Imperial College London

DrMathewBeale

Faculty of MedicineSchool of Public Health

Honorary Research Associate
 
 
 
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m.beale

 
 
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VC9Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
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26 results found

Beale M, Marks M, Cole M, Lee M, Pitt R, Ruis C, Naidu P, Unemo M, Krajden M, Lukehart S, Morshed M, Fifer H, Thomson Net al., 2021, CONTEMPORARY SYPHILIS IS CHARACTERISED BY RAPID GLOBAL SPREAD OF PANDEMIC TREPONEMA PALLIDUM LINEAGES, Publisher: BMJ PUBLISHING GROUP, Pages: A17-A17, ISSN: 1368-4973

Conference paper

Hamilton WL, Tonkin-Hill G, Smith ER, Aggarwal D, Houldcroft CJ, Warne B, Meredith LW, Hosmillo M, Jahun AS, Curran MD, Parmar S, Caller LG, Caddy SL, Khokhar FA, Yakovleva A, Hall G, Feltwell T, Pinckert ML, Georgana I, Chaudhry Y, Brown CS, Gonçalves S, Amato R, Harrison EM, Brown NM, Beale MA, Spencer Chapman M, Jackson DK, Johnston I, Alderton A, Sillitoe J, Langford C, Dougan G, Peacock SJ, Kwiatowski DP, Goodfellow IG, Torok ME, COVID-19 Genomics Consortium UKet al., 2021, Genomic epidemiology of COVID-19 in care homes in the east of England., Elife, Vol: 10

COVID-19 poses a major challenge to care homes, as SARS-CoV-2 is readily transmitted and causes disproportionately severe disease in older people. Here, 1167 residents from 337 care homes were identified from a dataset of 6600 COVID-19 cases from the East of England. Older age and being a care home resident were associated with increased mortality. SARS-CoV-2 genomes were available for 700 residents from 292 care homes. By integrating genomic and temporal data, 409 viral clusters within the 292 homes were identified, indicating two different patterns - outbreaks among care home residents and independent introductions with limited onward transmission. Approximately 70% of residents in the genomic analysis were admitted to hospital during the study, providing extensive opportunities for transmission between care homes and hospitals. Limiting viral transmission within care homes should be a key target for infection control to reduce COVID-19 mortality in this population.

Journal article

Rodrigues AM, Beale MA, Hagen F, Fisher MC, Terra PPD, de Hoog S, Brilhante RSN, de Aguiar Cordeiro R, de Souza Collares Maia Castelo-Branco D, Rocha MFG, Sidrim JJC, de Camargo ZPet al., 2020, The global epidemiology of emerging Histoplasma species in recent years, Studies in Mycology, Vol: 97, ISSN: 0166-0616

Histoplasmosis is a serious infectious disease in humans caused by Histoplasma spp. (Onygenales), whose natural reservoirs are thought to be soil enriched with bird and bat guano. The true global burden of histoplasmosis is underestimated and frequently the pulmonary manifestations are misdiagnosed as tuberculosis. Molecular data on epidemiology of Histoplasma are still scarce, even though there is increasing recognition of histoplasmosis in recent years in areas distant from the traditional endemic regions in the Americas. We used multi-locus sequence data from protein coding loci (ADP-ribosylation factor, H antigen precursor, and delta-9 fatty acid desaturase), DNA barcoding (ITS1/2+5.8s), AFLP markers and mating type analysis to determine the genetic diversity, population structure and recognise the existence of different phylogenetic species among 436 isolates of Histoplasma obtained globally. Our study describes new phylogenetic species and the molecular characteristics of Histoplasma lineages causing outbreaks with a high number of severe outcomes in Northeast Brazil between 2011 and 2015. Genetic diversity levels provide evidence for recombination, common ancestry and clustering of Brazilian isolates at different geographic scales with the emergence of LAm C, a new genotype assigned to a separate population cluster in Northeast Brazil that exhibited low diversity indicative of isolation. The global survey revealed that the high genetic variability among Brazilian isolates along with the presence of divergent cryptic species and/or genotypes may support the hypothesis of Brazil being the center of dispersion of Histoplasma in South America, possibly with the contribution of migratory hosts such as birds and bats. Outside Brazil, the predominant species depends on the region. We confirm that histoplasmosis has significantly broadened its area of occurrence, an important feature of emerging pathogens. From a practical point of view, our data point to the emergen

