Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity

Ates, Louis S.; Dippenaar, Anzaan; Sayes, Fadel; Pawlik, Alexandre; Bouchier, Christiane; Ma, Laurence; Warren, Robin M.; Sougakoff, Wladimir; Majlessi, Laleh; Heijst, Jeroen W. J. van; Brossier, Florence; Brosch, Roland

doi:10.1093/gbe/evy145

Cited by 42 publications

(77 citation statements)

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“…As previously reported, Rv1979c was deleted independently in all M. africanum lineage 5 strains (del Rv1978-Rv1979c [37]), in our two M. pinnipedii strains (del Rv1964-Rv1979c [38]), and also in more recently derived BCG variants (Rv1964-Rv1988, i.e. RD2) [39,40].…”

Section: Convergent Evolution: Impact On Resistancesupporting

confidence: 86%

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

et al. 2020

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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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Section: Convergent Evolution: Impact On Resistancesupporting

confidence: 86%

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

et al. 2020

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“…Similarly, also the closely related human‐adapted M. africanum Lineage six seems to have mostly intact RD5 regions (Fig. ; Brosch et al , ; Brites et al , ; Ates et al , ). Together, these evolutionary observations suggest an advantage for the loss of the ppe38 locus only under specific conditions.…”

Section: Implications Of Pe and Ppe Gene Variation For The Evolution mentioning

confidence: 87%

“…4. Only one out of 18 M. africanum L5 isolates was found to have an RD5-like deletion (Ates et al, 2018a). In a study by Brodin et al three M. microti isolates from humans had an intact RD5-locus, while four strains isolated from voles had RD5-deletions .…”

Section: Implications Of Pe and Ppe Gene Variation For The Evolution mentioning

confidence: 94%

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New insights into the mycobacterial PE and PPE proteins provide a framework for future research

Ates

2019

Molecular Microbiology

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The PE and PPE proteins of Mycobacterium tuberculosis have been studied with great interest since their discovery. Named after the conserved proline (P) and glutamic acid (E) residues in their N-terminal domains, these proteins are postulated to perform wide-ranging roles in virulence and immune modulation. However, technical challenges in studying these proteins and their encoding genes have hampered the elucidation of molecular mechanisms and leave many open questions regarding the biological functions mediated by these proteins. Here, I review the shared and unique characteristics of PE and PPE proteins from a molecular perspective linking this information to their functions in mycobacterial virulence. I discuss how the different subgroups (PE_PGRS, PPE-PPW, PPE-SVP and PPE-MPTR) are defined and why this classification of paramount importance to understand the PE and PPE proteins as individuals and or groups. The goal of this MicroReview is to summarize and structure the existing information on this gene family into a simplified framework of thinking about PE and PPE proteins and genes. Thereby, I hope to provide helpful starting points in studying these genes and proteins for researchers with different backgrounds. This has particular implications for the design and monitoring of novel vaccine candidates and in understanding the evolution of the M. tuberculosis complex.

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“…This convergence largely found in MTB lineages 1, 2, 3 and the MAF lineages, indicates there may be a selective advantage for this. Interestingly, these lineages, compared to MTB L4 strains, have been associated with slower growth and cytokine induction patterns suggestive of immune evasion (8, 14, 65, 83–85, 107, 110, 111).…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomics Shows Differences in the Electron Transport and Carbon Metabolic Pathways ofMycobacterium africanumrelative toMycobacterium tuberculosisand suggests an adaptation to low oxygen tension

Ofori-Anyinam

Riley

Jobarteh

et al. 2019

Preprint

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Pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an 3 adaptation to low oxygen tension 4 5 Summary: 27 The geographically restricted M. africanum lineages (MAF) are primarily found in West Africa, where 28 they account for a significant proportion of tuberculosis. Despite this phenomenon, little is known 29 about the co-evolution of these ancient lineages with West Africans. MAF and M. tuberculosis sensu 30 stricto lineages (MTB) differ in their clinical, in vitro and in vivo characteristics for reasons not fully 31 understood. Therefore, we compared genomes of 289 MAF and 205 MTB clinical isolates from the 32 6 main human-adapted M. tuberculosis complex lineages, for mutations in their Electron Transport 33 Chain and Central Carbon Metabolic pathway in an attempt to explain these metabolic differences. 34 Furthermore, we determined, in silico, whether each mutation could affect the function of genes 35 encoding enzymes in these pathways. 36 We found more potentially deleterious mutations in these pathways in MAF lineages compared to 37 MTB lineages. Additionally, we found that convergent evolution in these pathways occurred 38 between MAF and some MTB lineages. 39 Generally, our findings show further differences between MAF and MTB lineages that may have 40 contributed to the MAF clinical-and growth phenotype and may indicate potential adaptation of 41 MAF lineages to a distinct ecological niche, that we suggest may include areas characterized by low 42 oxygen tension. 43 44 Running title: The M. africanum respiratory chain and carbon metabolic pathway 45 46 Transport, Carbon Metabolism 48 49 50 51 3 1 Introduction 52 The Mycobacterium tuberculosis complex (MTBC) consists of a group of human-adapted ecotypes-53 Mycobacterium tuberculosis sensu stricto, Mycobacterium africanum, Mycobacterium canetti and 54 animal-adapted ecotypes (1-4). There are seven known MTBC lineages (L) associated with particular 55 geographic regions and adapted to specific human populations. These are the five lineages that 56 make up M. tuberculosis sensu stricto (lineages 1-4 and lineage 7) and the two M. africanum lineages 57 (lineages 5 and 6). Africa uniquely has a representation of all seven lineages. 58 MTBC strains from the seven lineages differ on average by about 1200 single nucleotide 59 polymorphisms (5), with clear distinction between MAF and MTB lineages (6-8). 60 MTB Lineages 2 and 4 are more widespread geographically, more pathogenic and more 61 transmissible, while MAF Lineages are exclusively found in West Africa and less transmissible (5, 9, 62 10). Clinically, MTB L4 is relatively more virulent than MAF L6 as evidenced by significantly faster 63 progression, in contacts of infectious cases, to active disease (11). MAF lineages are associated with 64 extrapulmonary disease and MAF L6 more commonly causes disease in immunocompromised 65 persons and those with lower Body Mass Index, implying a more opportunistic pathogen (10, 12). 66 Furthermore, MAF L5 a...

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Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity

Cited by 42 publications

References 92 publications

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

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

New insights into the mycobacterial PE and PPE proteins provide a framework for future research

Comparative Genomics Shows Differences in the Electron Transport and Carbon Metabolic Pathways ofMycobacterium africanumrelative toMycobacterium tuberculosisand suggests an adaptation to low oxygen tension

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