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Article ; Online: Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants.

Reuschl, Ann-Kathrin / Thorne, Lucy G / Whelan, Matthew V X / Ragazzini, Roberta / Furnon, Wilhelm / Cowton, Vanessa M / De Lorenzo, Giuditta / Mesner, Dejan / Turner, Jane L E / Dowgier, Giulia / Bogoda, Nathasha / Bonfanti, Paola / Palmarini, Massimo / Patel, Arvind H / Jolly, Clare / Towers, Greg J

Nature microbiology

2024 Volume 9, Issue 2, Page(s) 451–463

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human adaptation resulted in distinct lineages with enhanced transmissibility called variants of concern (VOCs). Omicron is the first VOC to evolve distinct globally dominant subvariants. Here ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human adaptation resulted in distinct lineages with enhanced transmissibility called variants of concern (VOCs). Omicron is the first VOC to evolve distinct globally dominant subvariants. Here we compared their replication in human cell lines and primary airway cultures and measured host responses to infection. We discovered that subvariants BA.4 and BA.5 have improved their suppression of innate immunity when compared with earlier subvariants BA.1 and BA.2. Similarly, more recent subvariants (BA.2.75 and XBB lineages) also triggered reduced innate immune activation. This correlated with increased expression of viral innate antagonists Orf6 and nucleocapsid, reminiscent of VOCs Alpha to Delta. Increased Orf6 levels suppressed host innate responses to infection by decreasing IRF3 and STAT1 signalling measured by transcription factor phosphorylation and nuclear translocation. Our data suggest that convergent evolution of enhanced innate immune antagonist expression is a common pathway of human adaptation and link Omicron subvariant dominance to improved innate immune evasion.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Cell Line ; Immune Evasion ; Immunity, Innate
Language	English
Publishing date	2024-01-16
Publishing country	England
Document type	Journal Article
ISSN	2058-5276
ISSN (online)	2058-5276
DOI	10.1038/s41564-023-01588-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Murine norovirus virulence factor 1 (VF1) protein contributes to viral fitness during persistent infection.

Borg, Constantina / Jahun, Aminu S / Thorne, Lucy / Sorgeloos, Frédéric / Bailey, Dalan / Goodfellow, Ian G

The Journal of general virology

2021 Volume 102, Issue 9

Abstract: Murine norovirus (MNV) is widely used as a model for studying norovirus biology. While MNV isolates vary in their pathogenesis, infection of immunocompetent mice mostly results in persistent infection. The ability of a virus to establish a persistent ... ...

Abstract	Murine norovirus (MNV) is widely used as a model for studying norovirus biology. While MNV isolates vary in their pathogenesis, infection of immunocompetent mice mostly results in persistent infection. The ability of a virus to establish a persistent infection is dependent on its ability to subvert or avoid the host immune response. Previously, we described the identification and characterization of virulence factor 1 (VF1) in MNV, and demonstrated its role as an innate immune antagonist. Here, we explore the role of VF1 during persistent MNV infection in an immunocompetent host. Using reverse genetics, we generated MNV-3 viruses carrying a single or a triple termination codon inserted in the VF1 ORF. VF1-deleted MNV-3 replicated to comparable levels to the wildtype virus in tissue culture. Comparative studies between MNV-3 and an acute MNV-1 strain show that MNV-3 VF1 exerts the same functions as MNV-1 VF1, but with reduced potency. C57BL/6 mice infected with VF1-deleted MNV-3 showed significantly reduced replication kinetics during the acute phase of the infection, but viral loads rapidly reached the levels seen in mice infected with wildtype virus after phenotypic restoration of VF1 expression. Infection with an MNV-3 mutant that had three termination codons inserted into VF1, in which reversion was suppressed, resulted in consistently lower replication throughout a 3 month persistent infection in mice, suggesting a role for VF1 in viral fitness
MeSH term(s)	Animals ; Apoptosis ; Caliciviridae Infections/immunology ; Caliciviridae Infections/virology ; Cell Line ; Immunity, Innate ; Interferon-beta/biosynthesis ; Male ; Mice ; Mice, Inbred C57BL ; Norovirus/genetics ; Norovirus/pathogenicity ; Norovirus/physiology ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virulence ; Virulence Factors/genetics ; Virulence Factors/metabolism ; Virus Replication ; Virus Shedding
Chemical Substances	Viral Proteins ; Virulence Factors ; Interferon-beta (77238-31-4)
Language	English
Publishing date	2021-09-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/jgv.0.001651
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Article ; Online: SARS-CoV-2 variant biology: immune escape, transmission and fitness.

