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Article: Cystic fibrosis modulator therapy can reverse cystic bronchiectasis.

Middleton, Peter G / Simmonds, Nicholas J

2023 Volume 11, Issue 7, Page(s) e01172

Abstract: Bronchiectasis is often considered progressive and irreversible, so cases of regression or reversal are an important step in understanding the underlying pathophysiological mechanisms. Cystic fibrosis, (CF) caused by pathogenic variants in ... ...

Abstract	Bronchiectasis is often considered progressive and irreversible, so cases of regression or reversal are an important step in understanding the underlying pathophysiological mechanisms. Cystic fibrosis, (CF) caused by pathogenic variants in the
Language	English
Publishing date	2023-06-12
Publishing country	United States
Document type	Case Reports
ZDB-ID	2750180-2
ISSN	2051-3380
ISSN	2051-3380
DOI	10.1002/rcr2.1172
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Article ; Online: Diagnosing Cystic Fibrosis in Adults.

Barry, Peter J / Simmonds, Nicholas J

Seminars in respiratory and critical care medicine

2023 Volume 44, Issue 2, Page(s) 242–251

Abstract: Diagnosing cystic fibrosis (CF) in adulthood is not a rare occurrence for CF centers despite the popular belief that the diagnosis is achieved almost universally in childhood by means of newborn screening or early clinical presentation. The purpose of ... ...

Abstract	Diagnosing cystic fibrosis (CF) in adulthood is not a rare occurrence for CF centers despite the popular belief that the diagnosis is achieved almost universally in childhood by means of newborn screening or early clinical presentation. The purpose of this review article is to highlight specific considerations of adult diagnosis of CF. Obtaining a diagnosis of CF at any age is exceptionally important to ensure optimal treatment, monitoring, and support. In the new era of more personalized treatment with the advent of transformative therapies targeting the underlying protein defect, accurate diagnosis is of increasing importance. This review highlights the diagnostic algorithm leading to a new diagnosis of CF in adults. The diagnosis is usually confirmed in the presence of a compatible clinical presentation, evidence of cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction, and/or identification of variants in the
MeSH term(s)	Adult ; Humans ; Cystic Fibrosis/diagnosis ; Cystic Fibrosis/genetics ; Cystic Fibrosis/drug therapy ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Genetic Testing ; Mutation ; Neonatal Screening ; Prognosis
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2023-01-09
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	1183617-9
ISSN	1098-9048 ; 1069-3424
ISSN (online)	1098-9048
ISSN	1069-3424
DOI	10.1055/s-0042-1759881
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Zs.A 1555: Show issues

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Article ; Online: The roles of nucleic acid editing in adaptation of zoonotic viruses to humans.

Ratcliff, Jeremy / Simmonds, Peter

Current opinion in virology

2023 Volume 60, Page(s) 101326

Abstract: Following spillover, viruses must adapt to new selection pressures exerted by antiviral responses in their new hosts. In mammals, cellular defense mechanisms often include viral nucleic acid editing pathways mediated through protein families ... ...

Abstract	Following spillover, viruses must adapt to new selection pressures exerted by antiviral responses in their new hosts. In mammals, cellular defense mechanisms often include viral nucleic acid editing pathways mediated through protein families apolipoprotein-B mRNA-editing complex (APOBEC) and Adenosine Deaminase Acting on ribonucleic acid (ADAR). APOBECs induce C→U transitions in viral genomes; the APOBEC locus is highly polymorphic with variable numbers of APOBEC3 paralogs and target preferences in humans and other mammals. APOBEC3 paralogs have shaped the evolutionary history of human immunodeficiency virus, with compelling bioinformatic evidence also for its mutagenic impact on monkeypox virus and severe acute respiratory syndrome coronavirus 2. ADAR-1 induces adenose-to-inosine (A→I) substitutions in double-stranded ribonucleic acid (RNA); its role in virus adaptation is less clear, as are epigenetic modifications to viral genomes, such as methylation. Nucleic acid editing restricts evolutionary space in which viruses can explore and may restrict viral-host range.
MeSH term(s)	Animals ; Humans ; Nucleic Acids ; COVID-19 ; Viruses/genetics ; Mammals ; RNA
Chemical Substances	Nucleic Acids ; RNA (63231-63-0)
Language	English
Publishing date	2023-04-07
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2023.101326
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Article ; Online: A clash of ideas - the varying uses of the 'species' term in virology and their utility for classifying viruses in metagenomic datasets.

Simmonds, Peter

The Journal of general virology

2018 Volume 99, Issue 3, Page(s) 277–287

Abstract: Species definitions of viruses are frequently descriptive, with assignments often being based on their disease manifestations, host range, geographical distribution and transmission routes. This method of categorizing viruses has recently been challenged ...

