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Publications in Virology by NOMIS researchers

The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

NOMIS Researcher(s)

Published in

December 1, 2022

The multifunctional nucleocapsid (N) protein in SARS-CoV-2 binds the ~30 kb viral RNA genome to aid its packaging into the 80–90 nm membrane-enveloped virion. The N protein is composed of N-terminal RNA-binding and C-terminal dimerization domains that are flanked by three intrinsically disordered regions. Here we demonstrate that the N protein’s central disordered domain drives phase separation with RNA, and that phosphorylation of an adjacent serine/arginine rich region modulates the physical properties of the resulting condensates. In cells, N forms condensates that recruit the stress granule protein G3BP1, highlighting a potential role for N in G3BP1 sequestration and stress granule inhibition. The SARS-CoV-2 membrane (M) protein independently induces N protein phase separation, and three-component mixtures of N + M + RNA form condensates with mutually exclusive compartments containing N + M or N + RNA, including annular structures in which the M protein coats the outside of an N + RNA condensate. These findings support a model in which phase separation of the SARS-CoV-2 N protein contributes both to suppression of the G3BP1-dependent host immune response and to packaging genomic RNA during virion assembly.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1038/s41467-020-20768-y

COVID-19 and seasonal flu vaccination hesitancy: Links to personality and general intelligence in a large, UK cohort

NOMIS Researcher(s)

Published in

July 30, 2022

Vaccines are a powerful and relatively safe tool to protect against a range of serious diseases. Nonetheless, a sizeable minority of people express ‘vaccination hesitancy’. Accordingly, understanding the bases of this hesitancy represents a significant public health opportunity. In the present study we sought to examine the role of Big Five personality traits and general intelligence as predictors of vaccination hesitancy across two vaccination types in a large (N = 9667) sample of UK adults drawn from the Understanding Society longitudinal household study. We found that lower levels of general intelligence were associated with COVID-19 and seasonal flu vaccination hesitancy, and lower levels of neuroticism was associated with COVID-19 vaccination hesitancy. Although the self-reported reasons for being vaccine hesitant indicated a range of factors were important to people, lower general intelligence was associated with virtually all of these reasons. In contrast, Big Five personality traits showed more nuanced patterns of association.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1016/j.vaccine.2022.05.062

Anti-prothrombin autoantibodies enriched after infection with SARS-CoV-2 and influenced by strength of antibody response against SARS-CoV-2 proteins

NOMIS Researcher(s)

Published in

December 1, 2021

Antiphospholipid antibodies (aPL), assumed to cause antiphospholipid syndrome (APS), are notorious for their heterogeneity in targeting phospholipids and phospholipid-binding proteins. The persistent presence of Lupus anticoagulant and/or aPL against cardiolipin and/or β2 glycoprotein I have been shown to be independent risk factors for vascular thrombosis and pregnancy morbidity in APS. aPL production is thought to be triggered by–among other factors–viral infections, though infection-associated aPL have mostly been considered non-pathogenic. Recently, the potential pathogenicity of infection-associated aPL has gained momentum since an increasing number of patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been described with coagulation abnormalities and hyperinflammation, together with the presence of aPL. Here, we present data from a multicentric, mixed-severity study including three cohorts of individuals who contracted SARS-CoV-2 as well as non-infected blood donors. We simultaneously measured 10 different criteria and non-criteria aPL (IgM and IgG) by using a line immunoassay. Further, IgG antibody response against three SARS-CoV-2 proteins was investigated using tripartite automated blood immunoassay technology. Our analyses revealed that selected non-criteria aPL were enriched concomitant to or after an infection with SARS-CoV-2. Linear mixed-effects models suggest an association of aPL with prothrombin (PT). The strength of the antibody response against SARS-CoV-2 was further influenced by SARS-CoV-2 disease severity and sex of the individuals. In conclusion, our study is the first to report an association between disease severity, anti-SARS-CoV-2 immunoreactivity, and aPL against PT in patients with SARS-CoV-2.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1371/journal.ppat.1010118

