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Virologist immunologist and animal models of virus disease
The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has triggered a worldwide health emergency. Here, we show that ferritin-like Dps from hyperthermophilic Sulfolobus islandicus, covalently coupled with SARS-CoV-2 antigens via the SpyCatcher system, forms stable multivalent dodecameric vaccine nanoparticles that remain intact even after lyophilisation. Immunisation experiments in mice demonstrated that the SARS-CoV-2 receptor binding domain (RBD) coupled to Dps (RBD-S-Dps) elicited a higher antibody titre and an enhanced neutralising antibody response compared to monomeric RBD. A single immunisation with RBD-S-Dps completely protected hACE2-expressing mice from serious illness and led to viral clearance from the lungs upon SARS-CoV-2 infection. Our data highlight that multimerised SARS-CoV-2 subunit vaccines are a highly efficacious modality, particularly when combined with an ultra-stable scaffold.
Ralf Salzer; Jordan J. Clark; Marina Vaysburd; Veronica T. Chang; Anna Albecka; Leo Kiss; Parul Sharma; Andres Gonzalez Llamazares; Anja Kipar; Julian A. Hiscox; Andrew Owen; A. Radu Aricescu; James P. Stewart; Leo C. James; Jan Löwe. Single‐dose immunisation with a multimerised SARS‐CoV‐2 receptor binding domain (RBD) induces an enhanced and protective response in mice. FEBS Letters 2021, 1 .
AMA StyleRalf Salzer, Jordan J. Clark, Marina Vaysburd, Veronica T. Chang, Anna Albecka, Leo Kiss, Parul Sharma, Andres Gonzalez Llamazares, Anja Kipar, Julian A. Hiscox, Andrew Owen, A. Radu Aricescu, James P. Stewart, Leo C. James, Jan Löwe. Single‐dose immunisation with a multimerised SARS‐CoV‐2 receptor binding domain (RBD) induces an enhanced and protective response in mice. FEBS Letters. 2021; ():1.
Chicago/Turabian StyleRalf Salzer; Jordan J. Clark; Marina Vaysburd; Veronica T. Chang; Anna Albecka; Leo Kiss; Parul Sharma; Andres Gonzalez Llamazares; Anja Kipar; Julian A. Hiscox; Andrew Owen; A. Radu Aricescu; James P. Stewart; Leo C. James; Jan Löwe. 2021. "Single‐dose immunisation with a multimerised SARS‐CoV‐2 receptor binding domain (RBD) induces an enhanced and protective response in mice." FEBS Letters , no. : 1.
This article provides a brief overview of drug resistance to antiviral therapy as well as known and emergent variability in key SARS-CoV-2 viral sequences. The purpose is to stimulate deliberation about the need to consider drug resistance prior to widespread roll-out of antivirals for SARS-CoV-2. Many existing candidate agents have mechanisms of action involving drug targets likely to be critical for future drug development. Resistance emerged quickly with monotherapies deployed for other pulmonary viruses such as influenza virus, and in HIV mutations in key drug targets compromised efficacy of multiple drugs within a class. The potential for drug resistance in SARS-CoV-2 has not yet been rigorously debated or assessed, and we call for more academic and industry research on this potentially important future threat prior to widespread roll-out of monotherapies for COVID-19 treatment and prevention.
Julian A Hiscox; Saye H Khoo; James P Stewart; Andrew Owen. Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance? Journal of Antimicrobial Chemotherapy 2021, 1 .
AMA StyleJulian A Hiscox, Saye H Khoo, James P Stewart, Andrew Owen. Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance? Journal of Antimicrobial Chemotherapy. 2021; ():1.
Chicago/Turabian StyleJulian A Hiscox; Saye H Khoo; James P Stewart; Andrew Owen. 2021. "Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance?" Journal of Antimicrobial Chemotherapy , no. : 1.
The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has triggered a worldwide health emergency. So far, several different types of vaccines have shown strong efficacy. However, both the emergence of new SARS-CoV-2 variants and the need to vaccinate a large fraction of the world’s population necessitate the development of alternative vaccines, especially those that are simple and easy to store, transport and administer. Here, we showed that ferritin-like Dps protein from hyperthermophilic Sulfolobus islandicus can be covalently coupled with different SARS-CoV-2 antigens via the SpyCatcher system, to form extremely stable and defined multivalent dodecameric vaccine nanoparticles that remain intact even after lyophilisation. Immunisation experiments in mice demonstrated that the SARS-CoV-2 receptor binding domain (RBD) coupled to Dps (RBD-S-Dps) shows particular promise as it elicited a higher antibody titre and an enhanced neutralising antibody response compared to the monomeric RBD. Furthermore, we showed that a single immunisation with the multivalent RBD-S-Dps completely protected hACE2-expressing mice from serious illness and led to efficient viral clearance from the lungs upon SARS-CoV-2 infection. Our data highlight that multimerised SARS-CoV-2 subunit vaccines are a highly efficacious modality, particularly when combined with an ultra-stable scaffold.
Ralf Salzer; Jordan J. Clark; Marina Vaysburd; Veronica T. Chang; Anna Albecka; Leo Kiss; Parul Sharma; Andres Gonzalez Llamazares; Anja Kipar; Julian A. Hiscox; Andrew Owen; A. Radu Aricescu; James P. Stewart; Leo C. James; Jan Löwe. Single-dose immunisation with a multimerised SARS-CoV-2 receptor binding domain (RBD) induces an enhanced and protective response in mice. 2021, 1 .
AMA StyleRalf Salzer, Jordan J. Clark, Marina Vaysburd, Veronica T. Chang, Anna Albecka, Leo Kiss, Parul Sharma, Andres Gonzalez Llamazares, Anja Kipar, Julian A. Hiscox, Andrew Owen, A. Radu Aricescu, James P. Stewart, Leo C. James, Jan Löwe. Single-dose immunisation with a multimerised SARS-CoV-2 receptor binding domain (RBD) induces an enhanced and protective response in mice. . 2021; ():1.
