Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations
Identifieur interne : 000808 ( Pmc/Curation ); précédent : 000807; suivant : 000809Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations
Auteurs : Abdallah M. Abdallah ; Grant A. Hill-Cawthorne [Australie] ; Thomas D. Otto [Royaume-Uni] ; Francesc Coll [Royaume-Uni] ; José Afonso Guerra-Assunção [Royaume-Uni] ; Ge Gao ; Raeece Naeem ; Hifzur Ansari ; Tareq B. Malas ; Sabir A. Adroub ; Theo Verboom [Pays-Bas] ; Roy Ummels [Pays-Bas] ; Huoming Zhang ; Aswini Kumar Panigrahi ; Ruth Mcnerney [Royaume-Uni] ; Roland Brosch [France] ; Taane G. Clark [Royaume-Uni] ; Marcel A. Behr [Canada] ; Wilbert Bitter [Pays-Bas] ; Arnab Pain [Japon]Source :
- Scientific Reports [ 2045-2322 ] ; 2015.
Abstract
Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains.
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DOI: 10.1038/srep15443
PubMed: 26487098
PubMed Central: 4614345
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Abdallah M. Abdallah<affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity and School and Public Health, University of Sydney</institution>, NSW 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation><nlm:aff id="a5"><institution>Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST)</institution>, Thuwal, 23955-6900, Jeddah,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation><nlm:aff id="a7"><institution>Bioscience Core Laboratory, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation><nlm:aff id="a7"><institution>Bioscience Core Laboratory, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:aff id="a11"><institution>Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University</institution>, Sapporo, 001-0020,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation>Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations</title><author><name sortKey="Abdallah, Abdallah M" sort="Abdallah, Abdallah M" uniqKey="Abdallah A" first="Abdallah M." last="Abdallah">Abdallah M. Abdallah</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Hill Cawthorne, Grant A" sort="Hill Cawthorne, Grant A" uniqKey="Hill Cawthorne G" first="Grant A." last="Hill-Cawthorne">Grant A. 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Malas</name><affiliation><nlm:aff id="a5"><institution>Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST)</institution>, Thuwal, 23955-6900, Jeddah,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Adroub, Sabir A" sort="Adroub, Sabir A" uniqKey="Adroub S" first="Sabir A." last="Adroub">Sabir A. Adroub</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Verboom, Theo" sort="Verboom, Theo" uniqKey="Verboom T" first="Theo" last="Verboom">Theo Verboom</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Medical Microbiology and Infection Control, VU University Medical Center</institution>, 1081 BT Amsterdam,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ummels, Roy" sort="Ummels, Roy" uniqKey="Ummels R" first="Roy" last="Ummels">Roy Ummels</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Medical Microbiology and Infection Control, VU University Medical Center</institution>, 1081 BT Amsterdam,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Huoming" sort="Zhang, Huoming" uniqKey="Zhang H" first="Huoming" last="Zhang">Huoming Zhang</name><affiliation><nlm:aff id="a7"><institution>Bioscience Core Laboratory, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Panigrahi, Aswini Kumar" sort="Panigrahi, Aswini Kumar" uniqKey="Panigrahi A" first="Aswini Kumar" last="Panigrahi">Aswini Kumar Panigrahi</name><affiliation><nlm:aff id="a7"><institution>Bioscience Core Laboratory, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Mcnerney, Ruth" sort="Mcnerney, Ruth" uniqKey="Mcnerney R" first="Ruth" last="Mcnerney">Ruth Mcnerney</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine</institution>, London,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brosch, Roland" sort="Brosch, Roland" uniqKey="Brosch R" first="Roland" last="Brosch">Roland Brosch</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Clark, Taane G" sort="Clark, Taane G" uniqKey="Clark T" first="Taane G." last="Clark">Taane G. Clark</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine</institution>, London,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a9"><institution>Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine</institution>, London,<country>United Kingdom</country>.</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Behr, Marcel A" sort="Behr, Marcel A" uniqKey="Behr M" first="Marcel A." last="Behr">Marcel A. Behr</name><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Department of Medicine, McGill University Health Centre, Montreal</institution>, QC,<country>Canada</country></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bitter, Wilbert" sort="Bitter, Wilbert" uniqKey="Bitter W" first="Wilbert" last="Bitter">Wilbert Bitter</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Medical Microbiology and Infection Control, VU University Medical Center</institution>, 1081 BT Amsterdam,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pain, Arnab" sort="Pain, Arnab" uniqKey="Pain A" first="Arnab" last="Pain">Arnab Pain</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:aff