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Article ; Online: The IMPORTance of the Nucleus during Flavivirus Replication

Adam J. Lopez-Denman / Jason M. Mackenzie

Viruses, Vol 9, Iss 1, p

2017 Volume 14

Abstract: Flaviviruses are a large group of arboviruses of significant medical concern worldwide. With outbreaks a common occurrence, the need for efficient viral control is required more than ever. It is well understood that flaviviruses modulate the composition ... ...

Abstract	Flaviviruses are a large group of arboviruses of significant medical concern worldwide. With outbreaks a common occurrence, the need for efficient viral control is required more than ever. It is well understood that flaviviruses modulate the composition and structure of membranes in the cytoplasm that are crucial for efficient replication and evading immune detection. As the flavivirus genome consists of positive sense RNA, replication can occur wholly within the cytoplasm. What is becoming more evident is that some viral proteins also have the ability to translocate to the nucleus, with potential roles in replication and immune system perturbation. In this review, we discuss the current understanding of flavivirus nuclear localisation, and the function it has during flavivirus infection. We also describe—while closely related—the functional differences between similar viral proteins in their nuclear translocation.
Keywords	flavivirus ; nucleus ; transport ; karyopherins ; nuclear pore complex ; nuclear localisation sequence ; Microbiology ; QR1-502 ; Science ; Q
Subject code	570
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Putative Lipid-Associating Motif in the West Nile Virus NS4A Protein Is Required for Efficient Virus Replication

Andrea Mikulasova / Leah K. Gillespie / Rebecca L. Ambrose / Turgut E. Aktepe / Alice M. Trenerry / Susann Liebscher / Jason M. Mackenzie

Frontiers in Cell and Developmental Biology, Vol

2021 Volume 9

Abstract: Flavivirus replication is intimately associated with re-organized cellular membranes. These virus-induced changes in membrane architecture form three distinct membranous “organelles” that have specific functions during the flavivirus life cycle. One of ... ...

Abstract	Flavivirus replication is intimately associated with re-organized cellular membranes. These virus-induced changes in membrane architecture form three distinct membranous “organelles” that have specific functions during the flavivirus life cycle. One of these structures is the replication complex in which the flaviviral RNA is replicated to produce progeny genomes. We have previously observed that this process is strictly dependent on cellular cholesterol. In this study we have identified a putative cholesterol recognition/interaction amino acid consensus (CRAC) motif within the West Nile virus strain Kunjin virus (WNVKUN) NS4A protein. Site-directed mutagenesis of this motif within a WNVKUN infectious clone severely attenuated virus replication and the capacity of the mutant viruses to form the replication complex. Replication of the mutant viruses also displayed reduced co-localization with cellular markers recruited to replication sites during wild-type virus replication. In addition, we observed that the mutant viruses were significantly impaired in their ability to remodel cytoplasmic membranes. However, after extensive analysis we are unable to conclusively reveal a role for the CRAC motif in direct cholesterol binding to NS4A, suggesting additional complex lipid-protein and protein-protein interactions. We believe this study highlights the crucial role for this region within NS4A protein in recruitment of cellular and viral proteins to specialized subdomains on membrane platforms to promote efficient virus replication.
Keywords	West Nile virus ; RNA replication ; membrane remodeling ; NS4A protein ; virus-host interactions ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Host Protein Reticulon 3.1A Is Utilized by Flaviviruses to Facilitate Membrane Remodelling

Turgut E. Aktepe / Susann Liebscher / Julia E. Prier / Cameron P. Simmons / Jason M. Mackenzie

Cell Reports, Vol 21, Iss 6, Pp 1639-

2017 Volume 1654

Abstract: Summary: Flaviviruses are enveloped, positive-sensed single-stranded RNA viruses that remodel host membranes, incorporating both viral and host factors facilitating viral replication. In this study, we identified a key role for the membrane-bending host ... ...

