High-throughput cytological profiling uncovers genotype-phenotype associations in <i>Mycobacterium tuberculosis</i> clinical isolates
Understanding how genetic variation in <i>Mycobacterium tuberculosis</i> (Mtb) shapes its physical traits is essential to unraveling the evolution of this global pathogen. Here, we introduce a systematically optimized, high-throughput imaging platform for the comprehensive characterization of Mtb clinical strains. We demonstrate that Mtb's phenotypic manifestation is shaped by both genetic background and culture density. By accounting for these factors, our analysis linked distinct cellular dynamics to specific lineages, sublineages, and even single nucleotide variations. Notably, we linked a recurring mutation to a unique cell-shortening phenotype, finding that it potentially acts by creating a cryptic antisense transcript. This platform provides a powerful framework for systematically dissecting the physiological dynamics underlying Mtb evolution and identifying new therapeutic vulnerabilities of this deadly pathogen.
Authors
- Yi Xiao (ORCID: https://orcid.org/0000-0002-9556-8074)
- Peter H. Culviner (ORCID: https://orcid.org/0000-0003-0605-5849)
- Eric J. Rubin (ORCID: https://orcid.org/0000-0001-5120-962X)
- Ian D. Wolf (ORCID: https://orcid.org/0000-0002-2455-6148)
- Yue J. Liu (ORCID: https://orcid.org/0000-0002-7785-857X)
- Guiming Zhang (ORCID: https://orcid.org/0000-0001-7064-2138)
- Junhao Zhu (ORCID: https://orcid.org/0000-0002-3301-5677)
- K. M. Chen
- Shoko Wakabayashi
- Yiwang Chen (ORCID: https://orcid.org/0000-0003-4709-7623)
- Mingyu Gan (ORCID: https://orcid.org/0009-0008-4405-092X)
- Sarah M. Fortune (ORCID: https://orcid.org/0000-0001-7565-9975)
- Nicole C. Howard (ORCID: https://orcid.org/0000-0003-0805-5914)
- Xin Wang (ORCID: https://orcid.org/0000-0002-2968-3082)
- Qingyun Liu (ORCID: https://orcid.org/0000-0002-2284-5050)
- Ruiyuan Liu (ORCID: https://orcid.org/0000-0003-4807-4909)
- