Revised Interpretation of the Hain Lifescience GenoType MTBC To Differentiate
            <i>Mycobacterium canettii</i>
            and Members of the Mycobacterium tuberculosis Complex

Loiseau, Chloé; Brites, Daniela; Moser, Irmgard; Coll, Francesc Español i; Pourcel, Christine; Robbe‐Austerman, Suelee; Escuyer, Vincent; Musser, Kimberlee A.; Peacock, Sharon J.; Feuerriegel, Silke; Kohl, Thomas A.; Niemann, Stefan; Gagneux, Sébastien; Köser, Claudio U.

doi:10.1128/aac.00159-19

Cited by 19 publications

(17 citation statements)

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“…Two deep divergence events in M. bovis populations were notorious: one giving rise to an unclassified lineage we named M. bovis PZA_sus_unknown1 (RD4 deleted as other M.bovis ), which included 5 samples from Uganda (isolated from Bos taurus cattle, Table S1), 3 from Malawi (isolated from Humans, Table S1) and one isolated from an antelope in Germany (Table S1). These M. bovis isolates lacked the PncA H57D mutation that is responsible for the intrinsic pyrazinamide resistance of canonical M. bovis as reported previously [50] (Fig. 2).…”

Section: Resultssupporting

confidence: 67%

An African origin forMycobacterium bovis

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Lay Summary: Mycobacterium bovis and M. caprae are both the most important agents 37 of tuberculosis in livestock and zoonotic tuberculosis in humans. Using phylogenetic and 38 molecular clock inferences based on an extensive collection of whole-genome sequences 39 we provide new insights into the global population structure, phylogeography and 40 evolutionary history of these pathogens. 41 42 Word count abstract: 180 43 Word count main text: 4366 44 Number of Figures: 3 45 46 ABSTRACT 47 48 Background and objectives 49 Mycobacterium bovis and Mycobacterium caprae are the two most important agents of 50 tuberculosis (TB) in livestock and the most important causes of zoonotic TB in humans. 51However, little is known about the global population structure, phylogeography and 52 evolutionary history of these pathogens. 53 Methodology 54We compiled a global collection of 3364 whole-genome sequences from M. bovis and M. 55 caprae originating from 35 countries and inferred their phylogenetic relationships, geographic 56 origins and age. 57 Results 58Our results resolve the phylogenetic relationship among the four previously defined clonal 59 complexes of M. bovis, and another eight newly described here. Our inferences indicate that 60 M. bovis emerged in East Africa likely between the 4 th and 10 th century. While some M. bovis 61 groups remained restricted to East-and West Africa, others have subsequently dispersed to 62 different parts of the world. 63 Conclusions and implications 64Our results allow a better understanding of the global population structure of M. bovis and its 65 evolutionary history. This knowledge can be used to define better molecular markers for 66 epidemiological investigations in settings where whole genome sequencing cannot easily be 67 implemented. 68 69 70 BACKGROUND AND OBJECTIVES 71 Tuberculosis (TB) remains an important burden for global health and the economy [1]. TB is 72 the number one cause of human death due to infection globally, with an estimated 10.0 73 million new cases and 1.6 million deaths occurring every year [1]. TB is caused by members 74 of the Mycobacterium tuberculosis complex (MTBC), which includes seven human-adapted 75 lineages, and several animal-adapted ecotypes including M. bovis and M. caprae. Animal TB 76 complicates the control of human TB due to the zoonotic transfer of TB bacilli from infected 77 animals to exposed human populations through e.g. the consumption of unpasteurized milk or 78 handling of contaminated meat [2]. M. bovis and M. caprae are the most important agents of 79 TB in livestock and the most important agents of zoonotic TB in humans, causing at least 147 80 000 new human cases and 12 500 deaths yearly [1, 3]. Zoonotic TB caused by M. bovis also 81 poses a challenge for patient treatment, due to its natural resistance to pyrazinamide (PZA), 82 one of the four first-line drugs used in the treatment of TB. In addition, TB in livestock 83 accounts for an estimated loss of three billion US dollars per year [4]. In Africa its prevalence 84 is highes...