Abstract	Summary: Flaviviruses are enveloped, positive-sensed single-stranded RNA viruses that remodel host membranes, incorporating both viral and host factors facilitating viral replication. In this study, we identified a key role for the membrane-bending host protein Reticulon 3.1 (RTN3.1A) during the replication cycle of three flaviviruses: West Nile virus (WNV), Dengue virus (DENV), and Zika virus (ZIKV). We observed that, during infection, RTN3.1A is redistributed and recruited to the viral replication complex, a recruitment facilitated via the WNV NS4A protein, however, not DENV or ZIKV NS4A. Critically, small interfering RNA (siRNA)-mediated knockdown of RTN3.1A expression attenuated WNV, DENV, and ZIKV replication and severely affected the stability and abundance of the NS4A protein, coinciding with a significant alternation and reduction of viral membrane structures in the endoplasmic reticulum. These observations identified a crucial role of RTN3.1A for the viral remodelling of host membranes during efficient flavivirus replication and the stabilization of viral proteins within the endoplasmic reticulum. : To study the underlying mechanism of flavivirus replication and membrane biogenesis, Aktepe et al. examine the role of the host membrane-shaping protein RTN3.1A during WNVKUN, DENV-2NGC, and ZIKVAFR replication. They find that RTN3.1A is required for NS4A-mediated membrane remodelling during biogenesis of the flavivirus replication complex. Keywords: virus replication, flavivirus, reticulon, membrane, host-virus interaction, NS4A, West Nile virus, Dengue virus, Zika virus
Keywords	Biology (General) ; QH301-705.5
Subject code	570 ; 612
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction

Maya Shemesh / Turgut E. Aktepe / Joshua M. Deerain / Julie L. McAuley / Michelle D. Audsley / Cassandra T. David / Damian F. J. Purcell / Victoria Urin / Rune Hartmann / Gregory W. Moseley / Jason M. Mackenzie / Gideon Schreiber / Daniel Harari

PLoS Pathogens, Vol 17, Iss

SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon

2021 Volume 12

Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon.

Maya Shemesh / Turgut E Aktepe / Joshua M Deerain / Julie L McAuley / Michelle D Audsley / Cassandra T David / Damian F J Purcell / Victoria Urin / Rune Hartmann / Gregory W Moseley / Jason M Mackenzie / Gideon Schreiber / Daniel Harari

PLoS Pathogens, Vol 17, Iss 8, p e

2021 Volume 1009800

Abstract: Type I Interferons (IFN-Is) are a family of cytokines which play a major role in inhibiting viral infection. Resultantly, many viruses have evolved mechanisms in which to evade the IFN-I response. Here we tested the impact of expression of 27 different ... ...

Abstract	Type I Interferons (IFN-Is) are a family of cytokines which play a major role in inhibiting viral infection. Resultantly, many viruses have evolved mechanisms in which to evade the IFN-I response. Here we tested the impact of expression of 27 different SARS-CoV-2 genes in relation to their effect on IFN production and activity using three independent experimental methods. We identified six gene products; NSP6, ORF6, ORF7b, NSP1, NSP5 and NSP15, which strongly (>10-fold) blocked MAVS-induced (but not TRIF-induced) IFNβ production. Expression of the first three of these SARS-CoV-2 genes specifically blocked MAVS-induced IFNβ-promoter activity, whereas all six genes induced a collapse in IFNβ mRNA levels, corresponding with suppressed IFNβ protein secretion. Five of these six genes furthermore suppressed MAVS-induced activation of IFNλs, however with no effect on IFNα or IFNγ production. In sharp contrast, SARS-CoV-2 infected cells remained extremely sensitive to anti-viral activity exerted by added IFN-Is. None of the SARS-CoV-2 genes were able to block IFN-I signaling, as demonstrated by robust activation of Interferon Stimulated Genes (ISGs) by added interferon. This, despite the reduced levels of STAT1 and phospho-STAT1, was likely caused by broad translation inhibition mediated by NSP1. Finally, we found that a truncated ORF7b variant that has arisen from a mutant SARS-CoV-2 strain harboring a 382-nucleotide deletion associating with mild disease (Δ382 strain identified in Singapore & Taiwan in 2020) lost its ability to suppress type I and type III IFN production. In summary, our findings support a multi-gene process in which SARS-CoV-2 blocks IFN-production, with ORF7b as a major player, presumably facilitating evasion of host detection during early infection. However, SARS-CoV-2 fails to suppress IFN-I signaling thus providing an opportunity to exploit IFN-Is as potential therapeutic antiviral drugs.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection.