Novel regulators of PrPC biosynthesis revealed by genome-wide RNA interference

NOMIS Researcher(s)

Published in

October 1, 2021

The cellular prion protein PrPC is necessary for prion replication, and its reduction greatly increases life expectancy in animal models of prion infection. Hence the factors controlling the levels of PrPC may represent therapeutic targets against human prion diseases. Here we performed an arrayed whole-transcriptome RNA interference screen to identify modulators of PrPC expression. We cultured human U251-MG glioblastoma cells in the presence of 64’752 unique siRNAs targeting 21’584 annotated human genes, and measured PrPC using a one-pot fluorescence-resonance energy transfer immunoassay in 51’128 individual micro-plate wells. This screen yielded 743 candidate regulators of PrPC. When downregulated, 563 of these candidates reduced and 180 enhanced PrPC expression. Recursive candidate attrition through multiple secondary screens yielded 54 novel regulators of PrPC, 9 of which were confirmed by CRISPR interference as robust regulators of PrPC biosynthesis and degradation. The phenotypes of 6 of the 9 candidates were inverted in response to transcriptional activation using CRISPRa. The RNA-binding post-transcriptional repressor Pumilio-1 was identified as a potent limiter of PrPC expression through the degradation of PRNP mRNA. Because of its hypothesis-free design, this comprehensive genetic-perturbation screen delivers an unbiased landscape of the genes regulating PrPC levels in cells, most of which were unanticipated, and some of which may be amenable to pharmacological targeting in the context of antiprion therapies.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1371/journal.ppat.1010013

Beyond tug-of-war: Iron metabolism in cooperative host–microbe interactions

NOMIS Researcher(s)

Published in

August 1, 2020

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Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1371/JOURNAL.PPAT.1008698

Genome-wide transcriptomics identifies an early preclinical signature of prion infection

NOMIS Researcher(s)

Published in

June 1, 2020

The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance and splicing alterations during the course of disease in prion-inoculated mice. Prion infection induced PrP-dependent transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs. In contrast, microglia-enriched genes displayed an increase simultaneous with the appearance of clinical signs, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, could be the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed signs in the terminal phase of the disease. The early onset of prion-induced molecular changes might thus point to novel biomarkers and potential interventional targets.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1371/journal.ppat.1008653

Sulfonation pathway inhibitors block reactivation of latent HIV-1

NOMIS Researcher(s)

Published in

December 1, 2014

Long-lived pools of latently infected cells are a significant barrier to the development of a cure for HIV-1 infection. A better understanding of the mechanisms of reactivation from latency is needed to facilitate the development of novel therapies that address this problem. Here we show that chemical inhibitors of the sulfonation pathway prevent virus reactivation, both in latently infected J-Lat and U1 cell lines and in a primary human CD4+ T cell model of latency. In each of these models, sulfonation inhibitors decreased transcription initiation from the HIV-1 promoter. These inhibitors block transcription initiation at a step that lies downstream of nucleosome remodeling and affects RNA polymerase II recruitment to the viral promoter. These results suggest that the sulfonation pathway acts by a novel mechanism to regulate efficient virus transcription initiation during reactivation from latency, and further that augmentation of this pathway could be therapeutically useful.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1016/j.virol.2014.08.016

CHD1 and CHD2 are positive regulators of HIV-1 gene expression

NOMIS Researcher(s)

Published in

October 8, 2014

Background: Retroviruses encode a very limited number of proteins and therefore must exploit a wide variety of host proteins for completion of their lifecycle. Methods: We performed an insertional mutagenesis screen to identify novel cellular regulators of retroviral replication. Results: This approach identified the ATP-dependent chromatin remodeler, chromodomain helicase DNA-binding protein 2 (CHD2), as well as the highly related CHD1 protein, as positive regulators of both MLV and HIV-1 replication in rodent and human cells. RNAi knockdown of either CHD2 or the related CHD1 protein, in human cells resulted in a block to infection by HIV-1, specifically at the level of transcription. Conclusions: These results demonstrate that CHD1 and CHD2 can act as positive regulators of HIV-1 gene expression.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1186/1743-422X-11-180