Chicago/Turabian StyleRalf Salzer; Jordan J. Clark; Marina Vaysburd; Veronica T. Chang; Anna Albecka; Leo Kiss; Parul Sharma; Andres Gonzalez Llamazares; Anja Kipar; Julian A. Hiscox; Andrew Owen; A. Radu Aricescu; James P. Stewart; Leo C. James; Jan Löwe. 2021. "Single-dose immunisation with a multimerised SARS-CoV-2 receptor binding domain (RBD) induces an enhanced and protective response in mice." , no. : 1.
Coronavirus disease 2019 (COVID-19) is a primarily respiratory disease with variable clinical courses for which animal models are needed to gather insights into the pathogenesis of its causative virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), in human patients. SARS-CoV-2 not only affects the respiratory tract but also the central nervous system (CNS), leading to neurological symptoms such as loss of smell and taste, headache, fatigue or severe complications like cerebrovascular diseases. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a well-known model of SARS-CoV-2 infection. In the present study, it served to investigate the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with relatively low SARS-CoV-2 doses and after prior influenza A virus infection. In K18-hACE2 mice, SARS-CoV-2 was found to frequently spread to and within the CNS during the later phase (day 7) of infection. Infection was restricted to neurons and appeared to first affect the olfactory bulb and spread from there mainly in basally orientated regions in the brain and into the spinal cord, in a dose dependent manner and independent of ACE2 expression. Neuronal infection was not associated with cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed. This was accompanied by apoptotic death of endothelial, microglial and immune cells, without evidence of viral infection of glial cells, endothelial cells and leukocytes. Taken together, microgliosis and immune cell apoptosis indicate a potential important role of microglial cells for the pathogenesis and viral effect in COVID-19 and possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates, and broadly support investigation of agents with adequate penetration into relevant regions of the CNS.
Frauke Seehusen; Jordan J. Clark; Parul Sharma; Krishanthi Subramaniam; Sabina Wunderlin Giuliani; Grant L. Hughes; Edward I. Patterson; Benedict D. Michael; Andrew Owen; Julian Alexander Hiscox; James P. Stewart; Anja Kipar. Viral neuroinvasion and neurotropism without neuronal damage in the hACE2 mouse model of COVID-19. 2021, 1 .
AMA StyleFrauke Seehusen, Jordan J. Clark, Parul Sharma, Krishanthi Subramaniam, Sabina Wunderlin Giuliani, Grant L. Hughes, Edward I. Patterson, Benedict D. Michael, Andrew Owen, Julian Alexander Hiscox, James P. Stewart, Anja Kipar. Viral neuroinvasion and neurotropism without neuronal damage in the hACE2 mouse model of COVID-19. . 2021; ():1.
Chicago/Turabian StyleFrauke Seehusen; Jordan J. Clark; Parul Sharma; Krishanthi Subramaniam; Sabina Wunderlin Giuliani; Grant L. Hughes; Edward I. Patterson; Benedict D. Michael; Andrew Owen; Julian Alexander Hiscox; James P. Stewart; Anja Kipar. 2021. "Viral neuroinvasion and neurotropism without neuronal damage in the hACE2 mouse model of COVID-19." , no. : 1.
The ability of acquired immune responses against SARS-CoV-2 to protect after subsequent exposure to emerging variants of concern (VOC) such as B1.1.7 and B1.351 is currently of high significance. Here, we use a hamster model of COVID-19 to show that prior infection with a strain representative of the original circulating lineage B of SARS-CoV-2 induces protection from clinical signs upon subsequent challenge with either B1.1.7 or B1.351 viruses, which recently emerged in the UK and South Africa, respectively. The results indicate that these emergent VOC may be unlikely to cause disease in individuals that are already immune due to prior infection, and this has positive implications for overall levels of infection and COVID-19 disease.
Jordan J. Clark; Parul Sharma; Eleanor G. Bentley; Adam C. Harding; Anja Kipar; Megan Neary; Helen Box; Grant L. Hughes; Edward I. Patterson; Jo Sharp; Tulio de Oliveira; Alex Sigal; Julian A. Hiscox; William S. James; Miles W. Carroll; Andrew Owen; James P. Stewart. Naturally-acquired immunity in Syrian Golden Hamsters provides protection from re-exposure to emerging heterosubtypic SARS-CoV-2 variants B.1.1.7 and B.1.351. 2021, 1 .
AMA StyleJordan J. Clark, Parul Sharma, Eleanor G. Bentley, Adam C. Harding, Anja Kipar, Megan Neary, Helen Box, Grant L. Hughes, Edward I. Patterson, Jo Sharp, Tulio de Oliveira, Alex Sigal, Julian A. Hiscox, William S. James, Miles W. Carroll, Andrew Owen, James P. Stewart. Naturally-acquired immunity in Syrian Golden Hamsters provides protection from re-exposure to emerging heterosubtypic SARS-CoV-2 variants B.1.1.7 and B.1.351. . 2021; ():1.
Chicago/Turabian StyleJordan J. Clark; Parul Sharma; Eleanor G. Bentley; Adam C. Harding; Anja Kipar; Megan Neary; Helen Box; Grant L. Hughes; Edward I. Patterson; Jo Sharp; Tulio de Oliveira; Alex Sigal; Julian A. Hiscox; William S. James; Miles W. Carroll; Andrew Owen; James P. Stewart. 2021. "Naturally-acquired immunity in Syrian Golden Hamsters provides protection from re-exposure to emerging heterosubtypic SARS-CoV-2 variants B.1.1.7 and B.1.351." , no. : 1.
Influenza A virus (IAV) and SARS‐CoV‐2 (COVID‐19) cause pandemic infections where cytokine storm syndrome and lung inflammation lead to high mortality. Given the high social and economic cost of respiratory viruses, there is an urgent need to understand how the airways defend against virus infection. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that ATG16L1‐dependent targeting of LC3 to single‐membrane, non‐autophagosome compartments – referred to as non‐canonical autophagy – protects mice from lethal IAV infection. Mice with systemic loss of non‐canonical autophagy are exquisitely sensitive to low‐pathogenicity IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV was controlled within epithelial barriers where non‐canonical autophagy reduced IAV fusion with endosomes and activation of interferon signalling. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung was independent of phagocytes and other leucocytes. This establishes non‐canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces.