Journal article

Aanensen DM, Abudahab K, Adams A, Afifi S, Alam MT, Alderton A, Alikhan N-F, Allan J, Almsaud M, Alrezaihi A, Alruwaili M, Amato R, Andersson M, Angyal A, Aranday-Cortes E, Ariani C, Armstrong SD, Asamaphan P, Attwood S, Aydin A, Badhan A, Baker D, Baker P, Balcazar CE, Ball J, Barton AE, Bashton M, Baxter L, Beale M, Beaver C, Beckett A, Beer R, Beggs A, Bell A, Bellis KL, Bentley EG, Berriman M, Betteridge E, Bibby D, Bicknell K, Birchley A, Black G, Blane B, Bloomfield S, Bolt F, Bonsall DG, Bosworth A, Bourgeois Y, Boyd O, Bradshaw D, Breuer J, Bridgewater H, Brooks T, Broos A, Brown JR, Brown RL, Brunker K, Bucca G, Buck D, Bull M, Butcher E, Caddy SL, Caller LG, Cambell S, Carlile M, Carmichael S, Carrilero L, Castellano S, Chaloner J, Chand M, Chapman MR, Chappell J, Charles I, Chauhan AJ, Chawla A, Cheng E, Churcher CM, Clark G, Clark JJ, Collins J, Colquhoun R, Connor TR, Constantinidou C, Coombes J, Corden S, Cottrell S, Cowell A, Curran MD, Curran T, Dabrera G, Danesh J, Darby AC, de Cesare M, Martins LDO, de Silva TI, Debebe B, Dervisevic S, Dewar RA, Dia M, Dorman M, Dougan G, Dover L, Downing F, Drury E, du Plessis L, Dyal PL, Eccles R, Edwards S, Ellaby N, Elliott S, Eltringham G, Elumogo N, Essex S, Evans CM, Evans J, Nascimento FF, Fairley DJ, Farr B, Feltwell T, Ferguson N, Filipe ADS, Findlay J, Forrest LM, Forrest S, Foulser L, Francois S, Fraser C, Frost L, Gallagher E, Gallagher MD, Garcia-Dorival I, Gaskin A, Gatica-Wilcox B, Gavriil A, Geidelberg L, Gemmell M, Gerada A, Gifford L, Gilbert L, Gilmore P, Gilroy R, Girgis S, Glaysher S, Golubchik T, Goncalves S, Goodfellow I, Goodwin S, Graham C, Graham L, Grammatopoulos D, Green A, Green LR, Greenaway J, Gregory R, Groves DC, Groves N, Guest M, Gunson R, Haldenby S, Hall G, Hamilton WL, Han X, Harris KA, Harrison EM, Hartley C, Herrera C, Hesketh A, Heyburn D, Hill V, Hiscox JA, Holden M, Holmes A, Holmes N, Holt GS, Hopes R, Hosmillo M, Houldcroft CJ, Howson-Wells H, Hubb J, Hughe J, Hughes Met al., 2020, An integrated national scale SARS-CoV-2 genomic surveillance network, The Lancet Microbe, Vol: 1, Pages: E99-E100, ISSN: 2666-5247

Journal article

Beale MA, Noguera-Julian M, Godornes C, Casadella M, Gonzalez-Beiras C, Parera M, Corbacho-Monne M, Paredes R, Gonzalez-Candelas F, Marks M, Lukehart SA, Thomson NR, Mitja Oet al., 2020, A genomic epidemiology investigation of yaws re-emergence and bacterial drug resistance selection

