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Article ; Online: The airborne transmission of viruses causes tight transmission bottlenecks.

Sinclair, Patrick / Zhao, Lei / Beggs, Clive B / Illingworth, Christopher J R

2024 Volume 15, Issue 1, Page(s) 3540

Abstract: The transmission bottleneck describes the number of viral particles that initiate an infection in a new host. Previous studies have used genome sequence data to suggest that transmission bottlenecks for influenza and SARS-CoV-2 involve few viral ... ...

Abstract	The transmission bottleneck describes the number of viral particles that initiate an infection in a new host. Previous studies have used genome sequence data to suggest that transmission bottlenecks for influenza and SARS-CoV-2 involve few viral particles, but the general principles of virus transmission are not fully understood. Here we show that, across a broad range of circumstances, tight transmission bottlenecks are a simple consequence of the physical process of airborne viral transmission. We use mathematical modelling to describe the physical process of the emission and inhalation of infectious particles, deriving the result that that the great majority of transmission bottlenecks involve few viral particles. While exceptions to this rule exist, the circumstances needed to create these exceptions are likely very rare. We thus provide a physical explanation for previous inferences of bottleneck size, while predicting that tight transmission bottlenecks prevail more generally in respiratory virus transmission.
MeSH term(s)	Humans ; COVID-19/transmission ; COVID-19/virology ; SARS-CoV-2/genetics ; Influenza, Human/transmission ; Influenza, Human/virology ; Air Microbiology ; Models, Theoretical ; Virion/genetics
Language	English
Publishing date	2024-04-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47923-z
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Article: Measurements of intrahost viral diversity require an unbiased diversity metric.

Zhao, Lei / Illingworth, Christopher J R

Virus evolution

2019 Volume 5, Issue 1, Page(s) vey041

Abstract: Viruses exist within hosts at large population sizes and are subject to high rates of mutation. As such, viral populations exhibit considerable sequence diversity. A variety of summary statistics have been developed which describe, in a single number, ... ...

Abstract	Viruses exist within hosts at large population sizes and are subject to high rates of mutation. As such, viral populations exhibit considerable sequence diversity. A variety of summary statistics have been developed which describe, in a single number, the extent of diversity in a viral population; such measurements allow the diversities of different populations to be compared, and the effect of evolutionary forces on a population to be assessed. Here we highlight statistical artefacts underlying some common measures of sequence diversity, whereby variation in the depth of genome sequencing may substantially affect the extent of diversity measured in a viral population, making comparisons of population diversity invalid. Specifically, naive estimation of sequence entropy provides a systematically biased metric, a lower read depth being expected to produce a lower estimate of diversity. The number of polymorphic loci per kilobase of genome is more unpredictably affected by read depth, giving potentially flawed results at lower sequencing depths. We show that the nucleotide diversity statistic
Language	English
Publishing date	2019-01-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2818949-8
ISSN	2057-1577
ISSN	2057-1577
DOI	10.1093/ve/vey041
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Article ; Online: Fitness Inference from Short-Read Data: Within-Host Evolution of a Reassortant H5N1 Influenza Virus.

Illingworth, Christopher J R

Molecular biology and evolution

2015 Volume 32, Issue 11, Page(s) 3012–3026

Abstract: We present a method to infer the role of selection acting during the within-host evolution of the influenza virus from short-read genome sequence data. Linkage disequilibrium between loci is accounted for by treating short-read sequences as noisy ... ...

Abstract	We present a method to infer the role of selection acting during the within-host evolution of the influenza virus from short-read genome sequence data. Linkage disequilibrium between loci is accounted for by treating short-read sequences as noisy multilocus emissions from an underlying model of haplotype evolution. A hierarchical model-selection procedure is used to infer the underlying fitness landscape of the virus insofar as that landscape is explored by the viral population. In a first application of our method, we analyze data from an evolutionary experiment describing the growth of a reassortant H5N1 virus in ferrets. Across two sets of replica experiments we infer multiple alleles to be under selection, including variants associated with receptor binding specificity, glycosylation, and with the increased transmissibility of the virus. We identify epistasis as an important component of the within-host fitness landscape, and show that adaptation can proceed through multiple genetic pathways.
MeSH term(s)	Adaptation, Physiological/genetics ; Alleles ; Animals ; Biological Evolution ; Evolution, Molecular ; Ferrets ; Genetic Fitness ; Hemagglutinin Glycoproteins, Influenza Virus/genetics ; Humans ; Influenza A Virus, H5N1 Subtype/genetics ; Influenza, Human/virology ; Linkage Disequilibrium ; Models, Genetic ; Orthomyxoviridae Infections/virology ; Reassortant Viruses/genetics ; Selection, Genetic
Chemical Substances	Hemagglutinin Glycoproteins, Influenza Virus
Language	English
Publishing date	2015-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/msv171
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Article ; Online: A qualitative process evaluation using the behaviour change wheel approach: Did a whole genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 within UK hospitals operate as anticipated?

