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Volume 9, Issue 9

Borderline mutations transmit at the same rate as common mutations in a tuberculosis cohort in Bangladesh Open Access

Abstract

The spread of multidrug-resistant tuberculosis (MDR-TB) is a growing problem in many countries worldwide. Resistance to one of the primary first-line drugs, rifampicin, is caused by mutations in the gene. So-called borderline mutations confer low-level resistance, in contrast to more common mutations which confer high-level resistance. While some borderline mutations show lower fitness than common mutations, their fitness is currently unknown. We used a dataset of 394 whole genome sequenced MDR-TB isolates from Bangladesh, representing around 44 % of notified MDR-TB cases over 6 years, to look at differences in transmission clustering between isolates with borderline mutations and those with common mutations. We found a relatively low percentage of transmission clustering in the dataset (34.8 %) but no difference in clustering between different types of mutations. Compensatory mutations in and were associated with higher levels of transmission clustering as were lineages two, three, and four relative to lineage one. Young people as well as patients with high sputum smear positive TB were more likely to be in a transmission cluster. Our findings show that although borderline mutations have lower growth potential this does not translate into lower transmission potential or fitness. Proper detection of these mutations is crucial to ensure they do not go unnoticed and spread MDR-TB within communities.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Drug resistance , Mycobacterium , Transmission and tuberculosis
Funding
This study was supported by the:
  • Action Damien
    • Principle Award Recipient: ArmandVan Deun
  • Fonds Wetenschappelijk Onderzoek (Award FWO G0A7720N)
    • Principle Award Recipient: BoukeC. de Jong
  • Academy of Medical Sciences (Award SBF006\1090)
    • Principle Award Recipient: ConorJ. Meehan
© 2023 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2023-09-26
2024-05-03
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References

  1. WHO Global tuberculosis report 2021; 2021 https://www.who.int/publications/i/item/9789240037021
  2. Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 2017S2213-2600(17)30079-6 [View Article] [PubMed]
     [Google Scholar]
  3. Comas I. Genomic epidemiology of tuberculosis. Adv Exp Med Biol 2017; 1019:79–93 [View Article] [PubMed]
     [Google Scholar]
  4. Gagneux S. Ecology and evolution of Mycobacterium tuberculosis. Nat Rev Microbiol 2018; 16:202–213 [View Article] [PubMed]
     [Google Scholar]
  5. Brandis G, Hughes D. Genetic characterization of compensatory evolution in strains carrying rpoB Ser531Leu, the rifampicin resistance mutation most frequently found in clinical isolates. J Antimicrob Chemother 2013; 68:2493–2497 [View Article] [PubMed]
     [Google Scholar]
  6. Comas I, Borrell S, Roetzer A, Rose G, Malla B et al. Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nat Genet 2011; 44:106–110 [View Article] [PubMed]
     [Google Scholar]
  7. Van Deun A, Aung KJM, Bola V, Lebeke R, Hossain MA et al. Rifampin drug resistance tests for tuberculosis: challenging the gold standard. J Clin Microbiol 2013; 51:2633–2640 [View Article] [PubMed]
     [Google Scholar]
  8. Van Deun A, Aung KJM, Hossain A, de Rijk P, Gumusboga M et al. Disputed rpoB mutations can frequently cause important rifampicin resistance among new tuberculosis patients. Int J Tuberc Lung Dis 2015; 19:185–190 [View Article] [PubMed]
     [Google Scholar]
  9. Miotto P, Cabibbe AM, Borroni E, Degano M, Cirillo DM. Role of disputed mutations in the rpoB gene in interpretation of automated liquid MGIT culture results for rifampin susceptibility testing of Mycobacterium tuberculosis. J Clin Microbiol 2018; 56:e01599-17 [View Article] [PubMed]
     [Google Scholar]