<jats:p>Background: In a longitudinal study assessing the WHO strategy for yaws eradication using mass azithromycin treatment, we observed resurgence of yaws cases with dominance of a single JG8 sequence type and emergence of azithromycin-resistant Treponema pallidum. Here, we analyse genomic changes in the bacterial population using samples collected during the study.Methods: We performed whole bacterial genome sequencing directly on DNA extracted from 37 lesion swabs collected from patients on Lihir Island, Papua New Guinea, between 2013 and 2016. We produced phylogenies and correlated these with temporo-spatial information to investigate the source of new cases and the emergence of five macrolide-resistant cases. We used deep amplicon sequencing of surveillance samples to assess the presence of minority macrolide resistance populations.Findings: We recovered 20 whole Treponema genomes, and phylogenetic analysis showed that the re-emerging JG8 sequence type was composed of three bacterial sub-lineages characterised by distinct temporo-spatial patterns. Of five patients with resistant Treponema, all epidemiologically linked, we recovered genomes from three and found no variants. Deep sequencing showed that pre-treatment, the index patient harboured fixed macrolide-sensitive Treponema, while the post-treatment sample harboured a fixed resistant genotype, as did three of four contact cases. We also found no evidence of pre-existing minority Treponema drug-resistance variants in the general population. Interpretation: In this study, re-emergence of yaws cases was polyphyletic, indicating multiple epidemiological sources. However, given the genomic and epidemiological linkage of resistant cases and the rarity of resistance alleles in the general population, it is likely that azithromycin resistance evolved only once in this study, followed by onward dissemination.</jats:p>

Journal article

Lassalle F, Beale MA, Bharucha T, Williams CA, Williams RJ, Cudini J, Goldstein R, Haque T, Depledge DP, Breuer Jet al., 2020, Whole genome sequencing of Herpes Simplex Virus 1 directly from human cerebrospinal fluid reveals selective constraints in neurotropic viruses, Virus Evolution, Vol: 6, Pages: 1-14, ISSN: 2057-1577

Herpes Simplex Virus type 1 (HSV-1) chronically infects over 70 per cent of the global population. Clinical manifestations are largely restricted to recurrent epidermal vesicles. However, HSV-1 also leads to encephalitis, the infection of the brain parenchyma, with high associated rates of mortality and morbidity. In this study, we performed target enrichment followed by direct sequencing of HSV-1 genomes, using target enrichment methods on the cerebrospinal fluid (CSF) of clinical encephalitis patients and from skin swabs of epidermal vesicles on non-encephalopathic patients. Phylogenetic analysis revealed high inter-host diversity and little population structure. In contrast, samples from different lesions in the same patient clustered with similar patterns of allelic variants. Comparison of consensus genome sequences shows HSV-1 has been freely recombining, except for distinct islands of linkage disequilibrium (LD). This suggests functional constraints prevent recombination between certain genes, notably those encoding pairs of interacting proteins. Distinct LD patterns characterised subsets of viruses recovered from CSF and skin lesions, which may reflect different evolutionary constraints in different body compartments. Functions of genes under differential constraint related to immunity or tropism and provide new hypotheses on tissue-specific mechanisms of viral infection and latency.

Journal article

Lassalle F, Beale MA, Bharucha T, Williams CA, Williams RJ, Cudini J, Goldstein R, Haque T, Depledge DP, Breuer Jet al., 2019, Whole genome sequencing of Herpes Simplex Virus 1 directly from human cerebrospinal fluid reveals selective constraints in neurotropic viruses, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:p>Herpes Simplex Virus type 1 (HSV-1) chronically infects over 70% of the global population. Clinical manifestations are largely restricted to recurrent epidermal vesicles. However, HSV-1 also leads to encephalitis, the infection of the brain parenchyma, with high associated rates of mortality and morbidity. In this study, we performed target enrichment followed by direct sequencing of HSV-1 genomes, using target enrichment methods on the cerebrospinal fluid (CSF) of clinical encephalitis patients and from skin swabs of epidermal vesicles on non-encephalopathic patients. Phylogenetic analysis revealed high inter-host diversity and little population structure. By contrast, samples from different lesions in the same patient clustered with similar patterns of allelic variants. Comparison of consensus genome sequences shows HSV-1 has been freely recombining, except for distinct islands of linkage disequilibrium (LD). This suggests functional constraints prevent recombination between certain genes, notably those encoding pairs of interacting proteins. Distinct LD patterns characterised subsets of viruses recovered from CSF and skin lesions, which may reflect different evolutionary constraints in different body compartments. Functions of genes under differential constraint related to immunity or tropism and provide new hypotheses on tissue-specific mechanisms of viral infection and latency.</jats:p>