Yingxue Wang; Parul Sharma; Matthew Jefferson; Weijiao Zhang; Ben Bone; Anja Kipar; David Bitto; Janine L Coombes; Timothy Pearson; Angela Man; Alex Zhekova; Yongping Bao; Ralph A Tripp; Simon R Carding; Yohei Yamauchi; Ulrike Mayer; Penny P Powell; James P Stewart; Thomas Wileman. Non‐canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus. The EMBO Journal 2021, 40, e105543 .
AMA StyleYingxue Wang, Parul Sharma, Matthew Jefferson, Weijiao Zhang, Ben Bone, Anja Kipar, David Bitto, Janine L Coombes, Timothy Pearson, Angela Man, Alex Zhekova, Yongping Bao, Ralph A Tripp, Simon R Carding, Yohei Yamauchi, Ulrike Mayer, Penny P Powell, James P Stewart, Thomas Wileman. Non‐canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus. The EMBO Journal. 2021; 40 (6):e105543.
Chicago/Turabian StyleYingxue Wang; Parul Sharma; Matthew Jefferson; Weijiao Zhang; Ben Bone; Anja Kipar; David Bitto; Janine L Coombes; Timothy Pearson; Angela Man; Alex Zhekova; Yongping Bao; Ralph A Tripp; Simon R Carding; Yohei Yamauchi; Ulrike Mayer; Penny P Powell; James P Stewart; Thomas Wileman. 2021. "Non‐canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus." The EMBO Journal 40, no. 6: e105543.
Malignant catarrhal fever (MCF) is a sporadic, generally fatal disease caused by gammaherpesviruses in susceptible dead-end hosts. A key pathological process is systemic vasculitis in which productively infected cytotoxic T cells play a major role. Nonetheless, the pathogenesis of MCF vasculitis is not yet clear. We hypothesized that it develops due to an interaction between virus-infected cells and immune cells, and we undertook a retrospective in situ study on the rete mirabile arteries of confirmed ovine gammaherpesvirus-2 (OvHV-2)-associated MCF cases in cattle, buffalo, and bison. Our results suggest that the arteritis develops from an adventitial infiltration of inflammatory cells from the vasa vasorum, and recruitment of leukocytes from the arterial lumen that leads to a superimposed infiltration of the intima and media that can result in chronic changes including neointimal proliferation. We found macrophages and T cells to be the dominant infiltrating cells, and both could proliferate locally. Using RNA in situ hybridization and immunohistology, we showed that the process is accompanied by widespread viral infection, not only in infiltrating leukocytes but also in vascular endothelial cells, medial smooth muscle cells, and adventitial fibroblasts. Our results suggest that OvHV-2-infected T cells, monocytes, and locally proliferating macrophages contribute to the vasculitis in MCF. The initial trigger or insult that leads to leukocyte recruitment and activation is not yet known, but there is evidence that latently infected, activated endothelial cells play a role in this. Activated macrophages might then release the necessary pro-inflammatory mediators and, eventually, induce the characteristic vascular changes.
Helena Saura-Martinez; Mohammed Al-Saadi; James P. Stewart; Anja Kipar. Sheep-Associated Malignant Catarrhal Fever: Role of Latent Virus and Macrophages in Vasculitis. Veterinary Pathology 2020, 58, 332 -345.
AMA StyleHelena Saura-Martinez, Mohammed Al-Saadi, James P. Stewart, Anja Kipar. Sheep-Associated Malignant Catarrhal Fever: Role of Latent Virus and Macrophages in Vasculitis. Veterinary Pathology. 2020; 58 (2):332-345.
Chicago/Turabian StyleHelena Saura-Martinez; Mohammed Al-Saadi; James P. Stewart; Anja Kipar. 2020. "Sheep-Associated Malignant Catarrhal Fever: Role of Latent Virus and Macrophages in Vasculitis." Veterinary Pathology 58, no. 2: 332-345.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Sequencing the viral genome as the outbreak progresses is important, particularly in the identification of emerging isolates with different pathogenic potential and to identify whether nucleotide changes in the genome will impair clinical diagnostic tools such as real-time PCR assays. Although single nucleotide polymorphisms and point mutations occur during the replication of coronaviruses, one of the biggest drivers in genetic change is recombination. This can manifest itself in insertions and/or deletions in the viral genome. Therefore, sequencing strategies that underpin molecular epidemiology and inform virus biology in patients should take these factors into account. A long amplicon/read length-based RT-PCR sequencing approach focused on the Oxford Nanopore MinION/GridION platforms was developed to identify and sequence the SARS-CoV-2 genome in samples from patients with or suspected of COVID-19. The protocol, termed Rapid Sequencing Long Amplicons (RSLAs) used random primers to generate cDNA from RNA purified from a sample from a patient, followed by single or multiplex PCRs to generate longer amplicons of the viral genome. The base protocol was used to identify SARS-CoV-2 in a variety of clinical samples and proved sensitive in identifying viral RNA in samples from patients that had been declared negative using other nucleic acid-based assays (false negative). Sequencing the amplicons revealed that a number of patients had a proportion of viral genomes with deletions.
Shona C. Moore; Rebekah Penrice-Randall; Muhannad Alruwaili; Nadine Randle; Stuart Armstrong; Catherine Hartley; Sam Haldenby; Xiaofeng Dong; Abdulrahman Alrezaihi; Mai Almsaud; Eleanor Bentley; Jordan Clark; Isabel García-Dorival; Paul Gilmore; Ximeng Han; Benjamin Jones; Lisa Luu; Parul Sharma; Ghada Shawli; Yani Sun; Qin Zhao; Steven T. Pullan; Daniel P. Carter; Kevin Bewley; Jake Dunning; En-Min Zhou; Tom Solomon; Michael Beadsworth; James Cruise; Derrick W. Crook; David A. Matthews; Andrew D. Davidson; Zana Mahmood; Waleed Aljabr; Julian Druce; Richard Vipond; Lisa Ng; Laurent Renia; Peter J. M. Openshaw; J. Kenneth Baillie; Miles W. Carroll; James Stewart; Alistair Darby; Malcolm Semple; Lance Turtle; Julian A. Hiscox. Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism. Viruses 2020, 12, 1164 .
AMA StyleShona C. Moore, Rebekah Penrice-Randall, Muhannad Alruwaili, Nadine Randle, Stuart Armstrong, Catherine Hartley, Sam Haldenby, Xiaofeng Dong, Abdulrahman Alrezaihi, Mai Almsaud, Eleanor Bentley, Jordan Clark, Isabel García-Dorival, Paul Gilmore, Ximeng Han, Benjamin Jones, Lisa Luu, Parul Sharma, Ghada Shawli, Yani Sun, Qin Zhao, Steven T. Pullan, Daniel P. Carter, Kevin Bewley, Jake Dunning, En-Min Zhou, Tom Solomon, Michael Beadsworth, James Cruise, Derrick W. Crook, David A. Matthews, Andrew D. Davidson, Zana Mahmood, Waleed Aljabr, Julian Druce, Richard Vipond, Lisa Ng, Laurent Renia, Peter J. M. Openshaw, J. Kenneth Baillie, Miles W. Carroll, James Stewart, Alistair Darby, Malcolm Semple, Lance Turtle, Julian A. Hiscox. Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism. Viruses. 2020; 12 (10):1164.
Chicago/Turabian StyleShona C. Moore; Rebekah Penrice-Randall; Muhannad Alruwaili; Nadine Randle; Stuart Armstrong; Catherine Hartley; Sam Haldenby; Xiaofeng Dong; Abdulrahman Alrezaihi; Mai Almsaud; Eleanor Bentley; Jordan Clark; Isabel García-Dorival; Paul Gilmore; Ximeng Han; Benjamin Jones; Lisa Luu; Parul Sharma; Ghada Shawli; Yani Sun; Qin Zhao; Steven T. Pullan; Daniel P. Carter; Kevin Bewley; Jake Dunning; En-Min Zhou; Tom Solomon; Michael Beadsworth; James Cruise; Derrick W. Crook; David A. Matthews; Andrew D. Davidson; Zana Mahmood; Waleed Aljabr; Julian Druce; Richard Vipond; Lisa Ng; Laurent Renia; Peter J. M. Openshaw; J. Kenneth Baillie; Miles W. Carroll; James Stewart; Alistair Darby; Malcolm Semple; Lance Turtle; Julian A. Hiscox. 2020. "Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism." Viruses 12, no. 10: 1164.
COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that has rapidly caused a pandemic. Coalescence of a second wave of this virus with seasonal respiratory viruses, particularly influenza virus is a possible global health concern. To investigate this, transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) were first infected with IAV followed by SARS-CoV-2. The host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 only. Infection of mice with each individual virus resulted in a disease phenotype compared to control mice. Although SARS-CoV-2 RNA synthesis appeared significantly reduced in the sequentially infected mice, these mice had a more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to singly infected or control mice. The sequential infection also exacerbated the extrapulmonary manifestations associated with SARS-CoV-2. This included a more severe encephalitis. Taken together, the data suggest that the concept of ‘twinfection’ is deleterious and mitigation steps should be instituted as part of a comprehensive public health response to the COVID-19 pandemic.
Jordan J. Clark; Rebekah Penrice-Randal; Parul Sharma; Anja Kipar; Xiaofeng Dong; Shaun H. Pennington; Amy E. Marriott; Stefano Colombo; Andrew Davidson; Maia Kavanagh Williamson; David A. Matthews; Lance Turtle; Tessa Prince; Grant L. Hughes; Edward I. Patterson; Ghada Shawli; Krishanthi Subramaniam; Jo Sharp; Lynn McLaughlin; En-Min Zhou; Joseph D. Turner; Giancarlo Biagini; Andrew Owen; Julian A. Hiscox; James P. Stewart. Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19. 2020, 1 .
AMA StyleJordan J. Clark, Rebekah Penrice-Randal, Parul Sharma, Anja Kipar, Xiaofeng Dong, Shaun H. Pennington, Amy E. Marriott, Stefano Colombo, Andrew Davidson, Maia Kavanagh Williamson, David A. Matthews, Lance Turtle, Tessa Prince, Grant L. Hughes, Edward I. Patterson, Ghada Shawli, Krishanthi Subramaniam, Jo Sharp, Lynn McLaughlin, En-Min Zhou, Joseph D. Turner, Giancarlo Biagini, Andrew Owen, Julian A. Hiscox, James P. Stewart. Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19. . 2020; ():1.
Chicago/Turabian StyleJordan J. Clark; Rebekah Penrice-Randal; Parul Sharma; Anja Kipar; Xiaofeng Dong; Shaun H. Pennington; Amy E. Marriott; Stefano Colombo; Andrew Davidson; Maia Kavanagh Williamson; David A. Matthews; Lance Turtle; Tessa Prince; Grant L. Hughes; Edward I. Patterson; Ghada Shawli; Krishanthi Subramaniam; Jo Sharp; Lynn McLaughlin; En-Min Zhou; Joseph D. Turner; Giancarlo Biagini; Andrew Owen; Julian A. Hiscox; James P. Stewart. 2020. "Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19." , no. : 1.
SummaryRespiratory viruses such as influenza A virus (IAV) and SARS-CoV-2 (Covid-19) cause pandemic infections where cytokine storm syndrome, lung inflammation and pneumonia lead to high mortality. Given the high social and economic cost of these viruses, there is an urgent need for a comprehensive understanding of how the airways defend against virus infection. Viruses entering cells by endocytosis are killed when delivered to lysosomes for degradation. Lysosome delivery is facilitated by non-canonical autophagy pathways that conjugate LC3 to endo-lysosome compartments to enhance lysosome fusion. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that non-canonical autophagy protects mice from lethal IAV infection of the airways. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity murine-adapted IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV infection was controlled within epithelial barriers where non-canonical autophagy slowed fusion of IAV with endosomes and reduced activation of interferon signalling. This was consistent with conditional mouse models and ex vivo analysis showing that protection against IAV infection of lung was independent of phagocytes and other leukocytes. This establishes non-canonical autophagy pathways in airway epithelial cells as a novel innate defence mechanism that can restrict IAV infection and lethal inflammation at respiratory surfaces.