id="a11"><institution>Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University</institution>, Sapporo, 001-0020,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26487098</idno><idno type="pmc">4614345</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614345</idno><idno type="RBID">PMC:4614345</idno><idno type="doi">10.1038/srep15443</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000809</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000809</idno><idno type="wicri:Area/Pmc/Curation">000808</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000808</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations</title><author><name sortKey="Abdallah, Abdallah M" sort="Abdallah, Abdallah M" uniqKey="Abdallah A" first="Abdallah M." last="Abdallah">Abdallah M. Abdallah</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Hill Cawthorne, Grant A" sort="Hill Cawthorne, Grant A" uniqKey="Hill Cawthorne G" first="Grant A." last="Hill-Cawthorne">Grant A. Hill-Cawthorne</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity and School and Public Health, University of Sydney</institution>, NSW 2006,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Otto, Thomas D" sort="Otto, Thomas D" uniqKey="Otto T" first="Thomas D." last="Otto">Thomas D. Otto</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Pathogen Genomics, The Wellcome Trust Sanger Institute</institution>, Hinxton, Cambridge CB10 1SA,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Coll, Francesc" sort="Coll, Francesc" uniqKey="Coll F" first="Francesc" last="Coll">Francesc Coll</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine</institution>, London,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Guerra Assuncao, Jose Afonso" sort="Guerra Assuncao, Jose Afonso" uniqKey="Guerra Assuncao J" first="José Afonso" last="Guerra-Assunção">José Afonso Guerra-Assunção</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine</institution>, London,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Ge" sort="Gao, Ge" uniqKey="Gao G" first="Ge" last="Gao">Ge Gao</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Naeem, Raeece" sort="Naeem, Raeece" uniqKey="Naeem R" first="Raeece" last="Naeem">Raeece Naeem</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Ansari, Hifzur" sort="Ansari, Hifzur" uniqKey="Ansari H" first="Hifzur" last="Ansari">Hifzur Ansari</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Malas, Tareq B" sort="Malas, Tareq B" uniqKey="Malas T" first="Tareq B." last="Malas">Tareq B. Malas</name><affiliation><nlm:aff id="a5"><institution>Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST)</institution>, Thuwal, 23955-6900, Jeddah,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Adroub, Sabir A" sort="Adroub, Sabir A" uniqKey="Adroub S" first="Sabir A." last="Adroub">Sabir A. Adroub</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Verboom, Theo" sort="Verboom, Theo" uniqKey="Verboom T" first="Theo" last="Verboom">Theo Verboom</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Medical Microbiology and Infection Control, VU University Medical Center</institution>, 1081 BT Amsterdam,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ummels, Roy" sort="Ummels, Roy" uniqKey="Ummels R" first="Roy" last="Ummels">Roy Ummels</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Medical Microbiology and Infection Control, VU University Medical Center</institution>, 1081 BT Amsterdam,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Huoming" sort="Zhang, Huoming" uniqKey="Zhang H" first="Huoming" last="Zhang">Huoming Zhang</name><affiliation><nlm:aff id="a7"><institution>Bioscience Core Laboratory, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Panigrahi, Aswini Kumar" sort="Panigrahi, Aswini Kumar" uniqKey="Panigrahi A" first="Aswini Kumar" last="Panigrahi">Aswini Kumar Panigrahi</name><affiliation><nlm:aff id="a7"><institution>Bioscience Core Laboratory, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation></author><author><name sortKey="Mcnerney, Ruth" sort="Mcnerney, Ruth" uniqKey="Mcnerney R" first="Ruth" last="Mcnerney">Ruth Mcnerney</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine</institution>, London,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brosch, Roland" sort="Brosch, Roland" uniqKey="Brosch R" first="Roland" last="Brosch">Roland Brosch</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Clark, Taane G" sort="Clark, Taane G" uniqKey="Clark T" first="Taane G." last="Clark">Taane G. Clark</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine</institution>, London,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a9"><institution>Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine</institution>, London,<country>United Kingdom</country>.