Working paper

Beale MA, Marks M, Sahi SK, Tantalo LC, Nori A, French P, Lukehart SA, Marra CM, Thomson NRet al., 2019, Genomic epidemiology of syphilis reveals independent emergence of macrolide resistance across multiple circulating lineages, NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723

Journal article

Houldcroft CJ, Beale MA, Abu Sayeed M, Qadri F, Dougan G, Mutreja Aet al., 2018, Identification of novel adenovirus genotype 90 in children from Bangladesh, MICROBIAL GENOMICS, Vol: 4, ISSN: 2057-5858

Journal article

Beale MA, Marks M, Sahi SK, Tantalo LC, Nori AV, French P, Lukehart SA, Marra CM, Thomson NRet al., 2018, Genomic epidemiology of syphilis reveals independent emergence of macrolide resistance across multiple circulating lineages

<jats:title>Abstract</jats:title><jats:p>Syphilis is a sexually transmitted infection caused by<jats:italic>Treponema pallidum</jats:italic>subspecies<jats:italic>pallidum</jats:italic>and may lead to severe complications. Recent years have seen striking increases in syphilis in many countries. Previous analyses have suggested one lineage of syphilis, SS14, may have expanded recently, indicating emergence of a single pandemic azithromycin-resistant cluster. We used direct sequencing of<jats:italic>T. pallidum</jats:italic>combined with phylogenomic analyses to show that both SS14- and Nichols-lineages are simultaneously circulating in clinically relevant populations in multiple countries. We correlate the appearance of genotypic macrolide resistance with multiple independently evolved SS14 sub-lineages and show that genotypically resistant and sensitive sub-lineages are spreading contemporaneously, incompatible with the notion that SS14-lineage expansion is driven purely by macrolide resistance. These findings inform our understanding of the current syphilis epidemic by demonstrating how macrolide resistance evolves in<jats:italic>Treponema</jats:italic>subspecies and provide a warning on broader issues of antimicrobial resistance.</jats:p>

Journal article

Rhodes J, Desjardins CA, Sykes SM, Beale MA, Vanhove M, Sakthikumar S, Chen Y, Gujja S, Saif S, Chowdhary A, Lawson DJ, Ponzio V, Colombo AL, Meyer W, Engelthaler DM, Hagen F, Illnait-Zaragozi MT, Alanio A, Vreulink J-M, Heitman J, Perfect JR, Litvintseva A, Bicanic T, Harrison TS, Fisher MC, Cuomo CAet al., 2017, Tracing genetic exchange and biogeography of cryptococcus neoformans var. grubii at the global population level, Genetics, Vol: 207, Pages: 327-346, ISSN: 0016-6731

Cryptococcus neoformans var. grubii is the causative agent of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals, typically HIV/AIDS patients from developing countries. Despite the worldwide emergence of this ubiquitous infection, little is known about the global molecular epidemiology of this fungal pathogen. Here we sequence the genomes of 188 diverse isolates and characterized the major subdivisions, their relative diversity and the level of genetic exchange between them. While most isolates of C. neoformans var. grubii belong to one of three major lineages (VNI, VNII, and VNB), some haploid isolates show hybrid ancestry including some that appear to have recently interbred, based on the detection of large blocks of each ancestry across each chromosome. Many isolates display evidence of aneuploidy, which was detected for all chromosomes. In diploid isolates of C. neoformans var. grubii (serotype A/A) and of hybrids with C. neoformans var. neoformans (serotype A/D) such aneuploidies have resulted in loss of heterozygosity, where a chromosomal region is represented by the genotype of only one parental isolate. Phylogenetic and population genomic analyses of isolates from Brazil reveal that the previously 'African' VNB lineage occurs naturally in the South American environment. This suggests migration of the VNB lineage between Africa and South America prior to its diversification, supported by finding ancestral recombination events between isolates from different lineages and regions. The results provide evidence of substantial population structure, with all lineages showing multi-continental distributions demonstrating the highly dispersive nature of this pathogen.