Yingxue Wang; Weijiao Zhang; Matthew Jefferson; Parul Sharma; Ben Bone; Anja Kipar; Janine L. Coombes; Timothy Pearson; Angela Mann; Aleksandra Zhekova; Yongping Bao; Ralph A Tripp; Yohei Yamauchi; Simon R. Carding; Ulrike Mayer; Penny P. Powell; James P. Stewart; Thomas Wileman. The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal respiratory infection by influenza A virus at epithelial surfaces. 2020, 1 .
AMA StyleYingxue Wang, Weijiao Zhang, Matthew Jefferson, Parul Sharma, Ben Bone, Anja Kipar, Janine L. Coombes, Timothy Pearson, Angela Mann, Aleksandra Zhekova, Yongping Bao, Ralph A Tripp, Yohei Yamauchi, Simon R. Carding, Ulrike Mayer, Penny P. Powell, James P. Stewart, Thomas Wileman. The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal respiratory infection by influenza A virus at epithelial surfaces. . 2020; ():1.
Chicago/Turabian StyleYingxue Wang; Weijiao Zhang; Matthew Jefferson; Parul Sharma; Ben Bone; Anja Kipar; Janine L. Coombes; Timothy Pearson; Angela Mann; Aleksandra Zhekova; Yongping Bao; Ralph A Tripp; Yohei Yamauchi; Simon R. Carding; Ulrike Mayer; Penny P. Powell; James P. Stewart; Thomas Wileman. 2020. "The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal respiratory infection by influenza A virus at epithelial surfaces." , no. : 1.
Gram-negative bacteria naturally produce and secrete nanosized outer membrane vesicles (OMVs). In the human gastrointestinal tract, OMVs produced by commensal Gram-negative bacteria can mediate interactions amongst host cells (including between epithelial cells and immune cells) and maintain microbial homeostasis. This OMV-mediated pathway for host-microbe interactions could be exploited to deliver biologically active proteins to the body. To test this we engineered the Gram-negative bacterium Bacteroides thetaiotaomicron (Bt), a prominent member of the intestinal microbiota of all animals, to incorporate bacteria-, virus- and human-derived proteins into its OMVs. We then used the engineered Bt OMVs to deliver these proteins to the respiratory and gastrointestinal (GI)-tract to protect against infection, tissue inflammation and injury. Our findings demonstrate the ability to express and package both Salmonella enterica ser. Typhimurium-derived vaccine antigens and influenza A virus (IAV)-derived vaccine antigens within or on the outer membrane of Bt OMVs. These antigens were in a form capable of eliciting antigen-specific immune and antibody responses in both mucosal tissues and systemically. Furthermore, immunisation with OMVs containing the core stalk region of the IAV H5 hemagglutinin from an H5N1 strain induced heterotypic protection in mice to a 10-fold lethal dose of an unrelated subtype (H1N1) of IAV. We also showed that OMVs could express the human therapeutic protein, keratinocyte growth factor-2 (KGF-2), in a stable form that, when delivered orally, reduced disease severity and promoted intestinal epithelial repair and recovery in animals administered colitis-inducing dextran sodium sulfate. Collectively, our data demonstrates the utility and effectiveness of using Bt OMVs as a mucosal biologics and drug delivery platform technology.
Ana L. Carvalho; Sonia Fonseca; Ariadna Miquel-Clopés; Kathryn Cross; Khoon-S. Kok; Udo Wegmann; Katherine Gil Cardoso; Eleanor G. Bentley; Sanaria H.M. Al Katy; Janine L. Coombes; Anja Kipar; Regis Stentz; James P. Stewart; Simon R. Carding. Bioengineering commensal bacteria-derived outer membrane vesicles for delivery of biologics to the gastrointestinal and respiratory tract. Journal of Extracellular Vesicles 2019, 8, 1632100 .
AMA StyleAna L. Carvalho, Sonia Fonseca, Ariadna Miquel-Clopés, Kathryn Cross, Khoon-S. Kok, Udo Wegmann, Katherine Gil Cardoso, Eleanor G. Bentley, Sanaria H.M. Al Katy, Janine L. Coombes, Anja Kipar, Regis Stentz, James P. Stewart, Simon R. Carding. Bioengineering commensal bacteria-derived outer membrane vesicles for delivery of biologics to the gastrointestinal and respiratory tract. Journal of Extracellular Vesicles. 2019; 8 (1):1632100.
Chicago/Turabian StyleAna L. Carvalho; Sonia Fonseca; Ariadna Miquel-Clopés; Kathryn Cross; Khoon-S. Kok; Udo Wegmann; Katherine Gil Cardoso; Eleanor G. Bentley; Sanaria H.M. Al Katy; Janine L. Coombes; Anja Kipar; Regis Stentz; James P. Stewart; Simon R. Carding. 2019. "Bioengineering commensal bacteria-derived outer membrane vesicles for delivery of biologics to the gastrointestinal and respiratory tract." Journal of Extracellular Vesicles 8, no. 1: 1632100.
We hypothesized that increased expression of antiviral host factors at portals of viral entry may protect exposed tissues from the constant threat of invading pathogens. Comparative transcriptomic analysis identified the broad-acting restriction factor TRIM22 (TRIpartite Motif 22) to be among the most abundantly expressed antiviral host factors in the lung, a major portal of entry for many respiratory pathogens. This was surprising, as TRIM22 is currently considered to be an interferon stimulated gene (ISG) product that confers protection following the activation of pathogen-induced cytokine-mediated innate immune defences. Using human respiratory cell lines and the airways of rhesus macaques, we experimentally confirmed high levels of constitutive TRIM22 expression in the lung. In contrast, TRIM22 expression in many widely used transformed cell lines could only be observed following immune stimulation. Endogenous levels of TRIM22 in non-transformed cells were sufficient to restrict human and avian influenza A virus (IAV) infection by inhibiting the onset of viral transcription independently of cytokine-mediated innate immune defences. Thus, TRIM22 confers a pre-existing (intrinsic) tissue-specific immune barrier to IAV infection in the respiratory tract. We investigated whether the constitutive expression of TRIM22 was a characteristic shared by other ISGs in human lung tissue. Transcriptomic analysis identified a large group of ISGs and IAV immuno-regulatory host factors that were similarly enriched in the lung relative to other mucosal tissues, but whose expression was downregulated in transformed cell-lines. We identify common networks of immune gene downregulation which correlated with enhanced permissivity of transformed cells to initiate IAV replication. Our data highlight the importance of tissue-specific and cell-type dependent patterns of pre-existing immune gene expression in the intrinsic intracellular restriction of IAV; findings highly relevant to the immune regulation of many clinically important respiratory pathogens.Author SummaryThe respiratory tract is a major portal of virus entry for many clinically important viruses, including seasonal and pandemic influenza A virus (IAV). We reasoned that cells within the respiratory tract might differentially express antiviral host factors to protect against the constant challenge of viral infection. We found the broad-acting antiviral protein TRIM22, conventionally regarded as an interferon stimulated gene (ISG) product upregulated in response to virus infection, to be constitutively expressed to high levels in the lung. We found that constitutive expression of TRIM22 restricted the initiation of human and avian IAV infection independently of cytokine-mediated innate immune defences. We identified pre-existing tissue-specific and cell-type dependent patterns of constitutive immune gene expression that strongly correlated with enhanced resistance to IAV replication from the outset of...