</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Behr, Marcel A" sort="Behr, Marcel A" uniqKey="Behr M" first="Marcel A." last="Behr">Marcel A. Behr</name><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Department of Medicine, McGill University Health Centre, Montreal</institution>, QC,<country>Canada</country></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bitter, Wilbert" sort="Bitter, Wilbert" uniqKey="Bitter W" first="Wilbert" last="Bitter">Wilbert Bitter</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Medical Microbiology and Infection Control, VU University Medical Center</institution>, 1081 BT Amsterdam,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pain, Arnab" sort="Pain, Arnab" uniqKey="Pain A" first="Arnab" last="Pain">Arnab Pain</name><affiliation><nlm:aff id="a1"><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></nlm:aff><wicri:noCountry code="nlm country">Kingdom of Saudi Arabia</wicri:noCountry></affiliation><affiliation wicri:level="1"><nlm:aff id="a11"><institution>Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University</institution>, Sapporo, 001-0020,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Frothingham, R" uniqKey="Frothingham R">R. Frothingham</name></author><author><name sortKey="Hills, H G" uniqKey="Hills H">H. G. Hills</name></author><author><name sortKey="Wilson, K H" uniqKey="Wilson K">K. H. Wilson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Imaeda, T" uniqKey="Imaeda T">T. Imaeda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zwerling, A" uniqKey="Zwerling A">A. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26487098</article-id><article-id pub-id-type="pmc">4614345</article-id><article-id pub-id-type="pii">srep15443</article-id><article-id pub-id-type="doi">10.1038/srep15443</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Abdallah</surname><given-names>Abdallah M.</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Hill-Cawthorne</surname><given-names>Grant A.</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Otto</surname><given-names>Thomas D.</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Coll</surname><given-names>Francesc</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Guerra-Assunção</surname><given-names>José Afonso</given-names></name><xref ref-type="aff" rid="a4">4</xref><xref ref-type="author-notes" rid="n2">†</xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Ge</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Naeem</surname><given-names>Raeece</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ansari</surname><given-names>Hifzur</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Malas</surname><given-names>Tareq B.</given-names></name><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Adroub</surname><given-names>Sabir A.</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Verboom</surname><given-names>Theo</given-names></name><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Ummels</surname><given-names>Roy</given-names></name><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Huoming</given-names></name><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Panigrahi</surname><given-names>Aswini Kumar</given-names></name><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>McNerney</surname><given-names>Ruth</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Brosch</surname><given-names>Roland</given-names></name><xref ref-type="aff" rid="a8">8</xref></contrib><contrib contrib-type="author"><name><surname>Clark</surname><given-names>Taane G.</given-names></name><xref ref-type="aff" rid="a4">4</xref><xref ref-type="aff" rid="a9">9</xref></contrib><contrib contrib-type="author"><name><surname>Behr</surname><given-names>Marcel A.</given-names></name><xref ref-type="aff" rid="a10">10</xref></contrib><contrib contrib-type="author"><name><surname>Bitter</surname><given-names>Wilbert</given-names></name><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Pain</surname><given-names>Arnab</given-names></name><xref ref-type="corresp" rid="c2">b</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a11">11</xref></contrib><aff id="a1"><label>1</label><institution>Pathogen Genomics Group, Biological, Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></aff><aff id="a2"><label>2</label><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity and School and Public Health, University of Sydney</institution>, NSW 2006,<country>Australia</country></aff><aff id="a3"><label>3</label><institution>Pathogen Genomics, The Wellcome Trust Sanger Institute</institution>, Hinxton, Cambridge CB10 1SA,<country>United Kingdom</country></aff><aff id="a4"><label>4</label><institution>Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine</institution>, London,<country>United Kingdom</country></aff><aff id="a5"><label>5</label><institution>Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST)</institution>, Thuwal, 23955-6900, Jeddah,<country>Kingdom of Saudi Arabia</country></aff><aff id="a6"><label>6</label><institution>Department of Medical Microbiology and Infection Control, VU University Medical Center</institution>, 1081 BT Amsterdam,<country>The Netherlands</country></aff><aff id="a7"><label>7</label><institution>Bioscience Core Laboratory, King Abdullah University of Science and Technology</institution>, Thuwal, 23955-6900,<country>Kingdom of Saudi Arabia</country></aff><aff id="a8"><label>8</label><institution>Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics</institution>, Paris,<country>France</country></aff><aff id="a9"><label>9</label><institution>Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine</institution>, London,<country>United Kingdom</country>.