Journal article

Illingworth CJR, Roy S, Beale MA, Tutill H, Williams R, Breuer Jet al., 2017, On the effective depth of viral sequence data, VIRUS EVOLUTION, Vol: 3

Journal article

Rhodes J, Desjardins CA, Sykes SM, Beale MA, Vanhove M, Sakthikumar S, Chen Y, Gujja S, Saif S, Chowdhary A, Lawson DJ, Ponzio V, Colombo AL, Meyer W, Engelthaler DM, Hagen F, Illnait-Zaragozi MT, Alanio A, Vreulink J-M, Heitman J, Perfect JR, Litvintseva A, Bicanic T, Harrison TS, Fisher MC, Cuomo CAet al., 2017, Population genomics ofCryptococcus neoformansvar.grubiireveals new biogeographic relationships and finely maps hybridization, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:p><jats:italic>Cryptococcus neoformans</jats:italic>var.<jats:italic>grubii</jats:italic>is the causative agent of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals, typically HIV/AIDS patients from developing countries. Despite the worldwide emergence of this ubiquitous infection, little is known about the global molecular epidemiology of this fungal pathogen. Here we sequence the genomes of 188 diverse isolates and characterized the major subdivisions, their relative diversity and the level of genetic exchange between them. While most isolates of<jats:italic>C. neoformans</jats:italic>var.<jats:italic>grubii</jats:italic>belong to one of three major lineages (VNI, VNII, and VNB), some haploid isolates show hybrid ancestry including some that appear to have recently interbred, based on the detection of large blocks of each ancestry across each chromosome. Many isolates display evidence of aneuploidy, which was detected for all chromosomes. In diploid isolates of<jats:italic>C. neoformans</jats:italic>var.<jats:italic>grubii (</jats:italic>serotype A/A) and of hybrids with<jats:italic>C. neoformans</jats:italic>var.<jats:italic>neoformans</jats:italic>(serotype A/D) such aneuploidies have resulted in loss of heterozygosity, where a chromosomal region is represented by the genotype of only one parental isolate. Phylogenetic and population genomic analyses of isolates from Brazil revealed that the previously ‘African’ VNB lineage occurs naturally in the South American environment. This suggests migration of the VNB lineage between Africa and South America prior to its diversification, supported by finding ancestral recombination events between isolates from different lineages and regions. The results provide evidence of substantial population structure, with all li

Working paper

Rhodes J, Beale MA, Vanhove M, Jarvis JN, Kannambath S, Simpson JA, Ryan A, Meintjes G, Harrison TS, Fisher MC, Bicanic Tet al., 2017, A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent Cryptococcal Meningitis Infection, G3-GENES GENOMES GENETICS, Vol: 7, Pages: 1165-1176, ISSN: 2160-1836

Recurrence of meningitis due to Cryptococcus neoformans after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing (WGS) to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis (CM). Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, while the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5, and RAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and nonsynonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in C. neoformans, and represent a novel pathway for rapid within-host adaptation and evolution of resistance to first-line antifungal drugs.

Journal article

Houldcroft CJ, Beale MA, Breuer J, 2017, Clinical and biological insights from viral genome sequencing, NATURE REVIEWS MICROBIOLOGY, Vol: 15, Pages: 183-192, ISSN: 1740-1526

Journal article

Rhodes J, Beale MA, Vanhove M, Jarvis JN, Kannambath S, Simpson JA, Ryan A, Meintjes G, Harrison TS, Fisher MC, Bicanic Tet al., 2016, A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:p>Recurrence of meningitis due to<jats:italic>Cryptococcus neoformans</jats:italic>after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis. Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, whilst the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins<jats:italic>MSH2, MSH5</jats:italic>and<jats:italic>RAD5</jats:italic>. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and non-synonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in<jats:italic>Cryptococcus neoformans</jats:italic>and represent a novel pathway for rapid within-host adaptation and evolution of resistance to firstline antifungal drugs.</jats:p>

Working paper

Vanhove M, Beale MA, Rhodes J, Chanda D, Lakhi S, Kwenda G, Molloy S, Karunaharan N, Stone N, Harrison TS, Bicanic T, Fisher Met al., 2016, Genomic epidemiology of Cryptococcus yeasts identifies adaptation to environmental niches underpinning infection across an African HIV/AIDS cohort, Molecular Ecology, Vol: 26, Pages: 1991-2005, ISSN: 1365-294X

Emerging infections caused by fungi have become a widely recognized global phenomenon and are causing an increasing burden of disease. Genomic techniques are providing new insights into the structure of fungal populations, revealing hitherto undescribed fine-scale adaptations to environments and hosts that govern their emergence as infections. Cryptococcal meningitis is a neglected tropical disease that is responsible for a large proportion of AIDS-related deaths across Africa; however, the ecological determinants that underlie a patient's risk of infection remain largely unexplored. Here, we use genome sequencing and ecological genomics to decipher the evolutionary ecology of the aetiological agents of cryptococcal meningitis, Cryptococcus neoformans and Cryptococcus gattii, across the central African country of Zambia. We show that the occurrence of these two pathogens is differentially associated with biotic (macroecological) and abiotic (physical) factors across two key African ecoregions, Central Miombo woodlands and Zambezi Mopane woodlands. We show that speciation of Cryptococcus has resulted in adaptation to occupy different ecological niches, with C. neoformans found to occupy Zambezi Mopane woodlands and C. gattii primarily recovered from Central Miombo woodlands. Genome sequencing shows that C. neoformans causes 95% of human infections in this region, of which over three-quarters belonged to the globalized lineage VNI. We show that VNI infections are largely associated with urbanized populations in Zambia. Conversely, the majority of C. neoformans isolates recovered in the environment belong to the genetically diverse African-endemic lineage VNB, and we show hitherto unmapped levels of genomic diversity within this lineage. Our results reveal the complex evolutionary ecology that underpins the reservoirs of infection for this, and likely other, deadly pathogenic fungi.

Journal article

Abdolrasouli A, Rhodes J, Beale MA, Hagen F, Rogers TR, Chowdhary A, Meis JF, Armstrong-James D, Fisher MCet al., 2015, Genomic Context of Azole Resistance Mutations in Aspergillus fumigatus Determined Using Whole-Genome Sequencing (vol 6, e00536, 2015), MBIO, Vol: 6, ISSN: 2150-7511

Journal article

Fisher M, 2015, Genotypic diversity is associated with clinical outcome and phenotype in Cryptococcal meningitis across Southern Africa, PLOS Neglected Tropical Diseases, Vol: 9, ISSN: 1935-2735