Matthew Charman; Steven McFarlane; Joanna K. Wojtus; Elizabeth Sloan; Rebecca Dewar; Gail Leeming; Mohammed Al-Saadi; Laura Hunter; Miles Carroll; James P. Stewart; Paul Digard; Edward Hutchinson; Chris Boutell. Constitutive TRIM22 expression within the respiratory tract identifies tissue-specific and cell-type dependent intrinsic immune barriers to influenza A virus infection. 2019, 679159 .
AMA StyleMatthew Charman, Steven McFarlane, Joanna K. Wojtus, Elizabeth Sloan, Rebecca Dewar, Gail Leeming, Mohammed Al-Saadi, Laura Hunter, Miles Carroll, James P. Stewart, Paul Digard, Edward Hutchinson, Chris Boutell. Constitutive TRIM22 expression within the respiratory tract identifies tissue-specific and cell-type dependent intrinsic immune barriers to influenza A virus infection. . 2019; ():679159.
Chicago/Turabian StyleMatthew Charman; Steven McFarlane; Joanna K. Wojtus; Elizabeth Sloan; Rebecca Dewar; Gail Leeming; Mohammed Al-Saadi; Laura Hunter; Miles Carroll; James P. Stewart; Paul Digard; Edward Hutchinson; Chris Boutell. 2019. "Constitutive TRIM22 expression within the respiratory tract identifies tissue-specific and cell-type dependent intrinsic immune barriers to influenza A virus infection." , no. : 679159.
The process of viral infection is centered around the interaction between the virus and host cells. Due to the lack of a highly effective cell culture system in vitro , there is little understanding about the interaction between avian HEV and its host cells. In this study, a total of seven host proteins were screened in chicken liver cells by a truncated avian HEV capsid protein (ap237) in which the host protein OATP1A2 interacted with ap237. Overexpression of OATP1A2 in the cells can promote ap237 adsorption as well as avian HEV adsorption and infection of the cells. When the function of OATP1A2 in cells was inhibited by substrates or inhibitors, attachment and infection by avian HEV significantly decreased. The distribution of OATP1A2 in different chicken tissues corresponded with that in tissues during avian HEV infection. This is the first finding that OATP1A2 is involved in viral infection of host cells.
Huixia Li; Mengnan Fan; BaoYuan Liu; Pinpin Ji; Yiyang Chen; Beibei Zhang; Yani Sun; Baicheng Huang; Yuchen Nan; Zhenzhao Sun; James P. Stewart; Julian A. Hiscox; Qin Zhao; En-Min Zhou. Chicken Organic Anion-Transporting Polypeptide 1A2, a Novel Avian Hepatitis E Virus (HEV) ORF2-Interacting Protein, Is Involved in Avian HEV Infection. Journal of Virology 2019, 93, 1 .
AMA StyleHuixia Li, Mengnan Fan, BaoYuan Liu, Pinpin Ji, Yiyang Chen, Beibei Zhang, Yani Sun, Baicheng Huang, Yuchen Nan, Zhenzhao Sun, James P. Stewart, Julian A. Hiscox, Qin Zhao, En-Min Zhou. Chicken Organic Anion-Transporting Polypeptide 1A2, a Novel Avian Hepatitis E Virus (HEV) ORF2-Interacting Protein, Is Involved in Avian HEV Infection. Journal of Virology. 2019; 93 (11):1.
Chicago/Turabian StyleHuixia Li; Mengnan Fan; BaoYuan Liu; Pinpin Ji; Yiyang Chen; Beibei Zhang; Yani Sun; Baicheng Huang; Yuchen Nan; Zhenzhao Sun; James P. Stewart; Julian A. Hiscox; Qin Zhao; En-Min Zhou. 2019. "Chicken Organic Anion-Transporting Polypeptide 1A2, a Novel Avian Hepatitis E Virus (HEV) ORF2-Interacting Protein, Is Involved in Avian HEV Infection." Journal of Virology 93, no. 11: 1.
There is an urgent and unmet need to develop effective vaccines to reduce the global burden of infectious disease in both animals and humans, and in particular for the majority of pathogens that infect via mucosal sites. Here we summarise the impediments to developing mucosal vaccines and review the new and emerging technologies aimed at overcoming the lack of effective vaccine delivery systems that is the major obstacle to developing new mucosal vaccines.
A. Miquel‐Clopés; E. G. Bentley; J. P. Stewart; S. R. Carding. Mucosal vaccines and technology. Clinical & Experimental Immunology 2019, 196, 205 -214.
AMA StyleA. Miquel‐Clopés, E. G. Bentley, J. P. Stewart, S. R. Carding. Mucosal vaccines and technology. Clinical & Experimental Immunology. 2019; 196 (2):205-214.
Chicago/Turabian StyleA. Miquel‐Clopés; E. G. Bentley; J. P. Stewart; S. R. Carding. 2019. "Mucosal vaccines and technology." Clinical & Experimental Immunology 196, no. 2: 205-214.
Correction to: Mucosal Immunology (2017); advance online publication, 17 May 2017; doi:10.1038/mi.2017.45 This article was originally published under NPG's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly.
K M Akram; N A Moyo; G H Leeming; L Bingle; S Jasim; S Hussain; A Schorlemmer; A Kipar; P Digard; R A Tripp; R V Shohet; Colin Bingle; J P Stewart. Erratum: An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection. Mucosal Immunology 2018, 11, 1008 -1008.