Carabelli, Alessandro M / Peacock, Thomas P / Thorne, Lucy G / Harvey, William T / Hughes, Joseph / Peacock, Sharon J / Barclay, Wendy S / de Silva, Thushan I / Towers, Greg J / Robertson, David L

Nature reviews. Microbiology

2023 Volume 21, Issue 3, Page(s) 162–177

Abstract: In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates ...

Abstract	In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed 'variants of concern' (VOCs). Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19.
MeSH term(s)	Humans ; SARS-CoV-2/genetics ; COVID-19 ; Immunity, Innate ; Biology
Language	English
Publishing date	2023-01-18
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2139054-X
ISSN	1740-1534 ; 1740-1526
ISSN (online)	1740-1534
ISSN	1740-1526
DOI	10.1038/s41579-022-00841-7
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Article ; Online: SARS-CoV-2 evolution influences GBP and IFITM sensitivity.

Mesner, Dejan / Reuschl, Ann-Kathrin / Whelan, Matthew V X / Bronzovich, Taylor / Haider, Tafhima / Thorne, Lucy G / Ragazzini, Roberta / Bonfanti, Paola / Towers, Greg J / Jolly, Clare

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 5, Page(s) e2212577120

Abstract: SARS-CoV-2 spike requires proteolytic processing for viral entry. A polybasic furin-cleavage site (FCS) in spike, and evolution toward an optimized FCS by dominant variants of concern (VOCs), are linked to enhanced infectivity and transmission. Here we ... ...

Abstract	SARS-CoV-2 spike requires proteolytic processing for viral entry. A polybasic furin-cleavage site (FCS) in spike, and evolution toward an optimized FCS by dominant variants of concern (VOCs), are linked to enhanced infectivity and transmission. Here we show interferon-inducible restriction factors Guanylate-binding proteins (GBP) 2 and 5 interfere with furin-mediated spike cleavage and inhibit the infectivity of early-lineage isolates Wuhan-Hu-1 and VIC. By contrast, VOCs Alpha and Delta escape restriction by GBP2/5 that we map to the spike substitution D614G present in these VOCs. Despite inhibition of spike cleavage, these viruses remained sensitive to plasma membrane IFITM1, but not endosomal IFITM2 and 3, consistent with a preference for TMPRSS2-dependent plasma membrane entry. Strikingly, we find that Omicron is unique among VOCs, being sensitive to restriction factors GBP2/5, and also IFITM1, 2, and 3. Using chimeric spike mutants, we map the Omicron phenotype and show that the S1 domain determines Omicron's sensitivity to GBP2/5, whereas the S2' domain determines its sensitivity to endosomal IFITM2/3 and preferential use of TMPRSS2-independent entry. We propose that evolution of SARS-CoV-2 for the D614G substitution has allowed for escape from GBP restriction factors, but the selective pressures on Omicron for spike changes that mediate antibody escape, and altered tropism, have come at the expense of increased sensitivity to innate immune restriction factors that target virus entry.
MeSH term(s)	Humans ; Furin ; COVID-19/genetics ; SARS-CoV-2/genetics ; Antibodies ; Cell Membrane ; Factor V ; Spike Glycoprotein, Coronavirus/genetics ; Membrane Proteins/genetics
Chemical Substances	Furin (EC 3.4.21.75) ; Antibodies ; Factor V (9001-24-5) ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; IFITM2 protein, human ; Membrane Proteins
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2212577120
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Article ; Online: Norovirus gene expression and replication.

Thorne, Lucy G / Goodfellow, Ian G

The Journal of general virology

2013 Volume 95, Issue Pt 2, Page(s) 278–291

Abstract: Noroviruses are small, positive-sense RNA viruses within the family Caliciviridae, and are now accepted widely as a major cause of acute gastroenteritis in both developed and developing countries. Despite their impact, our understanding of the life cycle ...