Cryptococcal meningitis is a major cause of mortality throughout the developing world, yet little is known about the genetic markers underlying Cryptococcal virulence and patient outcome. We studied a cohort of 230 Cryptococcus neoformans (Cn) isolates from HIV-positive South African clinical trial patients with detailed clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn displayed high levels of genetic diversity and locus variability compared to globally distributed types, and we identified 50 sequence types grouped within the main molecular types VNI, VNII and VNB, with 72% of isolates typed into one of seven 'high frequency' sequence types. Spatial analysis of patients’ cryptococcal genotype was not shown to be clustered geographically, which might argue against recent local acquisition and in favour of reactivation of latent infection. Through comparison of MLST genotyping data with clinical parameters, we found a relationship between genetic lineage and clinical outcome, with patients infected with the VNB lineage having significantly worse survival (n=8, HR 3.35, CI 1.51-7.20, p=0.003), and this was maintained even after adjustment for known prognostic indicators and treatment regimen. Comparison of fungal genotype with in vitro phenotype (phagocytosis, laccase activity and CSF survival) performed on a subset of 89 isolates revealed evidence of lineage-associated virulence phenotype, with the VNII lineage displaying increased laccase activity (p=0.001) and ex vivo CSF survival (p=0.0001). These findings show that Cryptococcus neoformans is a phenotypically heterogeneous pathogen, and that lineage plays an important role in cryptococcal virulence during human infection. Furthermore, a detailed understanding of the genetic diversity in Southern Africa will support further investigation into how genetic diversity is

Journal article

Abdolrasouli A, Rhodes J, Beale M, Hagen F, Rogers TR, Chowdhary A, Meis JF, Armstrong-James, Fisher MCet al., 2015, Genomic context of Azole-resistance mutations in Aspergillus fumigatus using whole-genome sequencing, mBio, Vol: 6, ISSN: 2161-2129

A rapid and global emergence of azole resistance has been observed in the pathogenic fungus Aspergillus fumigatus over the past decade. The dominant resistance mechanism appears to be of environmental origin and involves mutations in the cyp51A gene, which encodes a protein targeted by triazole antifungal drugs. Whole-genome sequencing (WGS) was performed for high-resolution single-nucleotide polymorphism (SNP) analysis of 24 A. fumigatus isolates, including azole-resistant and susceptible clinical and environmental strains obtained from India, the Netherlands, and the United Kingdom, in order to assess the utility of WGS for characterizing the alleles causing resistance. WGS analysis confirmed that TR34/L98H (a mutation comprising a tandem repeat [TR] of 34 bases in the promoter of the cyp51A gene and a leucine-to-histidine change at codon 98) is the sole mechanism of azole resistance among the isolates tested in this panel of isolates. We used population genomic analysis and showed that A. fumigatus was panmictic, with as much genetic diversity found within a country as is found between continents. A striking exception to this was shown in India, where isolates are highly related despite being isolated from both clinical and environmental sources across >1,000 km; this broad occurrence suggests a recent selective sweep of a highly fit genotype that is associated with the TR34/L98H allele. We found that these sequenced isolates are all recombining, showing that azole-resistant alleles are segregating into diverse genetic backgrounds. Our analysis delineates the fundamental population genetic parameters that are needed to enable the use of genome-wide association studies to identify the contribution of SNP diversity to the generation and spread of azole resistance in this medically important fungus.

Journal article

Rhodes J, Beale MA, Fisher MC, 2014, Illuminating Choices for Library Prep: A Comparison of Library Preparation Methods for Whole Genome Sequencing of Cryptococcus neoformans Using Illumina HiSeq, PLOS ONE, Vol: 9, ISSN: 1932-6203

The industry of next-generation sequencing is constantly evolving, with novel library preparation methods and new sequencing machines being released by the major sequencing technology companies annually. The Illumina TruSeq v2 library preparation method was the most widely used kit and the market leader; however, it has now been discontinued, and in 2013 was replaced by the TruSeq Nano and TruSeq PCR-free methods, leaving a gap in knowledge regarding which is the most appropriate library preparation method to use. Here, we used isolates from the pathogenic fungi Cryptococcus neoformans var. grubii and sequenced them using the existing TruSeq DNA v2 kit (Illumina), along with two new kits: the TruSeq Nano DNA kit (Illumina) and the NEBNext Ultra DNA kit (New England Biolabs) to provide a comparison. Compared to the original TruSeq DNA v2 kit, both newer kits gave equivalent or better sequencing data, with increased coverage. When comparing the two newer kits, we found little difference in cost and workflow, with the NEBNext Ultra both slightly cheaper and faster than the TruSeq Nano. However, the quality of data generated using the TruSeq Nano DNA kit was superior due to higher coverage at regions of low GC content, and more SNPs identified. Researchers should therefore evaluate their resources and the type of application (and hence data quality) being considered when ultimately deciding on which library prep method to use.