AMA StyleK M Akram, N A Moyo, G H Leeming, L Bingle, S Jasim, S Hussain, A Schorlemmer, A Kipar, P Digard, R A Tripp, R V Shohet, Colin Bingle, J P Stewart. Erratum: An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection. Mucosal Immunology. 2018; 11 (3):1008-1008.
Chicago/Turabian StyleK M Akram; N A Moyo; G H Leeming; L Bingle; S Jasim; S Hussain; A Schorlemmer; A Kipar; P Digard; R A Tripp; R V Shohet; Colin Bingle; J P Stewart. 2018. "Erratum: An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection." Mucosal Immunology 11, no. 3: 1008-1008.
N-3 Fatty acids, flavonoids and resveratrol are well publicised for their beneficial effects on human health and wellbeing. Identifying common, underlying biological mechanisms targeted by these functional foods would therefore be informative for the public health sector for advising on nutritional health and disease, food and drug product development and consumer interest. The aim of this study was to explore the potential effects of gene expression changes associated with n-3 fatty acids EPA and DHA, flavonoids and resveratrol on modifying biological systems and disease pathways. To test this, publicly available human microarray data for significant gene expression changes associated with dietary intervention with EPA/DHA, flavonoids and resveratrol was subjected to pathway analysis and significance testing for overlap with signals from genome-wide association studies (GWAS) for common non-communicable diseases and biological functions. There was an enrichment of genes implicated in immune responses and disease pathways which was common to all of the treatment conditions tested. Analysis of biological functions and disease pathways indicated anti-tumorigenic properties for EPA/DHA. In line with this, significance testing of the intersection of genes associated with these functional foods and GWAS hits for common biological functions (ageing and cognition) and non-communicable diseases (breast cancer, CVD, diabesity, neurodegeneration and psychiatric disorders) identified significant overlap between the EPA/DHA and breast cancer gene sets. Dietary intervention with EPA/DHA, flavonoids and resveratrol can target important biological and disease pathways suggesting a potentially important role for these bioactive compounds in the prevention and treatment of dietary-related diseases.
Alix Warburton; Olga Vasieva; Peter Quinn; James P. Stewart; John P. Quinn. Statistical analysis of human microarray data shows that dietary intervention with n-3 fatty acids, flavonoids and resveratrol enriches for immune response and disease pathways. British Journal of Nutrition 2018, 119, 239 -249.
AMA StyleAlix Warburton, Olga Vasieva, Peter Quinn, James P. Stewart, John P. Quinn. Statistical analysis of human microarray data shows that dietary intervention with n-3 fatty acids, flavonoids and resveratrol enriches for immune response and disease pathways. British Journal of Nutrition. 2018; 119 (3):239-249.
Chicago/Turabian StyleAlix Warburton; Olga Vasieva; Peter Quinn; James P. Stewart; John P. Quinn. 2018. "Statistical analysis of human microarray data shows that dietary intervention with n-3 fatty acids, flavonoids and resveratrol enriches for immune response and disease pathways." British Journal of Nutrition 119, no. 3: 239-249.
Background: Incidental findings of virus-like particles were identified following electron microscopy of tissue-engineered tendon constructs (TETC) derived from equine tenocytes. We set out to determine the nature of these particles, as there are few studies which identify virus in tendons per se, and their presence could have implications for tissue-engineering using allogenic grafts. Methods: Virus particles were identified in electron microscopy of TETCs. Virion morphology was used to initially hypothesise the virus identity. Next generation sequencing was implemented to identify the virus. A pan herpesvirus PCR was used to validate the RNASeq findings using an independent platform. Histological analysis and biochemical analysis was undertaken on the TETCs. Results: Morphological features suggested the virus to be either a retrovirus or herpesvirus. Subsequent next generation sequencing mapped reads to Equid herpesvirus 2 (EHV2). Histological examination and biochemical testing for collagen content revealed no significant differences between virally affected TETCs and non-affected TETCs. An independent set of equine superficial digital flexor tendon tissue (n=10) examined using designed primers for specific EHV2 contigs identified at sequencing were negative. These data suggest that EHV is resident in some equine tendon. Conclusions: EHV2 was demonstrated in equine tenocytes for the first time; likely from in vivo infection. The presence of EHV2 could have implications to both tissue-engineering and tendinopathy.
Roisin Wardle; Jane A. Pullman; Sam Haldenby; Lorenzo Ressel; Marion Pope; Peter D. Clegg; Alan Radford; James P. Stewart; Mohammed Al-Saadi; Philip Dyer; Mandy J. Peffers. Identification of Equid herpesvirus 2 in tissue-engineered equine tendon. Wellcome Open Research 2017, 2, 60 .
AMA StyleRoisin Wardle, Jane A. Pullman, Sam Haldenby, Lorenzo Ressel, Marion Pope, Peter D. Clegg, Alan Radford, James P. Stewart, Mohammed Al-Saadi, Philip Dyer, Mandy J. Peffers. Identification of Equid herpesvirus 2 in tissue-engineered equine tendon. Wellcome Open Research. 2017; 2 ():60.
Chicago/Turabian StyleRoisin Wardle; Jane A. Pullman; Sam Haldenby; Lorenzo Ressel; Marion Pope; Peter D. Clegg; Alan Radford; James P. Stewart; Mohammed Al-Saadi; Philip Dyer; Mandy J. Peffers. 2017. "Identification of Equid herpesvirus 2 in tissue-engineered equine tendon." Wellcome Open Research 2, no. : 60.
The airway epithelium secretes proteins that function in innate defense against infection. Bactericidal/permeability-increasing fold-containing family member A1 (BPIFA1) is secreted into airways and has a protective role during bacterial infections, but it is not known whether it also has an antiviral role. To determine a role in host defense against influenza A virus (IAV) infection and to find the underlying defense mechanism, we developed transgenic mouse models that are deficient in BPIFA1 and used these, in combination with in vitro three-dimensional mouse tracheal epithelial cell (mTEC) cultures, to investigate its antiviral properties. We show that BPIFA1 has a significant role in mucosal defense against IAV infection. BPIFA1 secretion was highly modulated after IAV infection. Mice deficient in BPIFA1 lost more weight after infection, supported a higher viral load and virus reached the peripheral lung earlier, indicative of a defect in the control of infection. Further analysis using mTEC cultures showed that BPIFA1-deficient cells bound more virus particles, displayed increased nuclear import of IAV ribonucleoprotein complexes, and supported higher levels of viral replication. Our results identify a critical role of BPIFA1 in the initial phase of infection by inhibiting the binding and entry of IAV into airway epithelial cells.
