Brown C D, Lee B M, Liu H, Wu A, Tellez A, Zou H, Singh P, Saito K, Mishra S, Brown M, Saleh A, Odjourian N, Cristaldo M, Gan M, Liu Q, Gengenbacher M, Darst S, Campbell E, Nathan C, Rhee K Y
Weill Cornell Medical College, Department of Medicine, Division of Infectious Diseases; New York, NY 10065, United States.
Cornell University Meinig School of Biomedical Engineering, Ithaca, NY 14853, United States.
bioRxiv. 2025 Jun 4:2025.06.04.657859. doi: 10.1101/2025.06.04.657859.
(Mtb) is an obligate human pathogen that depends on its ability to spread from host-to-host to survive as a species. Yet, knowledge of transmission-specific traits remains lacking. Here, we report the discovery of a specific adaptive response to desiccation, a stress intrinsically linked to the generation of the aerosol droplets within which Mtb transmits. We show that desiccation inflicts oxidative damage and activates Mtb's DNA repair responses but that this repair is imperfect and results in mutations. We further show that activation of these DNA repair responses is accompanied by increased expression of the transcription-coupled repair factor, , but that this expression serves to buffer the fitness cost of specific resistance-conferring mutations in , the target of the frontline drug rifampin, rather than to facilitate transcription-coupled DNA repair. Silencing during aerosolization impairs survival of strains harboring the rifampin resistance allele S450L. This function is further supported by whole genome sequence data from over 50,000 clinically circulating strains. These studies indicate that Mtb has evolved transmission-specific stress responses that have enabled it to leverage desiccation-induced DNA damage as a potential source of genetic diversification and drug resistance.
结核分枝杆菌（Mtb）是一种专性人类病原体，其作为一个物种的生存依赖于它在宿主间传播的能力。然而，对于特定传播特性的了解仍然不足。在此，我们报告发现了一种对干燥的特异性适应性反应，干燥是一种与Mtb传播所依赖的气溶胶飞沫产生内在相关的应激。我们表明，干燥会造成氧化损伤并激活Mtb的DNA修复反应，但这种修复并不完美并导致突变。我们进一步表明，这些DNA修复反应的激活伴随着转录偶联修复因子的表达增加，但这种表达是为了缓冲一线药物利福平的靶标中特定赋予抗性的突变所带来的适应性代价，而非促进转录偶联的DNA修复。雾化过程中沉默该因子会损害携带利福平抗性等位基因S450L的菌株的存活。来自超过50000株临床流行菌株的全基因组序列数据进一步支持了这一功能。这些研究表明，Mtb已经进化出特定传播应激反应，使其能够利用干燥诱导的DNA损伤作为遗传多样化和耐药性的潜在来源。