Abstract	Species definitions of viruses are frequently descriptive, with assignments often being based on their disease manifestations, host range, geographical distribution and transmission routes. This method of categorizing viruses has recently been challenged by technology advances, such as high-throughput sequencing. These have dramatically increased knowledge of viral diversity in the wider environment that dwarfs the current catalogue of viruses classified by the International Committee for the Taxonomy of Viruses (ICTV). However, because such viruses are known only from their sequences without phenotypic information, it is unclear how they might be classified consistently with much of the existing taxonomy framework. This difficulty exposes deeper incompatibilities in how species are conceptualized. The original species assignments based on disease or other biological attributes were primarily descriptive, similar to principles used elsewhere in biology for species taxonomies. In contrast, purely sequence-based classifications rely on genetic metrics such as divergence thresholds that include or exclude viruses in individual species categories. These different approaches bring different preconceptions about the nature of a virus species, the former being more easily conceptualized as a category with a part/whole relationship of individuals and species, while species defined by divergence thresholds or other genetic metrics are essentially logically defined groups with specific inclusion and exclusion criteria. While descriptive species definitions match our intuitive division of viruses into natural kinds, rules-based genetic classifications are required for viruses known from sequence alone, whose incorporation into the ICTV taxonomy is essential if it is to represent the true diversity of viruses in nature.
Language	English
Publishing date	2018-01-12
Publishing country	England
Document type	Journal Article
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/jgv.0.001010
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Article ; Online: Evaluating the risk of transfusion and transplant-transmitted monkeypox infections.

Harvala, Heli / Simmonds, Peter

Transfusion medicine (Oxford, England)

2022 Volume 32, Issue 6, Page(s) 460–466

Abstract: The recent emergence of monkeypox virus (MPXV) in the UK and elsewhere is of urgent public health concern. Several aspects of MPXV epidemiology and pathogenesis, including its systemic spread and viraemia during acute infection, furthermore represent an ... ...

Abstract	The recent emergence of monkeypox virus (MPXV) in the UK and elsewhere is of urgent public health concern. Several aspects of MPXV epidemiology and pathogenesis, including its systemic spread and viraemia during acute infection, furthermore represent an important potential threat to the safety of blood transfusion and organ transplantation. Reported infections in the UK have been exponentially increasing over the last 2 months, with 1552 reported cases in the UK by 7th July 2022. This is likely to be considerable underestimate given current limitations in diagnostic capacity and clinical diagnoses hampered by its similar disease presentations to other causes of rash and genitourinary disease. While MPXV infections are currently most widespread in gay, bisexual or other men who have sex with men, wider spread of MPXV outside defined risk groups for infection may prevent identification of infection risk in donors. While typically mild disease outcomes have been reported in UK cases, case fatality rates ranging from 1% to over 10% are reported for different MPXV strains in its source area in sub-Saharan Africa. Recipients of blood components and organs transplant, especially those who are immunosuppressed, may reproduce the greater systemic spread and morbidity of those infected through percutaneous routes. There is a potential risk of MPXV transmission and severe disease outcomes in blood and transplant recipients. In addition to current risk assessments performed in the UK and exclusion of donors with recent MPXV exposure, determining viraemia frequencies in donors and directly evaluating transmission risk would be of considerable value in assessing whether MPXV nucleic acid screening should be implemented.
MeSH term(s)	Male ; Humans ; Mpox (monkeypox)/diagnosis ; Viremia ; Homosexuality, Male ; Sexual and Gender Minorities ; Monkeypox virus ; Blood Transfusion
Language	English
Publishing date	2022-09-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1067989-3
ISSN	1365-3148 ; 0958-7578
ISSN (online)	1365-3148
ISSN	0958-7578
DOI	10.1111/tme.12918
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Article ; Online: Biomarkers of transfusion transmitted occult hepatitis B virus infection: Where are we and what next?

Fu, Michael X / Simmonds, Peter / Andersson, Monique / Harvala, Heli

Reviews in medical virology

2024 Volume 34, Issue 2, Page(s) e2525

Abstract: Blood transfusion is a vital procedure, where transfusion-transmitted infection of hepatitis B virus (HBV) remains an important issue, especially from blood donors with occult hepatitis B virus infection (OBI). Occult hepatitis B virus infection is a ... ...

