. Journal of Virology. 2016; 90 (4):1888-1897.

Chicago/Turabian Style

Kathryn Edenborough; Suzanne Lowther; Karen Laurie; Manabu Yamada; Fenella Long; John Bingham; Jean Payne; Jennifer Harper; Jessica Haining; Rachel Arkinstall; Brad Gilbertson; Deborah Middleton; Lorena E. Brown. 2016. "Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes." Journal of Virology 90, no. 4: 1888-1897.

Journal article
Published: 26 January 2016 in Immunology & Cell Biology
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Immunology and Cell Biology focuses on the general functioning of the immune system in its broadest sense, with a particular emphasis on its cell biology. Areas that are covered include but are not limited to: Cellular immunology, Innate and adaptive immunity, Immune responses to pathogens,Tumour immunology,Immunopathology, Immunotherapy, Immunogenetics, Immunological studies in humans and model organisms (including mouse, rat, Drosophila etc)

ACS Style

Patricia (Hoi Yee) Lee; Nicola Bird; Charley MacKenzie-Kludas; Ashley Mansell; Katherine Kedzierska; Lorena Brown; Julie McAuley. Induction of memory cytotoxic T cells to influenza A virus and subsequent viral clearance is not modulated by PB1‐F2‐dependent inflammasome activation. Immunology & Cell Biology 2016, 94, 439 -446.

AMA Style

Patricia (Hoi Yee) Lee, Nicola Bird, Charley MacKenzie-Kludas, Ashley Mansell, Katherine Kedzierska, Lorena Brown, Julie McAuley. Induction of memory cytotoxic T cells to influenza A virus and subsequent viral clearance is not modulated by PB1‐F2‐dependent inflammasome activation. Immunology & Cell Biology. 2016; 94 (5):439-446.

Chicago/Turabian Style

Patricia (Hoi Yee) Lee; Nicola Bird; Charley MacKenzie-Kludas; Ashley Mansell; Katherine Kedzierska; Lorena Brown; Julie McAuley. 2016. "Induction of memory cytotoxic T cells to influenza A virus and subsequent viral clearance is not modulated by PB1‐F2‐dependent inflammasome activation." Immunology & Cell Biology 94, no. 5: 439-446.

Journal article
Published: 31 December 2015 in mBio
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The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R 4 Pam 2 Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R 4 Pam 2 Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R 4 Pam 2 Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8 + T cell responses are also induced by the use of R 4 Pam 2 Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8 + T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity. IMPORTANCE The innate and adaptive immune systems differ in mechanisms, specificities, and times at which they take effect. The innate immune system responds within hours of exposure to infectious agents, while adaptive immunity takes several days to become effective. Here we show, by using a simple lipopeptide-based TLR2 agonist, that an influenza detergent-split vaccine can be made to simultaneously stimulate and amplify both systems to provide immediate antiviral protection while giving the adaptive immune system time to implement long-term immunity. Both types of immunity induced by this approach protect against vaccine-matched as well as unrelated virus strains and potentially even against strains yet to be encountered. Conferring dual functionality to influenza vaccines is beneficial for improving community protection, particularly during periods between the onset of an outbreak and the time when a vaccine becomes available or in scenarios in which mass vaccination with a strain to which the population is immunologically naive is imperative.

ACS Style

Brendon Y. Chua; Chinn Yi Wong; Edin J. Mifsud; Kathryn M. Edenborough; Toshiki Sekiya; Amabel C. L. Tan; Francesca Mercuri; Steve Rockman; Weisan Chen; Stephen J. Turner; Peter C. Doherty; Anne Kelso; Lorena E. Brown; David C. Jackson. Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity. mBio 2015, 6, e01024-15 -15.

AMA Style

Brendon Y. Chua, Chinn Yi Wong, Edin J. Mifsud, Kathryn M. Edenborough, Toshiki Sekiya, Amabel C. L. Tan, Francesca Mercuri, Steve Rockman, Weisan Chen, Stephen J. Turner, Peter C. Doherty, Anne Kelso, Lorena E. Brown, David C. Jackson. Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity. mBio. 2015; 6 (6):e01024-15-15.

Chicago/Turabian Style

Brendon Y. Chua; Chinn Yi Wong; Edin J. Mifsud; Kathryn M. Edenborough; Toshiki Sekiya; Amabel C. L. Tan; Francesca Mercuri; Steve Rockman; Weisan Chen; Stephen J. Turner; Peter C. Doherty; Anne Kelso; Lorena E. Brown; David C. Jackson. 2015. "Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity." mBio 6, no. 6: e01024-15-15.

Journal article
Published: 01 September 2015 in Vaccine
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The emergence of the avian-origin influenza H7N9 virus and its pandemic potential has highlighted the ever-present need to develop vaccination approaches to induce cross-protective immunity. In this study, we examined the establishment of cross-reactive CD8(+) T cell immunity in mice following immunization with live A/Puerto Rico/8/1934 (PR8; H1N1) influenza virus via two non-productive inoculation routes. We found that immunization via the intramuscular (IM) route established functional influenza-virus specific memory CD8(+) T cell pools capable of cross-reactive recall responses. Epitope-specific primary, memory and recall CD8(+) T-cell responses induced by the IM route, highly relevant to human influenza immunisations, were of comparable magnitude and quality to those elicited by the intraperitoneal (IP) priming, commonly used in mice. Furthermore, IM immunisation resulted in lower lung viral titres following heterologous challenge with A/Aichi/68 (X31; H3N2) compared to the IP route. Examining the ability of DCs from lymphoid organs to present viral antigen revealed that immune induction following IM immunization occurred in draining lymph nodes, while immunization via the IP route resulted in the priming of responses in distal lymphoid organs, indicative of a systemic distribution of antigen. No major differences in the pulmonary cytokine environment of immunized animals following X31 challenge were observed that could account for the improved heterologous protection induced by the IM route. However, while both routes induced similar levels of PR8-specific antibodies, higher levels of cross-reactive antibodies against X31 were induced following IM inoculation. Our data demonstrate how non-replicative routes of infection can induce efficient cross-reactive CD8(+) T cell responses and strong strain-specific antibody responses, with the additional benefit from IM priming of enhanced heterosubtypic antibody production.

ACS Style

Zhongfang Wang; Brendon Y. Chua; Javier Vega Ramos; Sergio M. Quiñones Parra; Emily Fairmaid; Lorena E. Brown; David C. Jackson; Katherine Kedzierska. Establishment of functional influenza virus-specific CD8+ T cell memory pools after intramuscular immunization. Vaccine 2015, 33, 5148 -5154.

AMA Style

Zhongfang Wang, Brendon Y. Chua, Javier Vega Ramos, Sergio M. Quiñones Parra, Emily Fairmaid, Lorena E. Brown, David C. Jackson, Katherine Kedzierska. Establishment of functional influenza virus-specific CD8+ T cell memory pools after intramuscular immunization. Vaccine. 2015; 33 (39):5148-5154.

Chicago/Turabian Style

Zhongfang Wang; Brendon Y. Chua; Javier Vega Ramos; Sergio M. Quiñones Parra; Emily Fairmaid; Lorena E. Brown; David C. Jackson; Katherine Kedzierska. 2015. "Establishment of functional influenza virus-specific CD8+ T cell memory pools after intramuscular immunization." Vaccine 33, no. 39: 5148-5154.