Hanne Dubois / Frederic Sorgeloos / Soroush T Sarvestani / Liesbet Martens / Yvan Saeys / Jason M Mackenzie / Mohamed Lamkanfi / Geert van Loo / Ian Goodfellow / Andy Wullaert

PLoS Pathogens, Vol 15, Iss 4, p e

2019 Volume 1007709

Abstract: Norovirus infection is the leading cause of food-borne gastroenteritis worldwide, being responsible for over 200,000 deaths annually. Studies with murine norovirus (MNV) showed that protective STAT1 signaling controls viral replication and pathogenesis, ... ...

Abstract	Norovirus infection is the leading cause of food-borne gastroenteritis worldwide, being responsible for over 200,000 deaths annually. Studies with murine norovirus (MNV) showed that protective STAT1 signaling controls viral replication and pathogenesis, but the immune mechanisms that noroviruses exploit to induce pathology are elusive. Here, we show that gastrointestinal MNV infection leads to widespread IL-1β maturation in MNV-susceptible STAT1-deficient mice. MNV activates the canonical Nlrp3 inflammasome in macrophages, leading to maturation of IL-1β and to Gasdermin D (GSDMD)-dependent pyroptosis. STAT1-deficient macrophages displayed increased MAVS-mediated expression of pro-IL-1β, facilitating elevated Nlrp3-dependent release of mature IL-1β upon MNV infection. Accordingly, MNV-infected Stat1-/- mice showed Nlrp3-dependent maturation of IL-1β as well as Nlrp3-dependent pyroptosis as assessed by in vivo cleavage of GSDMD to its active N-terminal fragment. While MNV-induced diarrheic responses were not affected, Stat1-/- mice additionally lacking either Nlrp3 or GSDMD displayed lower levels of the fecal inflammatory marker Lipocalin-2 as well as delayed lethality after gastrointestinal MNV infection. Together, these results uncover new insights into the mechanisms of norovirus-induced inflammation and cell death, thereby revealing Nlrp3 inflammasome activation and ensuing GSDMD-driven pyroptosis as contributors to MNV-induced immunopathology in susceptible STAT1-deficient mice.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Monocyte apoptotic bodies are vehicles for influenza A virus propagation

Communications Biology, Vol 3, Iss 1, Pp 1-

2020 Volume 14

Abstract: Atkin-Smith et al. study apoptotic bodies formed when Influenza A (IAV)-infected monocytes undergo apoptosis. They find that apoptotic bodies contain components of IAV and can contribute to IAV propagation in vitro and in mice, and stimulate an innate ... ...

Abstract	Atkin-Smith et al. study apoptotic bodies formed when Influenza A (IAV)-infected monocytes undergo apoptosis. They find that apoptotic bodies contain components of IAV and can contribute to IAV propagation in vitro and in mice, and stimulate an innate and adaptive immune response. This study suggests that apoptotic bodies may take part in virus propagation and/or clearance.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccineResearch in context

Georgia Deliyannis / Nicholas A. Gherardin / Chinn Yi Wong / Samantha L. Grimley / James P. Cooney / Samuel J. Redmond / Paula Ellenberg / Kathryn C. Davidson / Francesca L. Mordant / Tim Smith / Marianne Gillard / Ester Lopez / Julie McAuley / Chee Wah Tan / Jing J. Wang / Weiguang Zeng / Mason Littlejohn / Runhong Zhou / Jasper Fuk-Woo Chan /

EBioMedicine, Vol 92, Iss , Pp 104574- (2023)

2023

Abstract: Summary: Background: The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage ...