Abstract	Noroviruses are small, positive-sense RNA viruses within the family Caliciviridae, and are now accepted widely as a major cause of acute gastroenteritis in both developed and developing countries. Despite their impact, our understanding of the life cycle of noroviruses has lagged behind that of other RNA viruses due to the inability to culture human noroviruses (HuNVs). Our knowledge of norovirus biology has improved significantly over the past decade as a result of numerous technological advances. The use of a HuNV replicon, improved biochemical and cell-based assays, combined with the discovery of a murine norovirus capable of replication in cell culture, has improved greatly our understanding of the molecular mechanisms of norovirus genome translation and replication, as well as the interaction with host cell processes. In this review, the current state of knowledge of the intracellular life of noroviruses is discussed with particular emphasis on the mechanisms of viral gene expression and viral genome replication.
MeSH term(s)	Animals ; Cell Culture Techniques/methods ; Gene Expression Regulation, Viral ; Humans ; Mice ; Norovirus/genetics ; Norovirus/physiology ; Virology/methods ; Virus Replication
Language	English
Publishing date	2013-11-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/vir.0.059634-0
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Article ; Online: SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation.

Thorne, Lucy G / Reuschl, Ann-Kathrin / Zuliani-Alvarez, Lorena / Whelan, Matthew V X / Turner, Jane / Noursadeghi, Mahdad / Jolly, Clare / Towers, Greg J

The EMBO journal

2021 Volume 40, Issue 15, Page(s) e107826

Abstract: SARS-CoV-2 infection causes broad-spectrum immunopathological disease, exacerbated by inflammatory co-morbidities. A better understanding of mechanisms underpinning virus-associated inflammation is required to develop effective therapeutics. Here, we ... ...

Abstract	SARS-CoV-2 infection causes broad-spectrum immunopathological disease, exacerbated by inflammatory co-morbidities. A better understanding of mechanisms underpinning virus-associated inflammation is required to develop effective therapeutics. Here, we discover that SARS-CoV-2 replicates rapidly in lung epithelial cells despite triggering a robust innate immune response through the activation of cytoplasmic RNA sensors RIG-I and MDA5. The inflammatory mediators produced during epithelial cell infection can stimulate primary human macrophages to enhance cytokine production and drive cellular activation. Critically, this can be limited by abrogating RNA sensing or by inhibiting downstream signalling pathways. SARS-CoV-2 further exacerbates the local inflammatory environment when macrophages or epithelial cells are primed with exogenous inflammatory stimuli. We propose that RNA sensing of SARS-CoV-2 in lung epithelium is a key driver of inflammation, the extent of which is influenced by the inflammatory state of the local environment, and that specific inhibition of innate immune pathways may beneficially mitigate inflammation-associated COVID-19.
MeSH term(s)	COVID-19/genetics ; COVID-19/immunology ; COVID-19/virology ; Cell Line ; Cytokines/genetics ; Cytokines/immunology ; DEAD Box Protein 58/immunology ; Epithelial Cells/immunology ; Epithelial Cells/virology ; Host-Pathogen Interactions ; Humans ; Immunity, Innate ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/virology ; Interferon-Induced Helicase, IFIH1/immunology ; Janus Kinases/immunology ; Lung/cytology ; Lung/immunology ; Lung/virology ; Macrophage Activation ; Macrophages/immunology ; NF-kappa B/immunology ; RNA, Viral/immunology ; Receptors, Immunologic/immunology ; Respiratory Mucosa/cytology ; Respiratory Mucosa/immunology ; Respiratory Mucosa/virology ; SARS-CoV-2/genetics ; SARS-CoV-2/physiology ; STAT Transcription Factors/immunology ; Virus Replication
Chemical Substances	Cytokines ; NF-kappa B ; RNA, Viral ; Receptors, Immunologic ; STAT Transcription Factors ; Janus Kinases (EC 2.7.10.2) ; RIGI protein, human (EC 3.6.1.-) ; IFIH1 protein, human (EC 3.6.1.-) ; DEAD Box Protein 58 (EC 3.6.4.13) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13)
Language	English
Publishing date	2021-07-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2021107826
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Article ; Online: SARS-CoV-2 Spike evolution influences GBP and IFITM sensitivity

Mesner, Dejan / Reuschl, Ann-Kathrin / Whelan, Matthew V.X. / Bronzovich, Taylor / Haider, Tafhima / Thorne, Lucy G / Towers, Greg J / Jolly, Clare

bioRxiv

Abstract: SARS-CoV-2 spike requires proteolytic processing for viral entry. The presence of a polybasic furin-cleavage site (FCS) in spike, and evolution towards an optimised FCS by dominant variants of concern (VOCs), are linked to enhanced infectivity and ... ...

Abstract	SARS-CoV-2 spike requires proteolytic processing for viral entry. The presence of a polybasic furin-cleavage site (FCS) in spike, and evolution towards an optimised FCS by dominant variants of concern (VOCs), are linked to enhanced infectivity and transmission. Guanylate binding proteins (GBP) are interferon-inducible restriction factors that target furin-mediated processing of viral envelope proteins and limit infectivity. Here we investigated whether GBPs restrict SARS-CoV-2 infection, and whether VOCs have evolved spikes that escape restriction. We show that GBP2 and 5 interfere with cleavage of the spike proteins of Wuhan-Hu-1, Alpha, Delta and Omicron, consistent with furin inhibition by GBPs. However, while GBP2/5 restrict Wuhan-Hu-1 infectivity, Alpha and Delta escape restriction. GBP exposure in producer cells influences viral entry route into target cells, with a shift towards endosomal entry. We therefore investigated whether GBP-targeting of spike alters sensitivity to endosomal restriction factors, IFITMs. We find IFITM1, but not IFITM 2 or 3, inhibit infection of naturally-permissive epithelial cells by early-lineage SARS-CoV-2, as well as Alpha and Delta, however GBPs did not sensitise to IFITM restriction. Strikingly, we find Omicron is unique amongst VOCs, being sensitive to restriction by GBP2/5, and also IFITM1, 2 and 3. We conclude evolution of Alpha and Delta spikes have conferred resistance to GBP restriction, but this is not solely due to acquisition of an enhanced FCS. Notably, Omicron, which has evolved under different selective pressures, has selected for changes in spike that not only mediate antibody escape, and shift in cell tropism and entry, but also impact the sensitivity of Omicron to innate immunity, potentially contributing to altered pathogenesis.
Keywords	covid19
Language	English
Publishing date	2022-03-07
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.03.07.481785
Database	COVID19

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Article: Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2.

Dicken, Samuel J / Murray, Matthew J / Thorne, Lucy G / Reuschl, Ann-Kathrin / Forrest, Calum / Ganeshalingham, Maaroothen / Muir, Luke / Kalemera, Mphatso D / Palor, Machaela / McCoy, Laura E / Jolly, Clare / Towers, Greg J / Reeves, Matthew B / Grove, Joe

bioRxiv : the preprint server for biology

2021

Abstract: The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their ... ...

Abstract	The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their evolutionary trajectories will guide current mitigation measures, future genetic surveillance and vaccination strategies. Here we examine virus entry by the B.1.1.7 lineage, commonly referred to as the UK/Kent variant. Pseudovirus infection of model cell lines demonstrate that B.1.1.7 entry is enhanced relative to the Wuhan-Hu-1 reference strain, particularly under low expression of receptor ACE2. Moreover, the entry characteristics of B.1.1.7 were distinct from that of its predecessor strain containing the D614G mutation. These data suggest evolutionary tuning of spike protein function. Additionally, we found that amino acid deletions within the N-terminal domain (NTD) of spike were important for efficient entry by B.1.1.7. The NTD is a hotspot of diversity across sarbecoviruses, therefore, we further investigated this region by examining the entry of closely related CoVs. Surprisingly, Pangolin CoV spike entry was 50-100 fold enhanced relative to SARS-CoV-2; suggesting there may be evolutionary pathways by which SARSCoV-2 may further optimise entry. Swapping the NTD between Pangolin CoV and SARS-CoV-2 demonstrates that changes in this region alone have the capacity to enhance virus entry. Thus, the NTD plays a hitherto unrecognised role in modulating spike activity, warranting further investigation and surveillance of NTD mutations.
Language	English
Publishing date	2021-03-22
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.22.436468
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Article ; Online: Enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants BA.4 and BA.5