Flowers, Paul / Leiser, Ruth / Mapp, Fiona / McLeod, Julie / Stirrup, Oliver / Illingworth, Christopher J R / Blackstone, James / Breuer, Judith

British journal of health psychology

2023 Volume 28, Issue 4, Page(s) 1011–1035

Abstract: Purpose: The aim of this study was to conduct a process evaluation of a whole-genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 through changing infection prevention and control (IPC) behaviours within the COVID-19 pandemic.: ... ...

Abstract	Purpose: The aim of this study was to conduct a process evaluation of a whole-genome sequence report form (SRF) used to reduce nosocomial SARS-CoV-2 through changing infection prevention and control (IPC) behaviours within the COVID-19 pandemic. Methods: We used a three-staged design. Firstly, we described and theorized the purported content of the SRF using the behaviour change wheel (BCW). Secondly, we used inductive thematic analysis of one-to-one interviews (n = 39) to explore contextual accounts of using the SRF. Thirdly, further deductive analysis gauged support for the intervention working as earlier anticipated. Results: It was possible to theorize the SRF using the BCW approach and visualize it within a simple logic model. Inductive thematic analyses identified the SRF's acceptability, ease of use and perceived effectiveness. However, major challenges to embedding it in routine practice during the unfolding COVID-19 crisis were reported. Notwithstanding this insight, deductive analysis showed support for the putative intervention functions 'Education', 'Persuasion' and 'Enablement'; behaviour change techniques '1.2 Problem solving', '2.6 Biofeedback', '2.7 Feedback on outcomes of behaviour' and '7.1 Prompts and cues'; and theoretical domains framework domains 'Knowledge' and 'Behavioural regulation'. Conclusions: Our process evaluation of the SRF, using the BCW approach to describe and theorize its content, provided granular support for the SRF working to change IPC behaviours as anticipated. However, our complementary inductive thematic analysis highlighted the importance of the local context in constraining its routine use. For SRFs to reach their full potential in reducing nosocomial infections, further implementation research is needed.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19/prevention & control ; Pandemics/prevention & control ; Cross Infection ; United Kingdom
Language	English
Publishing date	2023-05-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2026500-1
ISSN	2044-8287 ; 1359-107X
ISSN (online)	2044-8287
ISSN	1359-107X
DOI	10.1111/bjhp.12666
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Article: Mutational load causes stochastic evolutionary outcomes in acute RNA viral infection.

Zhao, Lei / Abbasi, Ali B / Illingworth, Christopher J R

Virus evolution

2019 Volume 5, Issue 1, Page(s) vez008

Abstract: Mutational load is known to be of importance for the evolution of RNA viruses, the combination of a high mutation rate and large population size leading to an accumulation of deleterious mutations. However, while the effects of mutational load on global ... ...

Abstract	Mutational load is known to be of importance for the evolution of RNA viruses, the combination of a high mutation rate and large population size leading to an accumulation of deleterious mutations. However, while the effects of mutational load on global viral populations have been considered, its quantitative effects at the within-host scale of infection are less well understood. We here show that even on the rapid timescale of acute disease, mutational load has an effect on within-host viral adaptation, reducing the effective selection acting upon beneficial variants by ∼10 per cent. Furthermore, mutational load induces considerable stochasticity in the pattern of evolution, causing a more than five-fold uncertainty in the effective fitness of a transmitted beneficial variant. Our work aims to bridge the gap between classic models from population genetic theory and the biology of viral infection. In an advance on some previous models of mutational load, we replace the assumption of a constant variant fitness cost with an experimentally-derived distribution of fitness effects. Expanding previous frameworks for evolutionary simulation, we introduce the Wright-Fisher model with continuous mutation, which describes a continuum of possible modes of replication within a cell. Our results advance our understanding of adaptation in the context of strong selection and a high mutation rate. Despite viral populations having large absolute sizes, critical events in viral adaptation, including antigenic drift and the onset of drug resistance, arise through stochastic evolutionary processes.
Language	English
Publishing date	2019-04-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2818949-8
ISSN	2057-1577
ISSN	2057-1577
DOI	10.1093/ve/vez008
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Article: Genetic consequences of effective and suboptimal dosing with mutagenic drugs in a hamster model of SARS-CoV-2 infection.

Illingworth, Christopher J R / Guerra-Assuncao, Jose A / Gregg, Samuel / Charles, Oscar / Pang, Juanita / Roy, Sunando / Abdelnabi, Rana / Neyts, Johan / Breuer, Judith

Virus evolution

2024 Volume 10, Issue 1, Page(s) veae001

Abstract: Mutagenic antiviral drugs have shown promise against multiple viruses, but concerns have been raised about whether their use might promote the emergence of new and harmful viral variants. Recently, genetic signatures associated with molnupiravir use have ...

