Genetic diversity within diagnostic sputum samples is mirrored in the culture of Mycobacterium tuberculosis across different settings

Carla Mariner-Llicer, Galo A. Goig, Manuela Torres-Puente, Sergo Vashakidze, Luis M. Villamayor, Belén Saavedra-Cervera, Edson Mambuque, Iza Khurtsilava, Zaza Avaliani, Alex Rosenthal, Andrei Gabrielian, Marika Shurgaia, Natalia Shubladze, Alberto L. García-Basteiro, Mariana G. López () and Iñaki Comas ()
Additional contact information
Carla Mariner-Llicer: CSIC
Galo A. Goig: University of Basel
Manuela Torres-Puente: CSIC
Sergo Vashakidze: National Center for Tuberculosis and Lung Diseases
Luis M. Villamayor: Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
Belén Saavedra-Cervera: Universitat de Barcelona
Edson Mambuque: Centro de Investigação em Saúde de Manhiça (CISM)
Iza Khurtsilava: National Center for Tuberculosis and Lung Diseases
Zaza Avaliani: National Center for Tuberculosis and Lung Diseases
Alex Rosenthal: National Institute of Allergy and Infectious Diseases
Andrei Gabrielian: National Institute of Allergy and Infectious Diseases
Marika Shurgaia: National Center for Tuberculosis and Lung Diseases
Natalia Shubladze: National Center for Tuberculosis and Lung Diseases
Alberto L. García-Basteiro: Universitat de Barcelona
Mariana G. López: CSIC
Iñaki Comas: CSIC

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Culturing and genomic sequencing of Mycobacterium tuberculosis (MTB) from tuberculosis (TB) cases is the basis for many research and clinical applications. The alternative, culture-free sequencing from diagnostic samples, is promising but poses challenges to obtain and analyse the MTB genome. Paradoxically, culture is assumed to impose a diversity bottleneck, which, if true, would entail unexplored consequences. To unravel this paradox we generate high-quality genomes of sputum-culture pairs from two different settings after developing a workflow for sequencing from sputum and a tailored bioinformatics analysis. Careful downstream comparisons reveal sources of sputum-culture incongruences due to false positive/negative variation associated with factors like low input MTB DNA or variable genomic depths. After accounting for these factors, contrary to the bottleneck dogma, we identify a 97% variant agreement within sputum-culture pairs, with a high correlation also in the variants’ frequency (0.98). The combined analysis from five different settings and more than 100 available samples shows that our results can be extrapolated to different TB epidemic scenarios, demonstrating that for the cases tested culture accurately mirrors clinical samples.

Date: 2024
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DOI: 10.1038/s41467-024-51266-0

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