Reuschl, Ann-Kathrin / Thorne, Lucy G. / Whelan, Matthew V.X. / Mesner, Dejan / Ragazzini, Roberta / Dowgier, Giulia / Bogoda, Nathasha / Turner, Jane L. E. / Furnon, Wilhelm / Cowton, Vanessa M. / de Lorenzo, Giuditta / Bonfanti, Paola / Palmarini, Massimo / Patel, Arvind H. / Jolly, Clare / Towers, Greg. J.

bioRxiv

Abstract: SARS-CoV-2 adaptation to its human host is evidenced by the emergence of new viral lineages with distinct genotypic and phenotypic characteristics, termed variants of concern (VOCs). Particular VOCs have become sequentially dominant globally (Alpha, ... ...

Abstract	SARS-CoV-2 adaptation to its human host is evidenced by the emergence of new viral lineages with distinct genotypic and phenotypic characteristics, termed variants of concern (VOCs). Particular VOCs have become sequentially dominant globally (Alpha, Delta, Omicron) with each evolving independently from the ancestral Wuhan strain. Omicron is notable for its large number of Spike mutations found to promote immune escape and re-infection. Most recently, Omicron BA.4 and BA.5 subvariants have emerged with increasing levels of adaptive immune escape threatening vaccine effectiveness and increasing hospitalisations. Here, we demonstrate that the most recent Omicron variants have enhanced capacity to antagonise or evade human innate immune defenses. We find Omicron BA.4 and BA.5 replication is associated with reduced activation of epithelial innate immune responses versus earlier BA.1 and BA.2 subvariants. We also find enhanced expression of innate immune antagonist proteins Orf6 and N, similar to Alpha, suggesting common pathways of human adaptation and linking VOC dominance to improved innate immune evasion. We conclude that Omicron BA.4 and BA.5 have combined evolution of antibody escape with enhanced antagonism of human innate immunity to improve transmission and possibly reduce immune protection from severe disease.
Keywords	covid19
Language	English
Publishing date	2022-07-12
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.07.12.499603
Database	COVID19

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Article: Are Evolution and the Intracellular Innate Immune System Key Determinants in HIV Transmission?

Sumner, Rebecca P / Thorne, Lucy G / Fink, Doug L / Khan, Hataf / Milne, Richard S / Towers, Greg J

Frontiers in immunology

2017 Volume 8, Page(s) 1246

Abstract: HIV-1 is the single most important sexually transmitted disease in humans from a global health perspective. Among human lentiviruses, HIV-1 M group has uniquely achieved pandemic levels of human-to-human transmission. The requirement to transmit between ... ...

Abstract	HIV-1 is the single most important sexually transmitted disease in humans from a global health perspective. Among human lentiviruses, HIV-1 M group has uniquely achieved pandemic levels of human-to-human transmission. The requirement to transmit between hosts likely provides the strongest selective forces on a virus, as without transmission, there can be no new infections within a host population. Our perspective is that evolution of all of the virus-host interactions, which are inherited and perpetuated from host-to-host, must be consistent with transmission. For example, CXCR4 use, which often evolves late in infection, does not favor transmission and is therefore lost when a virus transmits to a new host. Thus, transmission inevitably influences all aspects of virus biology, including interactions with the innate immune system, and dictates the biological niche in which the virus exists in the host. A viable viral niche typically does not select features that disfavor transmission. The innate immune response represents a significant selective pressure during the transmission process. In fact, all viruses must antagonize and/or evade the mechanisms of the host innate and adaptive immune systems that they encounter. We believe that viewing host-virus interactions from a transmission perspective helps us understand the mechanistic details of antiviral immunity and viral escape. This is particularly true for the innate immune system, which typically acts from the very earliest stages of the host-virus interaction, and must be bypassed to achieve successful infection. With this in mind, here we review the innate sensing of HIV, the consequent downstream signaling cascades and the viral restriction that results. The centrality of these mechanisms to host defense is illustrated by the array of countermeasures that HIV deploys to escape them, despite the coding constraint of a 10 kb genome. We consider evasion strategies in detail, in particular the role of the HIV capsid and the viral accessory proteins highlighting important unanswered questions and discussing future perspectives.
Language	English
Publishing date	2017-10-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2017.01246
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