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Article ; Online: The role of growth factor receptors in viral infections

Hubert Hondermarck / Nathan W. Bartlett / Victor Nurcombe

FASEB BioAdvances, Vol 2, Iss 5, Pp 296-

An opportunity for drug repurposing against emerging viral diseases such as COVID‐19?

2020 Volume 303

Abstract: Abstract Growth factor receptors are known to be involved in the process of viral infection. Many viruses not only use growth factor receptors to physically attach to the cell surface and internalize, but also divert receptor tyrosine kinase signaling in ...

Abstract	Abstract Growth factor receptors are known to be involved in the process of viral infection. Many viruses not only use growth factor receptors to physically attach to the cell surface and internalize, but also divert receptor tyrosine kinase signaling in order to replicate. Thus, repurposing drugs that have initially been developed to target growth factor receptors and their signaling in cancer may prove to be a fast track to effective therapies against emerging new viral infections, including the coronavirus disease 19 (COVID‐19).
Keywords	cancer drugs ; COVID‐19 ; growth factors ; heparan sulfate ; heparin ; inhibitors ; Biology (General) ; QH301-705.5 ; covid19
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: miR-122 promotes virus-induced lung disease by targeting SOCS1

Adam M. Collison / Leon A. Sokulsky / Elizabeth Kepreotes / Ana Pereira de Siqueira / Matthew Morten / Michael R. Edwards / Ross P. Walton / Nathan W. Bartlett / Ming Yang / Thi Hiep Nguyen / Sebastian L. Johnston / Paul S. Foster / Joerg Mattes

JCI Insight, Vol 6, Iss

2021 Volume 7

Abstract: Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of ... ...

Abstract	Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of all infants with bronchiolitis and the majority of children with an asthma exacerbation. Bronchiolitis in early life is a strong risk factor for the development of asthma. Here, we found that RV infection induced the expression of miRNA 122 (miR-122) in mouse lungs and in human airway epithelial cells. In vivo inhibition specifically in the lung reduced neutrophilic inflammation and CXCL2 expression, boosted innate IFN responses, and ameliorated airway hyperreactivity in the absence and in the presence of allergic lung inflammation. Inhibition of miR-122 in the lung increased the levels of suppressor of cytokine signaling 1 (SOCS1), which is an in vitro–validated target of miR-122. Importantly, gene silencing of SOCS1 in vivo completely reversed the protective effects of miR-122 inhibition on RV-induced lung disease. Higher miR-122 expression in nasopharyngeal aspirates was associated with a longer time on oxygen therapy and a higher rate of treatment failure in 87 infants hospitalized with moderately severe bronchiolitis. These results suggest that miR-122 promotes RV-induced lung disease via suppression of its target SOCS1 in vivo. Higher miR-122 expression was associated with worse clinical outcomes, highlighting the potential use of anti-miR-122 oligonucleotides, successfully trialed for treatment of hepatitis C, as potential therapeutics for RV-induced bronchiolitis and asthma exacerbations.
Keywords	Inflammation ; Virology ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: IL-25 blockade augments antiviral immunity during respiratory virus infection

Teresa C. Williams / Su-Ling Loo / Kristy S. Nichol / Andrew T. Reid / Punnam C. Veerati / Camille Esneau / Peter A. B. Wark / Christopher L. Grainge / Darryl A. Knight / Thomas Vincent / Crystal L. Jackson / Kirby Alton / Richard A. Shimkets / Jason L. Girkin / Nathan W. Bartlett

Communications Biology, Vol 5, Iss 1, Pp 1-

2022 Volume 13

Abstract: IL-25 and its receptor are expressed in airway epithelial cells of healthy individuals and patients with asthma and antibody-mediated blockade of IL-25 enhances antiviral immunity and blocks virus-exacerbated asthma responses. ...

Abstract	IL-25 and its receptor are expressed in airway epithelial cells of healthy individuals and patients with asthma and antibody-mediated blockade of IL-25 enhances antiviral immunity and blocks virus-exacerbated asthma responses.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease

The Journal of Clinical Investigation, Vol 132, Iss

2022 Volume 8

Abstract: The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and ... ...

Abstract	The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway mucin 5AC (MUC5AC) and MUC5B concentrations during spontaneous and experimentally induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with viral load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation, as Muc5ac-deficient (Muc5ac–/–) mice had attenuated RV-induced (RV-induced) airway inflammation, and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased the release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of RV-induced inflammation in mice. Therapeutic suppression of mucin production using an EGFR antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B expression suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identified a proinflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.
Keywords	Pulmonology ; Medicine ; R
Subject code	610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: TLR2-mediated activation of innate responses in the upper airways confers antiviral protection of the lungs

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

JCI Insight, Vol 6, Iss

2021 Volume 5

Abstract: 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 ...