</aff><aff id="a10"><label>10</label><institution>Department of Medicine, McGill University Health Centre, Montreal</institution>, QC,<country>Canada</country></aff><aff id="a11"><label>11</label><institution>Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University</institution>, Sapporo, 001-0020,<country>Japan</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>Abdallah.abdallah@kaust.edu.sa</email></corresp><corresp id="c2"><label>b</label><email>arnab.pain@kaust.edu.sa</email></corresp><fn id="n1"><label>*</label><p>These Authors contributed equally to this work.</p></fn><fn id="n2"><label>†</label><p>Present Address: Barts Cancer Institute, QMUL, EC1M 6BQ London, United Kingdom.</p></fn></author-notes><pub-date pub-type="epub"><day>21</day><month>10</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>5</volume><elocation-id>15443</elocation-id><history><date date-type="received"><day>16</day><month>05</month><year>2015</year></date><date date-type="accepted"><day>22</day><month>09</month><year>2015</year></date></history><permissions><copyright-statement>Copyright © 2015, Macmillan Publishers Limited</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><p>(<bold>A</bold>) A circular representation of Bacillus Calmette-Guérin (BCG) vaccine sub-strains chromosomes. Distribution of single nucleotide polymorphisms (SNPs) in fourteen BCG strains compared to <italic>Mycobacterium bovis</italic> AF2122/97. Each coloured blob corresponds to the SNP density in a non-overlapping window of 10000 nucleotides, with a unique colour per sample allowing easy visual assessment of similarities between samples. The scale is shown in megabases in the circle. (<bold>B</bold>) Phylogenetic relationships among BCG strains. Maximum likelihood phylogeny tree based on 700 + variable common nucleotide positions across fourteen BCG genome sequences. The tree was rooted using <italic>M. bovis</italic> AF2122/97.</p></caption><graphic xlink:href="srep15443-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Revised genealogy of Bacillus Calmete-Guérin (BCG) vaccine strains.</title><p>The genealogy of BCG vaccine strains, displays the original virulent ancestor strain <italic>M. bovis</italic> and the subsequent series of genomic alteration including deletions of regions of difference (RD), and some strain-specific insertion (‘Ins’) and deletions (‘Δ’). Genes with both insertions and deletions is also shown (‘Indels’). Genetic markers identified in this work have been added to the scheme (squares bordered with a red solid line). Note that the RD nomenclature in previous work differs between references<xref ref-type="bibr" rid="b16">16</xref><xref ref-type="bibr" rid="b18">18</xref> deletion of RD8<xref ref-type="bibr" rid="b16">16</xref> from BCG strains Connaught and Frappier corresponds to RD15 in reference<xref ref-type="bibr" rid="b18">18</xref>. Variants shown in boxes are novel in this study. All variants shown were manually inspected by read mapping as well as by assembled genomes.</p></caption><graphic xlink:href="srep15443-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Transcriptional profile of a global collection of BCG strains: Gene expression heat maps of genes showing expression profiles involved in;</title><p>(<bold>A</bold>) Catabolism of fatty acids. (<bold>B</bold>) phenolpthiocerol dimycocerosate (PDIM). (<bold>C</bold>) mycolic acid synthesis. (<bold>D</bold>) Transcriptional regulatory. (<bold>E</bold>) Mammalian cell entry genes. (<bold>F</bold>) Immunogenic surface and secreted proteins. Genes were selected based on their annotation. The color scales represent log2-fold changes in gene expression (DESeq), using the <italic>M. bovis</italic> AF2122/97 strain as reference.</p></caption><graphic xlink:href="srep15443-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>Pattern of increased and decreased expression in genes of BCG Japan and Danish compared to our own assembled genome of BCG Russia.</title><p>(<bold>A</bold>) Genes that are significantly down-regulated or up-regulated in BCG Japan compared to BCG Russia. Genes are categorized based on significant enrichment in biological processes of gene ontologies (p < 0.05). Left: total number of genes found to be down-regulated in each biological process category. Right: total number of genes found to be up-regulated in each biological process category. (<bold>B</bold>) Genes that are significantly down-regulated or up-regulated in BCG Danish compared to BCG Russia. Genes are categorized based on significant enrichment in biological processes of gene ontologies. Left: total number of genes found to be down-regulated in each biological process category. Right: total number of genes found to be up-regulated in each biological process category.</p></caption><graphic xlink:href="srep15443-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Heat map of differentially expressed proteins among five representative BCG strains compared to <italic>M. bovis.</italic></title><p>Differential expression of proteins involved in biochemical pathways related to energy metabolism (<bold>A</bold>), or to biosynthesis pathways (<bold>B</bold>,<bold>C</bold>) are shown. The color scale indicates differential regulation as the Fold Change of the protein amount relative to the <italic>M. bovis</italic> 2122/97 reference strain. Up-regulation is indicated in red, down-regulation in blue. Star (*) indicates lack of correlation with RNA-seq data for that gene.