Abstract	Summary: Background: The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. Methods: We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine. Findings: Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The ‘beta variant’ RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5. Interpretation: These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of ...
Keywords	SARS-CoV-2 ; COVID-19 ; Vaccine ; Receptor-binding domain ; RBD ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	572
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Phospholipase A2 activity during the replication cycle of the flavivirus West Nile virus.

Susann Liebscher / Rebecca L Ambrose / Turgut E Aktepe / Andrea Mikulasova / Julia E Prier / Leah K Gillespie / Adam J Lopez-Denman / Thusitha W T Rupasinghe / Dedreia Tull / Malcolm J McConville / Jason M Mackenzie

PLoS Pathogens, Vol 14, Iss 4, p e

2018 Volume 1007029

Abstract: Positive-sense RNA virus intracellular replication is intimately associated with membrane platforms that are derived from host organelles and comprised of distinct lipid composition. For flaviviruses, such as West Nile virus strain Kunjin virus (WNVKUN) ... ...

Abstract	Positive-sense RNA virus intracellular replication is intimately associated with membrane platforms that are derived from host organelles and comprised of distinct lipid composition. For flaviviruses, such as West Nile virus strain Kunjin virus (WNVKUN) we have observed that these membrane platforms are derived from the endoplasmic reticulum and are rich in (at least) cholesterol. To extend these studies and identify the cellular lipids critical for WNVKUN replication we utilized a whole cell lipidomics approach and revealed an elevation in phospholipase A2 (PLA2) activity to produce lyso-phosphatidylcholine (lyso-PChol). We observed that the PLA2 enzyme family is activated in WNVKUN-infected cells and the generated lyso-PChol lipid moieties are sequestered to the subcellular sites of viral replication. The requirement for lyso-PChol was confirmed using chemical inhibition of PLA2, where WNVKUN replication and production of infectious virus was duly affected in the presence of the inhibitors. Importantly, we could rescue chemical-induced inhibition with the exogenous addition of lyso-PChol species. Additionally, electron microscopy results indicate that lyso-PChol appears to contribute to the formation of the WNVKUN membranous replication complex (RC); particularly affecting the morphology and membrane curvature of vesicles comprising the RC. These results extend our current understanding of how flaviviruses manipulate lipid homeostasis to favour their own intracellular replication.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A versatile reverse genetics platform for SARS-CoV-2 and other positive-strand RNA viruses

Alberto A. Amarilla / Julian D. J. Sng / Rhys Parry / Joshua M. Deerain / James R. Potter / Yin Xiang Setoh / Daniel J. Rawle / Thuy T. Le / Naphak Modhiran / Xiaohui Wang / Nias Y. G. Peng / Francisco J. Torres / Alyssa Pyke / Jessica J. Harrison / Morgan E. Freney / Benjamin Liang / Christopher L. D. McMillan / Stacey T. M. Cheung / Darwin J. Da Costa Guevara /

Joshua M. Hardy / Mark Bettington / David A. Muller / Fasséli Coulibaly / Frederick Moore / Roy A. Hall / Paul R. Young / Jason M. Mackenzie / Jody Hobson-Peters / Andreas Suhrbier / Daniel Watterson / Alexander A. Khromykh

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 15

Abstract: Here the authors describe a simple reverse genetics method that relies on overlapping cDNA fragments for generation of positive-strand viruses including SARS-CoV-2 and characterize them in vitro and in vivo. ...

Abstract	Here the authors describe a simple reverse genetics method that relies on overlapping cDNA fragments for generation of positive-strand viruses including SARS-CoV-2 and characterize them in vitro and in vivo.
Keywords	Science ; Q
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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