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1. International links between Streptococcus pneumoniae vaccine serotype 4 sequence type (ST) 801 in Northern European shipyard outbreaks of invasive pneumococcal disease

Author

Gladstone, R.A., Siira, L., Brynildsrud, O.B., Vestrheim, D.F., Turner, P., Clarke, S.C., Srifuengfung, S., Ford, R., Lehmann, D., Egorova, E., Voropaeva, E., Haraldsson, G., Kristinsson, K.G., McGee, L., Breiman, R.F., Bentley, S.D., Sheppard, C.L., Fry, N.K., Corander, J., Toropainen, M., Steens, A., Akpaka, P.E., Ampofo, K., Antonio, M., Balaji, V., Beall, B.W., Belabbès, H., Benisty, R., Bigogo, G., Brooks, A.W., Carter, P.E., Cornick, J.E., Corso, A., Cristina de Cunto Brandileone, M., Cristine Grassi Almeida, S., Croucher, N.J., Dagan, R., Davydov, A., Diawara, I., Doiphode, S., du Plessis, M., Elmdaghri, N., Köseoglu Eser, Ö., Everett, D.B., Faccone, D., Gagetti, P., Givon-Lavi, N., Hasanuzzaman, M., Hawkins, P.A., Hryniewicz, W., Hulten, K.G., Ip, M., Kapusta, A., Kandasamy, R., Kastrin, T., Keenan, J., Klugman, K.P., Kwambana-Adams, B., Law, P.Y., Lees, J.A., Leung Ho, P., Li, Y., Lo, S.W., Ochoa Woodell, Theresa Jean, Madhi, S.A., Metcalf, B.J., Moïsi, J., Mucavele Fundação Manhiça, H., Ndlangisa, K.M., Nurse-Lucas, M., Nzenze, S.A., Obaro, S.K., Paragi, M., Pollard, A.J., Ravikumar, K.L., Sadowy, E., Saha, S.K., Sampane-Donkor, E., Devi Sekaran, S., Shakoor, S., Shrestha, S., Sigauque, B., Skoczynska, A., Soo ko, K., Tientcheu, P.-E., Titov, L., Urban, Y., Verani, J., van Tonder, A.J., von Gottberg, A., Wolter, N., The Global Pneumococcal Sequencing Consortium, and Consortium, The Global Pneumococcal Sequencing

Subjects
Northern Ireland, Serogroup, Polymorphism, Single Nucleotide, Pneumococcal Infections, Disease Outbreaks, Occupational Exposure, PPV23, Humans, Serotyping, Finland, Phylogeny, Ships, General Veterinary, General Immunology and Microbiology, Norway, Public Health, Environmental and Occupational Health, Outbreak, ST801, PCVs, Infectious Diseases, Streptococcus pneumoniae, Serotype 4, Whole genome sequencing, Molecular epidemiology, Molecular Medicine, Pneumococcal, Genome, Bacterial
Abstract

Background Pneumococcal disease outbreaks of vaccine preventable serotype 4 sequence type (ST)801 in shipyards have been reported in several countries. We aimed to use genomics to establish any international links between them. Methods Sequence data from ST801-related outbreak isolates from Norway (n = 17), Finland (n = 11) and Northern Ireland (n = 2) were combined with invasive pneumococcal disease surveillance from the respective countries, and ST801-related genomes from an international collection (n = 41 of > 40,000), totalling 106 genomes. Raw data were mapped and recombination excluded before phylogenetic dating. Results Outbreak isolates were relatively diverse, with up to 100 SNPs (single nucleotide polymorphisms) and a common ancestor estimated around the year 2000. However, 19 Norwegian and Finnish isolates were nearly indistinguishable (0–2 SNPs) with the common ancestor dated around 2017. Conclusion The total diversity of ST801 within the outbreaks could not be explained by recent transmission alone, suggesting that harsh environmental and associated living conditions reported in the shipyards may facilitate invasion of colonising pneumococci. However, near identical strains in the Norwegian and Finnish outbreaks does suggest that transmission between international shipyards also contributed to those outbreaks. This indicates the need for improved preventative measures in this working population including pneumococcal vaccination.