Abstract	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.
Keywords	Infectious disease ; Therapeutics ; Medicine ; R
Subject code	610 ; 570
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Emergence and antibody evasion of BQ, BA.2.75 and SARS-CoV-2 recombinant sub-lineages in the face of maturing antibody breadth at the population levelResearch in context

Anouschka Akerman / Vanessa Milogiannakis / Tyra Jean / Camille Esneau / Mariana Ruiz Silva / Timothy Ison / Christina Fichter / Joseph A. Lopez / Deborah Chandra / Zin Naing / Joanna Caguicla / Daiyang Li / Gregory Walker / Supavadee Amatayakul-Chantler / Nathan Roth / Sandro Manni / Thomas Hauser / Thomas Barnes / Anna Condylios /

Malinna Yeang / Maureen Wong / Charles S.P. Foster / Kenta Sato / Sharon Lee / Yang Song / Lijun Mao / Allison Sigmund / Amy Phu / Ann Marie Vande More / Stephanie Hunt / Mark Douglas / Ian Caterson / Warwick Britton / Kerrie Sandgren / Rowena Bull / Andrew Lloyd / Jamie Triccas / Stuart Tangye / Nathan W. Bartlett / David Darley / Gail Matthews / Damien J. Stark / Kathy Petoumenos / William D. Rawlinson / Ben Murrell / Fabienne Brilot / Anthony L. Cunningham / Anthony D. Kelleher / Anupriya Aggarwal / Stuart G. Turville

EBioMedicine, Vol 90, Iss , Pp 104545- (2023)

2023

Abstract: Summary: Background: The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a ... ...

Abstract	Summary: Background: The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a diverse grouping of Omicron sub-lineages emerged derived from BA.2, BA.5 and recombinants thereof. Whilst emerging from distinct lineages, all shared similar changes in the Spike glycoprotein affording them an outgrowth advantage through evasion of neutralising antibodies. Methods: Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants in the Australian community at three levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from stringently curated vaccine and convalescent cohorts. (iii) finally we determine the in vitro efficacy of clinically approved therapies Evusheld and Sotrovimab. Findings: In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases, we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst increasing neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR.2.1 and XBF share this phenotype and, in contrast to global variants, are ...
Keywords	SARS-CoV-2 ; Variants ; TMPRSS2 ; Covid-19 ; Neutralising antibodies ; Sotrovimab ; Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model

Pamela C. Proud / Daphne Tsitoura / Robert J. Watson / Brendon Y. Chua / Marilyn J. Aram / Kevin R. Bewley / Breeze E. Cavell / Rebecca Cobb / Stuart Dowall / Susan A. Fotheringham / Catherine M.K. Ho / Vanessa Lucas / Didier Ngabo / Emma Rayner / Kathryn A. Ryan / Gillian S. Slack / Stephen Thomas / Nadina I. Wand / Paul Yeates /

Christophe Demaison / Weiguang Zeng / Ian Holmes / David C. Jackson / Nathan W. Bartlett / Francesca Mercuri / Miles W. Carroll

EBioMedicine, Vol 63, Iss , Pp 103153- (2021)

2021

Abstract: Background: The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, ...

Abstract	Background: The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. Methods: SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 106 pfu/ml. Treatment groups received intranasal INNA-051, developed by Ena Respiratory. SARS-CoV-2 RNA was detected using the 2019-nCoV CDC RUO Kit and QuantStudio™ 7 Flex Real-Time PCR System. Histopathological analysis was performed using cut tissues stained with haematoxylin and eosin (H&E). Findings: We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=<0.0001) by up to a 24 fold (96% reduction) and in nasal wash (p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals. Interpretation: The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19. Funding: This work was funded by Ena Respiratory, Melbourne, Australia.
Keywords	Ferret ; COVID-19 ; SARS-CoV-2 ; Viral shedding ; TLR-2 ; INNA-051 ; Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

Aran Singanayagam / Nicholas Glanville / Jason L. Girkin / Yee Man Ching / Andrea Marcellini / James D. Porter / Marie Toussaint / Ross P. Walton / Lydia J. Finney / Julia Aniscenko / Jie Zhu / Maria-Belen Trujillo-Torralbo / Maria Adelaide Calderazzo / Chris Grainge / Su-Ling Loo / Punnam Chander Veerati / Prabuddha S. Pathinayake / Kristy S. Nichol / Andrew T. Reid /

Phillip L. James / Roberto Solari / Peter A. B. Wark / Darryl A. Knight / Miriam F. Moffatt / William O. Cookson / Michael R. Edwards / Patrick Mallia / Nathan W. Bartlett / Sebastian L. Johnston

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 16

Abstract: Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus ... ...

Abstract	Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus infection, which is restored by exogenous IFNβ.
Keywords	Science ; Q
Language	English
Publishing date	2018-06-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

Phillip L. James / Roberto Solari / Peter A. B. Wark / Darryl A. Knight / Miriam F. Moffatt / William O. Cookson / Michael R. Edwards / Patrick Mallia / Nathan W. Bartlett / Sebastian L. Johnston

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 16

Abstract	Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus infection, which is restored by exogenous IFNβ.
Keywords	Science ; Q
Language	English
Publishing date	2018-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cross-serotype immunity induced by immunization with a conserved rhinovirus capsid protein.

Nicholas Glanville / Gary R McLean / Bruno Guy / Valerie Lecouturier / Catherine Berry / Yves Girerd / Christophe Gregoire / Ross P Walton / Rebecca M Pearson / Tatiana Kebadze / Nicolas Burdin / Nathan W Bartlett / Jeffrey W Almond / Sebastian L Johnston

PLoS Pathogens, Vol 9, Iss 9, p e

2013 Volume 1003669

Abstract: Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ∼150 strains. We aimed to define highly conserved areas of the RV ... ...

Abstract	Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ∼150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model. Regions of the VP0 (VP4+VP2) capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, cellular and humoral immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after infection with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies and lung memory T cells, and caused more rapid virus clearance. Conserved domains of the RV capsid therefore induce cross-reactive immune responses and represent candidates for a subunit RV vaccine.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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