  10. Torrea G, Ng KCS, Van Deun A, André E, Kaisergruber J et al. Variable ability of rapid tests to detect Mycobacterium tuberculosis rpoB mutations conferring phenotypically occult rifampicin resistance. Sci Rep 2019; 9:11826 [View Article] [PubMed]
     [Google Scholar]
  11. Makhado NA, Matabane E, Faccin M, Pinçon C, Jouet A et al. Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study. Lancet Infect Dis 2018; 18:1350–1359 [View Article] [PubMed]
     [Google Scholar]
  12. Loiseau C, Brites D, Reinhard M, Zürcher K, Borrell S et al. HIV coinfection is associated with low-fitness rpoB variants in rifampicin-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 2020; 64:10 [View Article] [PubMed]
     [Google Scholar]
  13. Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010; 182:684–692 [View Article] [PubMed]
     [Google Scholar]
  14. Aung KJM, Van Deun A, Declercq E, Sarker MR, Das PK et al. Successful “9-month Bangladesh regimen” for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 2014; 18:1180–1187 [View Article] [PubMed]
     [Google Scholar]
  15. WHO Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance; 2021 https://www.who.int/publications/i/item/9789240028173
  16. Lempens P, Decroo T, Aung KJM, Hossain MA, Rigouts L et al. Initial resistance to companion drugs should not be considered an exclusion criterion for the shorter multidrug-resistant tuberculosis treatment regimen. Int J Infect Dis 2020; 100:357–365 [View Article] [PubMed]
     [Google Scholar]
  17. Lempens P, Meehan CJ, Vandelannoote K, Fissette K, de Rijk P et al. Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations. Sci Rep 2018; 8:3246 [View Article] [PubMed]
     [Google Scholar]
  18. Starks AM, Avilés E, Cirillo DM, Denkinger CM, Dolinger DL et al. Collaborative effort for a centralized worldwide tuberculosis relational sequencing data platform. Clin Infect Dis 2015; 61Suppl 3:S141–6 [View Article] [PubMed]
     [Google Scholar]
  19. Kim D, Song L, Breitwieser FP, Salzberg SL. Centrifuge: rapid and sensitive classification of metagenomic sequences. Genome Res 2016; 26:1721–1729 [View Article] [PubMed]
     [Google Scholar]
  20. Kohl TA, Utpatel C, Schleusener V, De Filippo MR, Beckert P et al. MTBseq: a comprehensive pipeline for whole genome sequence analysis of Mycobacterium tuberculosis complex isolates. PeerJ 2018; 6:e5895 [View Article] [PubMed]
     [Google Scholar]
  21. Coll F, McNerney R, Preston MD, Guerra-Assunção JA, Warry A et al. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences. Genome Med 2015; 7:51 [View Article] [PubMed]
     [Google Scholar]
  22. Phelan JE, O’Sullivan DM, Machado D, Ramos J, Oppong YEA et al. Integrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugs. Genome Med 2019; 11:41 [View Article] [PubMed]
     [Google Scholar]
  23. Meehan CJ, Moris P, Kohl TA, Pečerska J, Akter S et al. The relationship between transmission time and clustering methods in Mycobacterium tuberculosis epidemiology. EBioMedicine 2018; 37:410–416 [View Article] [PubMed]
     [Google Scholar]
  24. Oostvogels S, Ley SD, Heupink TH, Dippenaar A, Streicher EM et al. Transmission, distribution and drug resistance-conferring mutations of extensively drug-resistant tuberculosis in the Western Cape Province, South Africa. Microb Genom 2022; 8:000815 [View Article] [PubMed]
     [Google Scholar]
  25. Gagneux S. Fitness cost of drug resistance in Mycobacterium tuberculosis. Clin Microbiol Infect 2009; 15 Suppl 1:66–68 [View Article] [PubMed]
     [Google Scholar]
  26. Gygli SM, Loiseau C, Jugheli L, Adamia N, Trauner A et al. Prisons as ecological drivers of fitness-compensated multidrug-resistant Mycobacterium tuberculosis. Nat Med 2021; 27:1171–1177 [View Article] [PubMed]
     [Google Scholar]
  27. R Core Team R: A language and environment for statistical computing. R Foundation for Statistical Computing: Vienna, Austria; 2020
  28. Salvato RS, Reis AJ, Schiefelbein SH, Gómez MAA, Salvato SS et al. Genomic-based surveillance reveals high ongoing transmission of multi-drug-resistant Mycobacterium tuberculosis in Southern Brazil. Int J Antimicrob Agents 2021; 58:106401 [View Article] [PubMed]