Published
2022

2. Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

Author

Lees, J.A., Ferwerda, B., Kremer, P.H.C., Wheeler, N.E., Seron, M.V., Croucher, N.J., Gladstone, R.A., Bootsma, H.J., Rots, N.Y., Wijmega-Monsuur, A.J., Sanders, E.A. (Elisabeth), Trzcinski, K., Wyllie, AL, Zwinderman, A.H. (Ailko), Berg, L.H. (Leonard) van den, Rheenen, W. (Wouter) van, Veldink, J.H. (Jan), Harboe, Z.B., Lundbo, L.F., Groot, L., Schoor, N.M., van der Velde, N., Angquist, LH, Sorensen, H.G., Nohr, C. (Christian), Mentzer, A.J., Mills, T.C., Knight, J.C. (Julian), Plessis, M. (Michelle) du, Nzenze, S., Weiser, J.N., Parkhill, J. (Julian), Madhi, S., Benfield, T., von Gottberg, A., Ende, A. (A.) van der, Brouwer, MC, Barrett, JC, Bentley, S.D., van de Beek, D.., Lees, J.A., Ferwerda, B., Kremer, P.H.C., Wheeler, N.E., Seron, M.V., Croucher, N.J., Gladstone, R.A., Bootsma, H.J., Rots, N.Y., Wijmega-Monsuur, A.J., Sanders, E.A. (Elisabeth), Trzcinski, K., Wyllie, AL, Zwinderman, A.H. (Ailko), Berg, L.H. (Leonard) van den, Rheenen, W. (Wouter) van, Veldink, J.H. (Jan), Harboe, Z.B., Lundbo, L.F., Groot, L., Schoor, N.M., van der Velde, N., Angquist, LH, Sorensen, H.G., Nohr, C. (Christian), Mentzer, A.J., Mills, T.C., Knight, J.C. (Julian), Plessis, M. (Michelle) du, Nzenze, S., Weiser, J.N., Parkhill, J. (Julian), Madhi, S., Benfield, T., von Gottberg, A., Ende, A. (A.) van der, Brouwer, MC, Barrett, JC, Bentley, S.D., and van de Beek, D..

Abstract

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause lifethreatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved i

Published
2019
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3. The contribution of genetic variation of streptococcus pneumoniae to the clinical manifestation of invasive pneumococcal disease

Author

Cremers, A.J.H., Mobegi, Fredrick, Van Der Gaast-De Jongh, C., Van Weert, M., Van Opzeeland, F.J., Vehkala, M., Knol, M.J., Bootsma, H.J., Välimäki, N., Croucher, N.J., Meis, J.F., Bentley, S., Van Hijum, S.A.F.T., Corander, J., Zomer, A.L., Ferwerda, G., De Jonge, M.I., Cremers, A.J.H., Mobegi, Fredrick, Van Der Gaast-De Jongh, C., Van Weert, M., Van Opzeeland, F.J., Vehkala, M., Knol, M.J., Bootsma, H.J., Välimäki, N., Croucher, N.J., Meis, J.F., Bentley, S., Van Hijum, S.A.F.T., Corander, J., Zomer, A.L., Ferwerda, G., and De Jonge, M.I.

Abstract

© 2018 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. Background. Different clinical manifestations of invasive pneumococcal disease (IPD) have thus far mainly been explained by patient characteristics. Here we studied the contribution of pneumococcal genetic variation to IPD phenotype. Methods. The index cohort consisted of 349 patients admitted to 2 Dutch hospitals between 2000-2011 with pneumococcal bacteremia. We performed genome-wide association studies to identify pneumococcal lineages, genes, and allelic variants associated with 23 clinical IPD phenotypes. The identified associations were validated in a nationwide (n = 482) and a post-pneumococcal vaccination cohort (n = 121). The contribution of confirmed pneumococcal genotypes to the clinical IPD phenotype, relative to known clinical predictors, was tested by regression analysis. Results. Among IPD patients, the presence of pneumococcal gene slaA was a nationwide confirmed independent predictor of meningitis (odds ratio [OR], 10.5; P = .001), as was sequence cluster 9 (serotype 7F: OR, 3.68; P = .057). A set of 4 pneumococcal genes co-located on a prophage was a confirmed independent predictor of 30-day mortality (OR, 3.4; P = .003). We could detect the pneumococcal variants of concern in these patients' blood samples. Conclusions. In this study, knowledge of pneumococcal genotypic variants improved the clinical risk assessment for detrimental manifestations of IPD. This provides us with novel opportunities to target, anticipate, or avert the pathogenic effects related to particular pneumococcal variants, and indicates that information on pneumococcal genotype is important for the diagnostic and treatment strategy in IPD. Ongoing surveillance is warranted to monitor the clinical value of information on pneumococcal variants in dynamic microbial and susceptible host populations.

Published
2018

4. RNA-seq reveals the RNA binding proteins, Hfq and RsmA, play various roles in virulence, antibiotic production and genomic flux in Serratia sp. ATCC 39006

Author

University of Cambridge, Wilf, N.M., Reid, A.J., Ramsay, J.P., Williamson, N.R., Croucher, N.J., Gatto, Laurent, Hester, S.S., Goulding, D., Barquist, L., Lilley, K.S., Kingsley, R.A., Dougan, G., Salmond, G.P.C., University of Cambridge, Wilf, N.M., Reid, A.J., Ramsay, J.P., Williamson, N.R., Croucher, N.J., Gatto, Laurent, Hester, S.S., Goulding, D., Barquist, L., Lilley, K.S., Kingsley, R.A., Dougan, G., and Salmond, G.P.C.