</p></caption><graphic xlink:href="srep15443-f5"></graphic></fig><table-wrap position="float" id="t1"><label>Table 1</label><caption><title>Drug sensitivity testing of <italic>M. bovis</italic> BCG strains.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center" char="."></col><col align="center" char="."></col><col align="center" char="."></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th rowspan="2" align="left" valign="top" charoff="50">BCG strains</th><th colspan="5" align="center" valign="top" char="." charoff="50">Minimum inhibitory concentration (MIC, μg/ml)<hr></hr></th></tr><tr><th align="center" valign="top" char="." charoff="50">Streptomycin</th><th align="center" valign="top" char="." charoff="50">Rifampicin</th><th align="center" valign="top" char="." charoff="50">Rifabutin</th><th align="center" valign="top" charoff="50">Ethambutol</th><th align="center" valign="top" charoff="50">Isoniazid</th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">Pasteur</td><td align="center" valign="top" char="." charoff="50">0.125</td><td align="center" valign="top" char="." charoff="50">0.0005</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">0.5</td><td align="center" valign="top" charoff="50">1</td></tr><tr><td align="left" valign="top" charoff="50">Japan</td><td align="center" valign="top" char="." charoff="50">0.125</td><td align="center" valign="top" char="." charoff="50">0.0005</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">0.5</td><td align="center" valign="top" charoff="50">0.25</td></tr><tr><td align="left" valign="top" charoff="50">Tice</td><td align="center" valign="top" char="." charoff="50">0.125</td><td align="center" valign="top" char="." charoff="50">0.00025</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">0.5</td><td align="center" valign="top" charoff="50">1</td></tr><tr><td align="left" valign="top" charoff="50">Danish</td><td align="center" valign="top" char="." charoff="50">0.015</td><td align="center" valign="top" char="." charoff="50">0.000125</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">0.5</td><td align="center" valign="top" charoff="50">0,25</td></tr><tr><td align="left" valign="top" charoff="50">Phipps</td><td align="center" valign="top" char="." charoff="50">0.125</td><td align="center" valign="top" char="." charoff="50">0,001</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">1</td><td align="center" valign="top" charoff="50">1</td></tr><tr><td align="left" valign="top" charoff="50">Connaught</td><td align="center" valign="top" char="." charoff="50">0.125</td><td align="center" valign="top" char="." charoff="50">0.000125</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">1</td><td align="center" valign="top" charoff="50">1</td></tr><tr><td align="left" valign="top" charoff="50">Prague</td><td align="center" valign="top" char="." charoff="50">0.03</td><td align="center" valign="top" char="." charoff="50">0.000125</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">1</td><td align="center" valign="top" charoff="50">1.5</td></tr><tr><td align="left" valign="top" charoff="50">Birkhaug</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" charoff="50">—</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50">Frappier</td><td align="center" valign="top" char="." charoff="50">0.125</td><td align="center" valign="top" char="." charoff="50">0.0005</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">1</td><td align="center" valign="top" charoff="50">1</td></tr><tr><td align="left" valign="top" charoff="50">Glaxo</td><td align="center" valign="top" char="." charoff="50">0.125</td><td align="center" valign="top" char="." charoff="50">0.00025</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">1</td><td align="center" valign="top" charoff="50">1</td></tr><tr><td align="left" valign="top" charoff="50">Russia</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" charoff="50">0.5</td><td align="center" valign="top" charoff="50">0.03</td></tr><tr><td align="left" valign="top" charoff="50">Sweden</td><td align="center" valign="top" char="." charoff="50">0.03</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" char="." charoff="50">0.002</td><td align="center" valign="top" charoff="50">0.5</td><td align="center" valign="top" charoff="50">0.015</td></tr><tr><td align="left" valign="top" charoff="50">Moreau</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" char="." charoff="50">—</td><td align="center" valign="top" charoff="50">—</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50">China</td><td align="center" valign="top" char="." charoff="50">0.125</td><td align="center" valign="top" char="." charoff="50">00005</td><td align="center" valign="top" char="." charoff="50">0,002</td><td align="center" valign="top" charoff="50">1</td><td align="center" valign="top" charoff="50">1</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>The sensitivities of fourteen different BCG strains to streptomycin, rifampicin, rifabutin, ethambutol and isoniazid were determined.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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