Mycobacterium tuberculosis clinical isolates carry mutational signatures of host immune environments

9 páginas, 4 figuras. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. Sequencing reads have been submitted to the European Nucleotide Archive (EMBL-EBI) under study accession PRJEB34582 and PRJEB34609. The analysis scripts used in this study are available online at GitHub (https://github.com/StopTB/Single_Colony_Project).Mycobacterium tuberculosis (Mtb) infection results in a spectrum of clinical and histopathologic manifestations. It has been proposed that the environmental and immune pressures associated with different contexts of infection have different consequences for the associated bacterial populations, affecting drug susceptibility and the emergence of resistance. However, there is little concrete evidence for this model. We prospectively collected sputum samples from 18 newly diagnosed and treatment-naïve patients with tuberculosis and sequenced 795 colony-derived Mtb isolates. Mutant accumulation rates varied considerably between different bacilli isolated from the same individual, and where high rates of mutation were observed, the mutational spectrum was consistent with reactive oxygen species-induced mutagenesis. Elevated bacterial mutation rates were identified in isolates from HIV-negative but not HIV-positive individuals, suggesting that they were immune-driven. These results support the model that mutagenesis of Mtb in vivo is modulated by the host environment, which could drive the emergence of variants associated with drug resistance in a host-dependent manner.This work was supported by the National Natural Science Foundation of China (91631301 and 81661128043 to Q.G., 81701975 to Q.L., and 31771416 to X.L.), the National Science and Technology Major Project of China (2017ZX10201302 to Q.G. and 2018ZX10714002-001-005 to Z.Z.), the Sanming Project of Medicine in Shenzhen (SZSM201611030 to Q.G.), European Research Council 638553-TB-AcCELERATE (to I.C.), the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-220-1 to X.L.), and the CAS Light of West China Program (to X.L.). Y.F. is supported in part by NIH R01HG009524. Support was also received from NIH awards P01 AI132130 and AI142793 to S.M.F.Peer reviewe