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Section: Resultssupporting

confidence: 67%

An African origin forMycobacterium bovis

Loiseau

Menardo

Aseffa

et al. 2019

Preprint

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“…This, in turn, is a function of how deeply rooted this phenotype is in the phylogenetic tree of MTBC and how well these strains have subsequently transmitted. For example, the pncA H57D mutation, which is estimated to have evolved approximately 900 years ago [44], is shared by the vast majority of M. bovis strains and consequently renders them intrinsically resistant to PZA [45]. Yet, owing to the control policies introduced in well-resourced countries over the past century, M. bovis is responsible for fewer than 3% of human tuberculosis (TB) cases globally [46].…”

Section: Discussionmentioning

confidence: 99%

“…These include the intrinsic capreomycin resistance of some lineage 4.6.2 strains (Cameroon genotype) due to the tlyA N236K mutation [23], the high-level DCS resistance shared by all BCG variants [29], and the intrinsic resistance to INH and ETH/PRO of BCG variants derived after 1926 as a result of mmaA3 G98D [39]. Finally, M. canettii, which is not strictly speaking part of MTBC, is intrinsically resistant to PZA and pretomanid [45,47,48].…”

Section: Discussionmentioning

confidence: 99%

Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex

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Background: A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret wholegenome sequencing data for genotypic drug susceptibility testing (DST). Methods: We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes of 405 phylogenetically diverse MTBC strains. The role of phylogenetically informative mutations was assessed by routine phenotypic DST data for the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide from a separate collection of over 7000 clinical strains. Selected mutations/strains were further investigated by minimum inhibitory concentration (MIC) testing. Results: Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance to first-line drugs. MIC testing did not reveal a discernible impact of a Rv1979c deletion shared by M. africanum lineage 5 strains on resistance to clofazimine. Finally, we found molecular evidence that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine by different loss-of-function mutations affecting a drug efflux pump subunit (MmpL5). Conclusions: Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and to define sound epidemiologic cutoff values (ECOFFs) for new and repurposed anti-tuberculosis drugs. In that regard, our comprehensive variant catalogue provides a solid basis for the interpretation of mutations in genotypic as well as in phenotypic DST assays.

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“…The WHO (World Health Organization) estimated that 142,000 new cases and 12,500 deaths occurred due to zoonotic TB in 2017 (World Health Organization [WHO], 2018), numbers that are likely underestimated due to lack of routine surveillance data from most countries (Olea-Popelka et al, 2017). People with zoonotic TB face arduous challenges; most strains of the etiologic agent are resistant to pyrazinamide (Konno et al, 1967;Scorpio and Zhang, 1996;Loiseau et al, 2019), one of the first-line drugs used in TB treatment, and a possible association with extra-pulmonary disease (Dürr et al, 2013) often delays diagnostics and treatment initiation (World Health Organization [WHO] et al, 2017). In addition, bovine TB results in severe economic losses for livestock producers worldwide, respecting no borders and repeatedly affecting animal conservation efforts due to the establishment of wildlife reservoirs or spillover events from cattle to associated animal populations (Ayele et al, 2004;De Kantor and Ritacco, 2006;Godfray et al, 2013;Miller and Sweeney, 2013;Palmer, 2013;Nugent et al, 2015a,b).…”

Section: Introductionmentioning

confidence: 99%

Global Distribution and Evolution of Mycobacterium bovis Lineages

et al. 2020

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Mycobacterium bovis is the main causative agent of zoonotic tuberculosis in humans and frequently devastates livestock and wildlife worldwide. Previous studies suggested the existence of genetic groups of M. bovis strains based on limited DNA markers (a.k.a. clonal complexes), and the evolution and ecology of this pathogen has been only marginally explored at the global level. We have screened over 2,600 publicly available M. bovis genomes and newly sequenced four wildlife M. bovis strains, gathering 1,969 genomes from 23 countries and at least 24 host species, including humans, to complete a phylogenomic analyses. We propose the existence of four distinct global lineages of M. bovis (Lb1, Lb2, Lb3, and Lb4) underlying the current disease distribution. These lineages are not fully represented by clonal complexes and are dispersed based on geographic location rather than host species. Our data divergence analysis agreed with previous studies reporting independent archeological data of ancient M. bovis (South Siberian infected skeletons at ∼2,000 years before present) and indicates that extant M. bovis originated between 715 and 3,556 years BP, with later emergence in the New World and Oceania, likely influenced by trades among countries.

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Revised Interpretation of the Hain Lifescience GenoType MTBC To Differentiate Mycobacterium canettii and Members of the Mycobacterium tuberculosis Complex

Cited by 19 publications

References 25 publications

An African origin forMycobacterium bovis

An African origin forMycobacterium bovis

Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex

Global Distribution and Evolution of Mycobacterium bovis Lineages

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