K M Akram; N A Moyo; G H Leeming; L Bingle; S Jasim; S Hussain; A Schorlemmer; A Kipar; P Digard; R A Tripp; R V Shohet; Colin Bingle; J P Stewart. An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection. Mucosal Immunology 2017, 11, 71 -81.
AMA StyleK M Akram, N A Moyo, G H Leeming, L Bingle, S Jasim, S Hussain, A Schorlemmer, A Kipar, P Digard, R A Tripp, R V Shohet, Colin Bingle, J P Stewart. An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection. Mucosal Immunology. 2017; 11 (1):71-81.
Chicago/Turabian StyleK M Akram; N A Moyo; G H Leeming; L Bingle; S Jasim; S Hussain; A Schorlemmer; A Kipar; P Digard; R A Tripp; R V Shohet; Colin Bingle; J P Stewart. 2017. "An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection." Mucosal Immunology 11, no. 1: 71-81.
The Ebola virus (EBOV) variant Makona (which emerged in 2013) was the causative agent of the largest outbreak of Ebola Virus Disease recorded. Differences in virus-host interactions between viral variants have potential consequences for transmission, disease severity and mortality. A detailed profile of the cellular changes induced by the Makona variant compared with other Ebola virus variants was lacking. In this study, A549 cells, a human cell line with a robust innate response, were infected with the Makona variant or with the Ecran variant originating from the 1976 outbreak in Central Africa. The abundance of viral and cellular mRNA transcripts was profiled using RNASeq and differential gene expression analysis performed. Differences in effects of each virus on the expression of interferon-stimulated genes were also investigated in A549 NPro cells where the type 1 interferon response had been attenuated. Cellular transcriptomic changes were compared with those induced by human respiratory syncytial virus (HRSV), a virus with a similar genome organisation and replication strategy to EBOV. Pathway and gene ontology analysis revealed differential expression of functionally important genes; including genes involved in the inflammatory response, cell proliferation, leukocyte extravasation and cholesterol biosynthesis. Whilst there was overlap with HRSV, there was unique commonality to the EBOV variants.
Andrew Bosworth; Stuart D. Dowall; Isabel Garcia-Dorival; Natasha Rickett; Christine B. Bruce; David Matthews; Yongxiang Fang; Waleed Aljabr; John Kenny; Charlotte Nelson; Thomas R. Laws; E. Diane Williamson; James P. Stewart; Miles W. Carroll; Roger Hewson; Julian A. Hiscox. A comparison of host gene expression signatures associated with infection in vitro by the Makona and Ecran (Mayinga) variants of Ebola virus. Scientific Reports 2017, 7, 43144 .
AMA StyleAndrew Bosworth, Stuart D. Dowall, Isabel Garcia-Dorival, Natasha Rickett, Christine B. Bruce, David Matthews, Yongxiang Fang, Waleed Aljabr, John Kenny, Charlotte Nelson, Thomas R. Laws, E. Diane Williamson, James P. Stewart, Miles W. Carroll, Roger Hewson, Julian A. Hiscox. A comparison of host gene expression signatures associated with infection in vitro by the Makona and Ecran (Mayinga) variants of Ebola virus. Scientific Reports. 2017; 7 (1):43144.
Chicago/Turabian StyleAndrew Bosworth; Stuart D. Dowall; Isabel Garcia-Dorival; Natasha Rickett; Christine B. Bruce; David Matthews; Yongxiang Fang; Waleed Aljabr; John Kenny; Charlotte Nelson; Thomas R. Laws; E. Diane Williamson; James P. Stewart; Miles W. Carroll; Roger Hewson; Julian A. Hiscox. 2017. "A comparison of host gene expression signatures associated with infection in vitro by the Makona and Ecran (Mayinga) variants of Ebola virus." Scientific Reports 7, no. 1: 43144.
Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections.
Anthony C. Marriott; Mike Dennis; Jennifer A. Kane; Karen E. Gooch; Graham Hatch; Sally Sharpe; Claudia Prevosto; Gail Leeming; Elsa-Gayle Zekeng; Karl J. Staples; Graham Hall; Kathryn A. Ryan; Simon Bate; Nathifa Moyo; Catherine J. Whittaker; Bassam Hallis; Nigel J. Silman; Ajit Lalvani; Tom M. Wilkinson; Julian A. Hiscox; James P. Stewart; Miles W. Carroll. Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection. PLOS ONE 2016, 11, e0157887 .
AMA StyleAnthony C. Marriott, Mike Dennis, Jennifer A. Kane, Karen E. Gooch, Graham Hatch, Sally Sharpe, Claudia Prevosto, Gail Leeming, Elsa-Gayle Zekeng, Karl J. Staples, Graham Hall, Kathryn A. Ryan, Simon Bate, Nathifa Moyo, Catherine J. Whittaker, Bassam Hallis, Nigel J. Silman, Ajit Lalvani, Tom M. Wilkinson, Julian A. Hiscox, James P. Stewart, Miles W. Carroll. Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection. PLOS ONE. 2016; 11 (6):e0157887.
Chicago/Turabian StyleAnthony C. Marriott; Mike Dennis; Jennifer A. Kane; Karen E. Gooch; Graham Hatch; Sally Sharpe; Claudia Prevosto; Gail Leeming; Elsa-Gayle Zekeng; Karl J. Staples; Graham Hall; Kathryn A. Ryan; Simon Bate; Nathifa Moyo; Catherine J. Whittaker; Bassam Hallis; Nigel J. Silman; Ajit Lalvani; Tom M. Wilkinson; Julian A. Hiscox; James P. Stewart; Miles W. Carroll. 2016. "Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection." PLOS ONE 11, no. 6: e0157887.