Abstract	Mutagenic antiviral drugs have shown promise against multiple viruses, but concerns have been raised about whether their use might promote the emergence of new and harmful viral variants. Recently, genetic signatures associated with molnupiravir use have been identified in the global SARS-COV-2 population. Here, we examine the consequences of using favipiravir and molnupiravir to treat SARS-CoV-2 infection in a hamster model, comparing viral genome sequence data collected from (1) untreated hamsters, and (2) from hamsters receiving effective and suboptimal doses of treatment. We identify a broadly linear relationship between drug dose and the extent of variation in treated viral populations, with a high proportion of this variation being composed of variants at frequencies of less than 1 per cent, below typical thresholds for variant calling. Treatment with an effective dose of antiviral drug was associated with a gain of between 7 and 10 variants per viral genome relative to drug-free controls: even after a short period of treatment a population founded by a transmitted virus could contain multiple sequence differences to that of the original host. Treatment with a suboptimal dose of drug showed intermediate gains of variants. No dose-dependent signal was identified in the numbers of single-nucleotide variants reaching frequencies in excess of 5 per cent. We did not find evidence to support the emergence of drug resistance or of novel immune phenotypes. Our study suggests that where onward transmission occurs, a short period of treatment with mutagenic drugs may be sufficient to generate a significant increase in the number of viral variants transmitted.
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2818949-8
ISSN	2057-1577
ISSN	2057-1577
DOI	10.1093/ve/veae001
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Article ; Online: Inferring Transmission Bottleneck Size from Viral Sequence Data Using a Novel Haplotype Reconstruction Method.

Ghafari, Mahan / Lumby, Casper K / Weissman, Daniel B / Illingworth, Christopher J R

Journal of virology

2020 Volume 94, Issue 13

Abstract: The transmission bottleneck is defined as the number of viral particles that transmit from one host to establish an infection in another. Genome sequence data have been used to evaluate the size of the transmission bottleneck between humans infected with ...

Abstract	The transmission bottleneck is defined as the number of viral particles that transmit from one host to establish an infection in another. Genome sequence data have been used to evaluate the size of the transmission bottleneck between humans infected with the influenza virus; however, the methods used to make these estimates have some limitations. Specifically, viral allele frequencies, which form the basis of many calculations, may not fully capture a process which involves the transmission of entire viral genomes. Here, we set out a novel approach for inferring viral transmission bottlenecks; our method combines an algorithm for haplotype reconstruction with maximum likelihood methods for bottleneck inference. This approach allows for rapid calculation and performs well when applied to data from simulated transmission events; errors in the haplotype reconstruction step did not adversely affect inferences of the population bottleneck. Applied to data from a previous household transmission study of influenza A infection, we confirm the result that the majority of transmission events involve a small number of viruses, albeit with slightly looser bottlenecks being inferred, with between 1 and 13 particles transmitted in the majority of cases. While influenza A transmission involves a tight population bottleneck, the bottleneck is not so tight as to universally prevent the transmission of within-host viral diversity.
MeSH term(s)	Evolution, Molecular ; Genetic Variation/genetics ; Genome, Viral/genetics ; Haplotypes/genetics ; Humans ; Influenza A virus/genetics ; Influenza A virus/metabolism ; Influenza, Human/genetics ; Influenza, Human/transmission ; Models, Theoretical ; Sequence Analysis, DNA/methods ; Viruses/genetics
Language	English
Publishing date	2020-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00014-20
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Article ; Online: Inferring Fitness Effects from Time-Resolved Sequence Data with a Delay-Deterministic Model.

Nené, Nuno R / Dunham, Alistair S / Illingworth, Christopher J R

Genetics

2018 Volume 209, Issue 1, Page(s) 255–264

Abstract: A common challenge arising from the observation of an evolutionary system over time is to infer the magnitude of selection acting upon a specific genetic variant, or variants, within the population. The inference of selection may be confounded by the ... ...

Abstract	A common challenge arising from the observation of an evolutionary system over time is to infer the magnitude of selection acting upon a specific genetic variant, or variants, within the population. The inference of selection may be confounded by the effects of genetic drift in a system, leading to the development of inference procedures to account for these effects. However, recent work has suggested that deterministic models of evolution may be effective in capturing the effects of selection even under complex models of demography, suggesting the more general application of deterministic approaches to inference. Responding to this literature, we here note a case in which a deterministic model of evolution may give highly misleading inferences, resulting from the nondeterministic properties of mutation in a finite population. We propose an alternative approach that acts to correct for this error, and which we denote the delay-deterministic model. Applying our model to a simple evolutionary system, we demonstrate its performance in quantifying the extent of selection acting within that system. We further consider the application of our model to sequence data from an evolutionary experiment. We outline scenarios in which our model may produce improved results for the inference of selection, noting that such situations can be easily identified via the use of a regular deterministic model.
MeSH term(s)	Algorithms ; Genetic Fitness ; Haplotypes ; Host-Pathogen Interactions ; Models, Genetic ; Mutation
Language	English
Publishing date	2018-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1534/genetics.118.300790
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Article ; Online: A novel framework for inferring parameters of transmission from viral sequence data.