Abstract

Background: Serratia sp. ATCC 39006 (S39006) is a Gram-negative enterobacterium that is virulent in plant and animal models. It produces a red-pigmented trypyrrole secondary metabolite, prodigiosin (Pig), and a carbapenem antibiotic (Car), as well as the exoenzymes, pectate lyase and cellulase. Secondary metabolite production in this strain is controlled by a complex regulatory network involving quorum sensing (QS). Hfq and RsmA (two RNA binding proteins and major post-transcriptional regulators of gene expression) play opposing roles in the regulation of several key phenotypes within S39006. Prodigiosin and carbapenem production was abolished, and virulence attenuated, in an S39006 {increment}hfq mutant, while the converse was observed in an S39006 rsmA transposon insertion mutant.Results: In order to define the complete regulon of Hfq and RsmA, deep sequencing of cDNA libraries (RNA-seq) was used to analyse the whole transcriptome of S39006 {increment}hfq and rsmA::Tn mutants. Moreover, we investigated global changes in the proteome using an LC-MS/MS approach. Analysis of differential gene expression showed that Hfq and RsmA directly or indirectly regulate (at the level of RNA) 4% and 19% of the genome, respectively, with some correlation between RNA and protein expression. Pathways affected include those involved in antibiotic regulation, virulence, flagella synthesis, and surfactant production. Although Hfq and RsmA are reported to activate flagellum production in E. coli and an adherent-invasive E. coli hfq mutant was shown to have no flagella by electron microscopy, we found that flagellar production was increased in the S39006 rsmA and hfq mutants. Additionally, deletion of rsmA resulted in greater genomic flux with increased activity of two mobile genetic elements. This was confirmed by qPCR and analysis of rsmA culture supernatant revealed the presence of prophage DNA and phage particles. Finally, expression of a hypothetical protein containing DUF364 incre

Published
2013

5. Post-vaccine epidemiology of serotype 3 pneumococci identifies transformation inhibition through prophage-driven alteration of a non-coding RNA

Author

Min Jung Kwun, Alexandru V. Ion, Hsueh-Chien Cheng, Joshua C. D’Aeth, Sam Dougan, Marco R. Oggioni, David A. Goulding, Stephen D. Bentley, Nicholas J. Croucher, Kwun M.J., Ion A.V., Cheng H.-C., D'Aeth J.C., Dougan S., Oggioni M.R., Goulding D.A., Bentley S.D., and Croucher N.J.

Subjects
Selfish DNA, Vaccines, Conjugate, RNA, Untranslated, Prophages, Serogroup, Genomic epidemiology, Pneumococcal Infections, Pneumococcu, Recombination, Transformation, Pneumococcal Vaccines, Streptococcus pneumoniae, Genetics, Humans, Molecular Medicine, Prophage, Non-coding RNA, Molecular Biology, Vaccine, Genetics (clinical)
Abstract

Background The respiratory pathogen Streptococcus pneumoniae (the pneumococcus) is a genetically diverse bacterium associated with over 101 immunologically distinct polysaccharide capsules (serotypes). Polysaccharide conjugate vaccines (PCVs) have successfully eliminated multiple targeted serotypes, yet the mucoid serotype 3 has persisted despite its inclusion in PCV13. This capsule type is predominantly associated with a single globally disseminated strain, GPSC12 (clonal complex 180). Methods A genomic epidemiology study combined previous surveillance datasets of serotype 3 pneumococci to analyse the population structure, dynamics, and differences in rates of diversification within GPSC12 during the period of PCV introductions. Transcriptomic analyses, whole genome sequencing, mutagenesis, and electron microscopy were used to characterise the phenotypic impact of loci hypothesised to affect this strain’s evolution. Results GPSC12 was split into clades by a genomic analysis. Clade I, the most common, rarely underwent transformation, but was typically infected with the prophage ϕOXC141. Prior to the introduction of PCV13, this clade’s composition shifted towards a ϕOXC141-negative subpopulation in a systematically sampled UK collection. In the post-PCV13 era, more rapidly recombining non-Clade I isolates, also ϕOXC141-negative, have risen in prevalence. The low in vitro transformation efficiency of a Clade I isolate could not be fully explained by the ~100-fold reduction attributable to the serotype 3 capsule. Accordingly, prophage ϕOXC141 was found to modify csRNA3, a non-coding RNA that inhibits the induction of transformation. This alteration was identified in ~30% of all pneumococci and was particularly common in the unusually clonal serotype 1 GPSC2 strain. RNA-seq and quantitative reverse transcriptase PCR experiments using a genetically tractable pneumococcus demonstrated the altered csRNA3 was more effective at inhibiting production of the competence-stimulating peptide pheromone. This resulted in a reduction in the induction of competence for transformation. Conclusion This interference with the quorum sensing needed to induce competence reduces the risk of the prophage being deleted by homologous recombination. Hence the selfish prophage-driven alteration of a regulatory RNA limits cell-cell communication and horizontal gene transfer, complicating the interpretation of post-vaccine population dynamics.

Published
2022

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