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Transmission and drug resistance surveillance by whole-genome sequencing in a population-based cohort in Southern Mexico

F J Martínez-Martínez(1) P Cano-Jiménez(1) V Furió(1,2) M Torres-Puente(1) G Delgado-Sánchez(3) L Ferreyra-Reyes(3) E Ferreira-Guerrero(3) M Bobabilla del Valle(4) A Ordaz(4) N Mongua-Rodríguez(3) N Tellez(3) S Canizales-Quintero(3) J Sifuentes-Osornio(4) L García-García(3) I Comas(1,5) M G López(1)

1:Instituto de Biomedicina de Valencia (IBV-CSIC); 2:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO-CSISP); 3:Instituto Nacional de Salud Pública (INSP); 4:Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ); 5:Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP)

In contrast to global rates, tuberculosis in Mexico (25 cases/100,000) has increased since 2005. A population-based study was conducted in Southern Mexico during 1995-2010, including 1,018 sputum samples from 903 patients. Available data include: phenotypic drug-susceptibility testing (DST) using BACTEC for first-line antibiotics; molecular genotyping and clustering by MIRU-VNTR, and  IS6110 RFLP/Spoligotyping. 

Whole-genome sequencing (WGS) of this cohort using short-read Illumina technology is currently ongoing. A partial comprehensive genomic epidemiology study was conducted in 396 Mycobacterium tuberculosis complex clinical isolates. We performed: lineage typing by using phylogenetic SNPs; transmission investigation by SNP cut-off-based clustering method, and prediction of drug-susceptibility profiles by evaluating the mutations reported in the WHO Catalogue. Results from WGS were compared with molecular clustering and phenotypic DST. 

Analysis of the mycobacterial population structure revealed predominance of lineage 4 strains, particularly L4.1 (53%). Clustering was 47.5% (60 clusters) for 12 SNPs distance cut-off, ranging between 11.1-51.0% (0-15 SNPs); 47.2% for MIRU-VNTR (60 clusters, 20 of which were identical to WGS clusters); and 41.9% for RFLP/Spoligotyping (43 clusters). Mutations associated with resistance to isoniazid (INH) and rifampicin (RIF) were found in 12.6% and 5.5% of the isolates, respectively. Ten isolates (2.5%) were classified as MDR, most of them (8/10) in retreated cases.The specificity of WGS-based DST for INH and RIF was greater than 99%, while sensitivity was between 81-86%. WGS could improve tuberculosis control in Mexico by providing an in-depth understanding of transmission.

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