Abstract	Blood transfusion is a vital procedure, where transfusion-transmitted infection of hepatitis B virus (HBV) remains an important issue, especially from blood donors with occult hepatitis B virus infection (OBI). Occult hepatitis B virus infection is a complex entity to detect using surrogate blood biomarkers for intrahepatic viral transcriptional activity, requiring a continually refined battery of tests utilised for screening. This review aims to critically evaluate the latest advances in the current blood biomarkers to guide the identification of OBI donors and discuss novel HBV markers that could be introduced in future diagnostic practice. Challenges in detecting low HBV surface antigen levels, mutants, and complexes necessitate ultrasensitive multivalent dissociation assays, whilst HBV DNA testing requires improved sensitivity but worsens inaccessibility. Anti-core antibody assays defer almost all potentially infectious donations but have low specificity, and titres of anti-surface antibodies that prevent infectivity are poorly defined with suboptimal sensitivity. The challenges associated with these traditional blood HBV markers create an urgent need for alternative biomarkers that would help us better understand the OBI. Emerging viral biomarkers, such as pre-genomic RNA and HBV core-related antigen, immunological HBV biomarkers of T-cell reactivity and cytokine levels, and host biomarkers of microRNA and human leucocyte antigen molecules, present potential advances to gauge intrahepatic activity more accurately. Further studies on these markers may uncover an optimal diagnostic algorithm for OBI using quantification of various novel and traditional blood HBV markers. Addressing critical knowledge gaps identified in this review would decrease the residual risk of transfusion-transmitted HBV infection without compromising the sustainability of blood supplies.
MeSH term(s)	Humans ; Hepatitis B virus/genetics ; Hepatitis B Antibodies ; Hepatitis B ; Hepatitis B, Chronic ; Blood Transfusion ; Hepatitis B Core Antigens ; Blood Donors ; Biomarkers ; DNA, Viral
Chemical Substances	Hepatitis B Antibodies ; Hepatitis B Core Antigens ; Biomarkers ; DNA, Viral
Language	English
Publishing date	2024-02-20
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1086043-5
ISSN	1099-1654 ; 1052-9276
ISSN (online)	1099-1654
ISSN	1052-9276
DOI	10.1002/rmv.2525
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Article ; Online: Rampant C->U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses – causes and consequences for their short and long evolutionary trajectories

Simmonds, Peter

bioRxiv

Abstract: The pandemic of SARS coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a dataset of 985 complete SARS-CoV-2 ... ...

Abstract	The pandemic of SARS coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a dataset of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean 5.5-9.5 nucleotide differences from each other, commensurate with a mid-range coronavirus substitution rate of 3x10-4 substitutions/site/year. Almost half of sequence changes were C->U transitions with an 8-fold base frequency normalised directional asymmetry between C->U and U->C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV and MERS-CoV) and to a decreasing degree in other human coronaviruses (HCoV-NL63, OC43, 229E and HKU1) proportionate to their increasing divergence. C->U transitions underpinned almost half of the amino acid differences between SARS-CoV-2 variants, and occurred preferentially in both 59U/A and 39U/A flanking sequence contexts comparable to favoured motifs of human APOBEC3 proteins. Marked base asymmetries observed in non-pandemic human coronaviruses (U>>A>G>>C) and low G+C contents may represent long term effects of prolonged C->U hypermutation in their hosts. The evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short and long term evolution. Repeated cycles of mutation and reversion in favoured mutational hotspots and the widespread occurrence of amino acid changes with no adaptive value for the virus represents a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks that are typically used in molecular epidemiology investigations.
Keywords	covid19
Language	English
Publishing date	2020-05-01
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.05.01.072330
Database	COVID19

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Article ; Online: Pervasive RNA secondary structure in the genomes of SARS-CoV-2 and other coronaviruses – an endeavour to understand its biological purpose

Simmonds, Peter

bioRxiv

Abstract: The ultimate outcome of the COVID-19 pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility and population immunity. In the current study, the SARS coronavirus 2 (SARS-CoV-2) genome was investigated for the ... ...

Abstract	The ultimate outcome of the COVID-19 pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility and population immunity. In the current study, the SARS coronavirus 2 (SARS-CoV-2) genome was investigated for the presence of large scale internal RNA base pairing in its genome. This property, termed genome scale ordered RNA structure (GORS) has been previously associated with host persistence in other +strand RNA viruses, potentially through its shielding effect on viral RNA recognition in the cell. Genomes of SARS-CoV-2 were remarkably structured, with minimum folding energy differences (MFEDs) of 15%, substantially greater than previously examined viruses such as HCV (MFED 7-9%). High MFED values were shared with all coronavirus genomes analysed created by several hundred consecutive energetically favoured stem-loops throughout the genome. In contrast to replication-association RNA structure, GORS was poorly conserved in the positions and identities of base pairing with other sarbecoviruses - even similarly positioned stem-loops in SARS-CoV-2 and SARS-CoV rarely shared homologous pairings, indicative of more rapid evolutionary change in RNA structure than in the underlying coding sequences. Sites predicted to be base-paired in SARS-CoV-2 showed substantially less sequence diversity than unpaired sites, suggesting that disruption of RNA structure by mutation imposes a fitness cost on the virus which is potentially restrictive to its longer evolution. Although functionally uncharacterised, GORS in SARS-CoV-2 and other coronaviruses represent important elements in their cellular interactions that may contribute to their persistence and transmissibility.
Keywords	covid19
Language	English
Publishing date	2020-06-17
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.06.17.155200
Database	COVID19