     [Google Scholar]
  29. Borrell S, Gagneux S. Infectiousness, reproductive fitness and evolution of drug-resistant Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2009; 13:1456–1466 [PubMed]
     [Google Scholar]
  30. Rahman SMM, Rahman A, Nasrin R, Ather MF, Ferdous SS et al. Molecular epidemiology and genetic diversity of multidrug-resistant Mycobacterium tuberculosis isolates in Bangladesh. Microbiol Spectr 2022; 10:e0184821 [View Article] [PubMed]
     [Google Scholar]
  31. Bouzouita I, Cabibbe AM, Trovato A, Daroui H, Ghariani A et al. Whole-genome sequencing of drug-resistant Mycobacterium tuberculosis strains, Tunisia, 2012-2016. Emerg Infect Dis 2019; 25:538–546 [View Article] [PubMed]
     [Google Scholar]
  32. Al-Ghafli H, Kohl TA, Merker M, Varghese B, Halees A et al. Drug-resistance profiling and transmission dynamics of multidrug-resistant Mycobacterium tuberculosis in Saudi Arabia revealed by whole genome sequencing. Infect Drug Resist 2018; 11:2219–2229 [View Article] [PubMed]
     [Google Scholar]
  33. Jiang Q, Liu Q, Ji L, Li J, Zeng Y et al. Citywide transmission of multidrug-resistant tuberculosis under China’s rapid urbanization: a retrospective population-based genomic spatial epidemiological study. Clin Infect Dis 2020; 71:142–151 [View Article] [PubMed]
     [Google Scholar]
  34. Yang C, Luo T, Shen X, Wu J, Gan M et al. Transmission of multidrug-resistant Mycobacterium tuberculosis in Shanghai, China: a retrospective observational study using whole-genome sequencing and epidemiological investigation. Lancet Infect Dis 2017; 17:275–284 [View Article] [PubMed]
     [Google Scholar]
  35. Gagneux S. Host-pathogen coevolution in human tuberculosis. Philos Trans R Soc Lond B Biol Sci 2012; 367:850–859 [View Article] [PubMed]
     [Google Scholar]
  36. Correa-Macedo W, Cambri G, Schurr E. The interplay of human and Mycobacterium tuberculosis genomic variability. Front Genet 2019; 10:865 [View Article] [PubMed]
     [Google Scholar]
  37. Cardona P-J, Català M, Prats C. The origin and maintenance of tuberculosis is explained by the induction of smear-negative disease in the paleolithic. Pathogens 2022; 11:366 [View Article] [PubMed]
     [Google Scholar]
  38. Coscolla M, Gagneux S. Consequences of genomic diversity in Mycobacterium tuberculosis. Semin Immunol 2014; 26:431–444 [View Article] [PubMed]
     [Google Scholar]
  39. Walker TM, Choisy M, Dedicoat M, Drennan PG, Wyllie D et al. Mycobacterium tuberculosis transmission in Birmingham, UK, 2009-19: An observational study. Lancet Reg Health Eur 2022; 17:100361 [View Article] [PubMed]
     [Google Scholar]
  40. Menardo F, Duchêne S, Brites D, Gagneux S. The molecular clock of Mycobacterium tuberculosis. PLOS Pathog 2019; 15:e1008067 [View Article] [PubMed]
     [Google Scholar]
  41. Ford CB, Shah RR, Maeda MK, Gagneux S, Murray MB et al. Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat Genet 2013; 45:784–790 [View Article] [PubMed]
     [Google Scholar]
  42. Bank W. Bangladesh Social Protection Public Expenditure Review (PER); 2021 https://documents1.worldbank.org/curated/en/829251631088806963/pdf/BangladeshSocial-Protection-Public-Expenditure-Review.pdf
  43. Lönnroth K, Jaramillo E, Williams BG, Dye C, Raviglione M. Drivers of tuberculosis epidemics: the role of risk factors and social determinants. Soc Sci Med 2009; 68:2240–2246 [View Article] [PubMed]
     [Google Scholar]
  44. Loiseau C, Windels EM, Gygli SM, Jugheli L, Maghradze N et al. The relative transmission fitness of multidrug-resistant Mycobacterium tuberculosis in a drug resistance hotspot. Nat Commun 2023; 14:1988 [View Article] [PubMed]
     [Google Scholar]
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Borderline rpoB mutations transmit at the same rate as common rpoB mutations in a tuberculosis cohort in Bangladesh
M Gen 9, 001109 (2023); https://doi.org/10.1099/mgen.0.001109
/content/journal/mgen/10.1099/mgen.0.001109
/content/journal/mgen/10.1099/mgen.0.001109
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