Journal article

Sabiiti W, Robertson E, Beale MA, Johnston SA, Brouwer AE, Loyse A, Jarvis JN, Gilbert AS, Fisher MC, Harrison TS, May RC, Bicanic Tet al., 2014, Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis., J Clin Invest, Vol: 124, Pages: 2000-2008

BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis. METHODS: Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis. RESULTS: High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003). CONCLUSION: These findings underscore the contribution of cryptococcal-phagocyte interactions and laccase-dependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM. FUNDING: This work was

Journal article

Brown GD, Meintjes G, Kolls JK, Gray C, Horsnell Wet al., 2014, AIDS-related mycoses: the way forward, TRENDS IN MICROBIOLOGY, Vol: 22, Pages: 107-109, ISSN: 0966-842X

Journal article

Beale MA, Tettmar K, Szypulska R, Tedder RS, Ijaz Set al., 2011, Is there evidence of recent hepatitis E virus infection in English and North Welsh blood donors?, VOX SANGUINIS, Vol: 100, Pages: 340-342, ISSN: 0042-9007

Journal article

Beale MA, Ijaz S, Tedder RS, 2010, The genetic backbone modulates the phenotype of hepatitis B surface antigen mutants, JOURNAL OF GENERAL VIROLOGY, Vol: 91, Pages: 68-73, ISSN: 0022-1317

Journal article

Beale MA, Marks M, Cole MJ, Lee M-K, Pitt R, Ruis C, Balla E, Crucitti T, Ewens M, Fernández-Naval C, Grankvist A, Guiver M, Kenyon CR, Khairulin R, Kularatne R, Arando M, Molini BJ, Obukhov A, Page EE, Petrovay F, Rietmeijer C, Rowley D, Shokoples S, Smit E, Sweeney EL, Taiaroa G, Vera JH, Wennerås C, Whiley DM, Williamson DA, Hughes G, Naidu P, Unemo M, Krajden M, Lukehart SA, Morshed MG, Fifer H, Thomson NRet al., Contemporary syphilis is characterised by rapid global spread of pandemic Treponema pallidum lineages

<jats:title>Abstract</jats:title><jats:p>Syphilis is an important sexually transmitted infection caused by the bacterium <jats:italic>Treponema pallidum</jats:italic> subspecies <jats:italic>pallidum</jats:italic>. The last two decades have seen syphilis incidence rise in many high-income countries, yet the evolutionary and epidemiological relationships that underpin this are poorly understood, as is the global <jats:italic>T. pallidum</jats:italic> population structure. We assembled a geographically and temporally diverse collection of clinical and laboratory samples comprising 726 <jats:italic>T. pallidum</jats:italic> genomes. We used detailed phylogenetic analysis and clustering to show that syphilis globally can be described by only two deeply branching lineages, Nichols and SS14. We show that both of these lineages can be found circulating concurrently in 12 of the 23 countries sampled. To provide further phylodynamic resolution we subdivided <jats:italic>Treponema pallidum</jats:italic> subspecies <jats:italic>pallidum</jats:italic> into 17 distinct sublineages. Importantly, like SS14, we provide evidence that two Nichols sublineages have expanded clonally across 9 countries contemporaneously with SS14. Moreover, pairwise genome analysis showed that recent isolates circulating in 14 different countries were genetically identical in their core genome to those from other countries, suggesting frequent exchange through international transmission pathways. This contrasts with the majority of samples collected prior to 1983, which are phylogenetically distinct from these more recently isolated sublineages. Bayesian temporal analysis provided evidence of a population bottleneck and decline occurring during the late 1990s, followed by a rapid population expansion a decade later. This was driven by the dominant <jats:italic>T. pallidum</jats:italic> sublineages circu

Journal article

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