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Article: Diagnosing Cystic Fibrosis in Adults

Barry, Peter J. / Simmonds, Nicholas J.

Seminars in Respiratory and Critical Care Medicine

(Cystic Fibrosis)

2023 Volume 44, Issue 02, Page(s) 242–251

Series title	Cystic Fibrosis
Abstract	Diagnosing cystic fibrosis (CF) in adulthood is not a rare occurrence for CF centers despite the popular belief that the diagnosis is achieved almost universally in childhood by means of newborn screening or early clinical presentation. The purpose of this review article is to highlight specific considerations of adult diagnosis of CF. Obtaining a diagnosis of CF at any age is exceptionally important to ensure optimal treatment, monitoring, and support. In the new era of more personalized treatment with the advent of transformative therapies targeting the underlying protein defect, accurate diagnosis is of increasing importance. This review highlights the diagnostic algorithm leading to a new diagnosis of CF in adults. The diagnosis is usually confirmed in the presence of a compatible clinical presentation, evidence of cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction, and/or identification of variants in the CFTR gene believed to alter protein function. Achieving the diagnosis, however, is not always straightforward as CFTR protein function exists on a continuum with different organs displaying varying sensitivity to diminution in function. We highlight the current knowledge regarding the epidemiology of CF diagnosed in adults and outline the various clinical presentations, including pulmonary and extrapulmonary, which are more common in this population. We expand on the stepwise testing procedures that lead to diagnosis, paying particular attention to additional levels of testing which may be required to achieve an accurate diagnosis. There continues to be an important need for both pulmonary and other specialists to be aware of the potential for later presentation of CF, as the improvements in treatment over decades have had large positive impacts on prognosis for people with this condition.
Keywords	cystic fibrosis ; diagnosis ; late presentation ; CFTR-related disorder ; nasal potential difference ; sweat test
Language	English
Publishing date	2023-01-09
Publisher	Thieme Medical Publishers, Inc.
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	1183617-9
ISSN	1098-9048 ; 1069-3424
ISSN (online)	1098-9048
ISSN	1069-3424
DOI	10.1055/s-0042-1759881
Database	Thieme publisher's database

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Article ; Online: Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution.

Ratcliff, Jeremy / Simmonds, Peter

Virology

2021 Volume 556, Page(s) 62–72

Abstract: Members of the APOBEC family of cytidine deaminases show antiviral activities in mammalian cells through lethal editing in the genomes of small DNA viruses, herpesviruses and retroviruses, and potentially those of RNA viruses such as coronaviruses. ... ...

Abstract	Members of the APOBEC family of cytidine deaminases show antiviral activities in mammalian cells through lethal editing in the genomes of small DNA viruses, herpesviruses and retroviruses, and potentially those of RNA viruses such as coronaviruses. Consistent with the latter, APOBEC-like directional C→U transitions of genomic plus-strand RNA are greatly overrepresented in SARS-CoV-2 genome sequences of variants emerging during the COVID-19 pandemic. A C→U mutational process may leave evolutionary imprints on coronavirus genomes, including extensive homoplasy from editing and reversion at targeted sites and the occurrence of driven amino acid sequence changes in viral proteins. If sustained over longer periods, this process may account for the previously reported marked global depletion of C and excess of U bases in human seasonal coronavirus genomes. This review synthesizes the current knowledge on APOBEC evolution and function and the evidence of their role in APOBEC-mediated genome editing of SARS-CoV-2 and other coronaviruses.
MeSH term(s)	APOBEC Deaminases/chemistry ; APOBEC Deaminases/genetics ; APOBEC Deaminases/metabolism ; Animals ; Coronavirus/genetics ; Coronavirus Infections/virology ; Evolution, Molecular ; Genome, Viral/genetics ; Humans ; Mutation ; RNA Editing ; SARS-CoV-2/genetics
Chemical Substances	APOBEC Deaminases (EC 3.5.4.5)
Language	English
Publishing date	2021-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2020.12.018
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