Lumby, Casper K / Nene, Nuno R / Illingworth, Christopher J R

PLoS genetics

2018 Volume 14, Issue 10, Page(s) e1007718

Abstract: Transmission between hosts is a critical part of the viral lifecycle. Recent studies of viral transmission have used genome sequence data to evaluate the number of particles transmitted between hosts, and the role of selection as it operates during the ... ...

Abstract	Transmission between hosts is a critical part of the viral lifecycle. Recent studies of viral transmission have used genome sequence data to evaluate the number of particles transmitted between hosts, and the role of selection as it operates during the transmission process. However, the interpretation of sequence data describing transmission events is a challenging task. We here present a novel and comprehensive framework for using short-read sequence data to understand viral transmission events, designed for influenza virus, but adaptable to other viral species. Our approach solves multiple shortcomings of previous methods for this purpose; for example, we consider transmission as an event involving whole viruses, rather than sets of independent alleles. We demonstrate how selection during transmission and noisy sequence data may each affect naive inferences of the population bottleneck, accounting for these in our framework so as to achieve a correct inference. We identify circumstances in which selection for increased viral transmission may or may not be identified from data. Applying our method to experimental data in which transmission occurs in the presence of strong selection, we show that our framework grants a more quantitative insight into transmission events than previous approaches, inferring the bottleneck in a manner that accounts for selection, both for within-host virulence, and for inherent viral transmissibility. Our work provides new opportunities for studying transmission processes in influenza, and by extension, in other infectious diseases.
MeSH term(s)	Disease Transmission, Infectious/statistics & numerical data ; Genetics, Population/methods ; Genome/genetics ; Humans ; Influenza, Human/genetics ; Influenza, Human/transmission ; Influenza, Human/virology ; Models, Theoretical ; Sequence Analysis, DNA/methods ; Viruses/genetics
Keywords	covid19
Language	English
Publishing date	2018-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1007718
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Article ; Online: Building a mechanistic mathematical model of hepatitis C virus entry.

Kalemera, Mphatso / Mincheva, Dilyana / Grove, Joe / Illingworth, Christopher J R

PLoS computational biology

2019 Volume 15, Issue 3, Page(s) e1006905

Abstract: The mechanism by which hepatitis C virus (HCV) gains entry into cells is a complex one, involving a broad range of host proteins. Entry is a critical phase of the viral lifecycle, and a potential target for therapeutic or vaccine-mediated intervention. ... ...

Abstract	The mechanism by which hepatitis C virus (HCV) gains entry into cells is a complex one, involving a broad range of host proteins. Entry is a critical phase of the viral lifecycle, and a potential target for therapeutic or vaccine-mediated intervention. However, the mechanics of HCV entry remain poorly understood. Here we describe a novel computational model of viral entry, encompassing the relationship between HCV and the key host receptors CD81 and SR-B1. We conduct experiments to thoroughly quantify the influence of an increase or decrease in receptor availability upon the extent of viral entry. We use these data to build and parameterise a mathematical model, which we then validate by further experiments. Our results are consistent with sequential HCV-receptor interactions, whereby initial interaction between the HCV E2 glycoprotein and SR-B1 facilitates the accumulation CD81 receptors, leading to viral entry. However, we also demonstrate that a small minority of viruses can achieve entry in the absence of SR-B1. Our model estimates the impact of the different obstacles that viruses must surmount to achieve entry; among virus particles attaching to the cell surface, around one third of viruses accumulate sufficient CD81 receptors, of which 4-8% then complete the subsequent steps to achieve productive infection. Furthermore, we make estimates of receptor stoichiometry; in excess of 10 receptors are likely to be required to achieve viral entry. Our model provides a tool to investigate the entry characteristics of HCV variants and outlines a framework for future quantitative studies of the multi-receptor dynamics of HCV entry.
MeSH term(s)	Cell Line, Tumor ; Computational Biology ; Hepacivirus/chemistry ; Hepacivirus/physiology ; Hepatitis C/virology ; Host-Pathogen Interactions/physiology ; Humans ; Models, Molecular ; Receptors, Virus/chemistry ; Receptors, Virus/metabolism ; Virus Internalization
Chemical Substances	Receptors, Virus
Language	English
Publishing date	2019-03-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1006905
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