ZASC1 knockout mice exhibit an early bone marrow-specific defect in murine leukemia virus replication

NOMIS Researcher(s)

Published in

April 30, 2013

Background: ZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to specific DNA binding sites in the Moloney murine leukemia virus (Mo-MuLV) promoter and is required for efficient viral mRNA transcription (J. Virol. 84:7473-7483, 2010). Methods. To determine whether this cellular factor influences Mo-MuLV replication and viral disease pathogenesis in vivo, we generated a ZASC1 knockout mouse model and completed both early infection and long term disease pathogenesis studies. Results: Mice lacking ZASC1 were born at the expected Mendelian ratio and showed no obvious physical or behavioral defects. Analysis of bone marrow samples revealed a specific increase in a common myeloid progenitor cell population in ZASC1-deficient mice, a result that is of considerable interest because osteoclasts derived from the myeloid lineage are among the first bone marrow cells infected by Mo-MuLV (J. Virol. 73: 1617-1623, 1999). Indeed, Mo-MuLV infection of neonatal mice revealed that ZASC1 is required for efficient early virus replication in the bone marrow, but not in the thymus or spleen. However, the absence of ZASC1 did not influence the timing of subsequent tumor progression or the types of tumors resulting from virus infection. Conclusions: These studies have revealed that ZASC1 is important for myeloid cell differentiation in the bone marrow compartment and that this cellular factor is required for efficient Mo-MuLV replication in this tissue at an early time point post-infection. © 2013 Seidel et al.; licensee BioMed Central Ltd.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1186/1743-422X-10-130

Identification of a 3-aminoimidazo[1,2-a]pyridine inhibitor of HIV-1 reverse transcriptase

NOMIS Researcher(s)

Published in

January 1, 2012

Background: Despite the effectiveness of highly active antiretroviral therapy (HAART), there remains an urgent need to develop new human immunodeficiency virus type 1 (HIV-1) inhibitors with better pharmacokinetic properties that are well tolerated, and that block common drug resistant virus strains. Methods: Here we screened an in-house small molecule library for novel inhibitors of HIV-1 replication. Results: An active compound containing a 3-aminoimidazo[1,2-a]pyridine scaffold was identified and quantitatively characterized as a non-nucleoside reverse transcriptase inhibitor (NNRTI). Conclusions: The potency of this compound coupled with its inexpensive chemical synthesis and tractability for downstream SAR analysis make this inhibitor a suitable lead candidate for further development as an antiviral drug.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1186/1743-422X-9-305

Differential requirements for clathrin endocytic pathway components in cellular entry by Ebola and Marburg glycoprotein pseudovirions

NOMIS Researcher(s)

Published in

October 10, 2011

Clathrin-mediated endocytosis was previously implicated as one of the cellular pathways involved in filoviral glycoprotein mediated viral entry into target cells. Here we have further dissected the requirements for different components of this pathway in Ebola versus Marburg virus glycoprotein (GP) mediated viral infection. Although a number of these components were involved in both cases; Ebola GP-dependent viral entry specifically required the cargo recognition proteins Eps15 and DAB2 as well as the clathrin adaptor protein AP-2. In contrast, Marburg GP-mediated infection was independent of these three proteins and instead required beta-arrestin 1 (ARRB1). These findings have revealed an unexpected difference between the clathrin pathway requirements for Ebola GP versus Marburg GP pseudovirion infection. Anthrax toxin also uses a clathrin-, and ARRB1-dependent pathway for cellular entry, indicating that the mechanism used by Marburg GP pseudovirions may be more generally important for pathogen entry. © 2011 Elsevier Inc.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1016/j.virol.2011.07.018

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