Genomic analyses of Mycobacterium tuberculosis from human lung resections reveal a high frequency of polyclonal infections

Miguel Moreno-Molina, Natalia Shubladze, Iza Khurtsilava, Zaza Avaliani, Nino Bablishvili, Manuela Torres-Puente, Luis Villamayor, Andrei Gabrielian, Alex Rosenthal, Cristina Vilaplana, Sebastien Gagneux, Russell R. Kempker, Sergo Vashakidze and Iñaki Comas ()
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Miguel Moreno-Molina: Instituto de Biomedicina de Valencia IBV-CSIC
Natalia Shubladze: National Center for Tuberculosis and Lung Diseases of Georgia
Iza Khurtsilava: National Center for Tuberculosis and Lung Diseases of Georgia
Zaza Avaliani: National Center for Tuberculosis and Lung Diseases of Georgia
Nino Bablishvili: National Center for Tuberculosis and Lung Diseases of Georgia
Manuela Torres-Puente: Instituto de Biomedicina de Valencia IBV-CSIC
Luis Villamayor: FISABIO Public Health
Andrei Gabrielian: National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services
Alex Rosenthal: National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services
Cristina Vilaplana: Fundació Institut Germans Trias i Pujol (IGTP)
Sebastien Gagneux: Swiss Tropical and Public Health Institute
Russell R. Kempker: Emory University School of Medicine
Sergo Vashakidze: National Center for Tuberculosis and Lung Diseases of Georgia
Iñaki Comas: Instituto de Biomedicina de Valencia IBV-CSIC

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Polyclonal infections occur when at least two unrelated strains of the same pathogen are detected in an individual. This has been linked to worse clinical outcomes in tuberculosis, as undetected strains with different antibiotic resistance profiles can lead to treatment failure. Here, we examine the amount of polyclonal infections in sputum and surgical resections from patients with tuberculosis in the country of Georgia. For this purpose, we sequence and analyse the genomes of Mycobacterium tuberculosis isolated from the samples, acquired through an observational clinical study (NCT02715271). Access to the lung enhanced the detection of multiple strains (40% of surgery cases) as opposed to just using a sputum sample (0–5% in the general population). We show that polyclonal infections often involve genetically distant strains and can be associated with reversion of the patient’s drug susceptibility profile over time. In addition, we find different patterns of genetic diversity within lesions and across patients, including mutational signatures known to be associated with oxidative damage; this suggests that reactive oxygen species may be acting as a selective pressure in the granuloma environment. Our results support the idea that the magnitude of polyclonal infections in high-burden tuberculosis settings is underestimated when only testing sputum samples.

Date: 2021
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DOI: 10.1038/s41467-021-22705-z

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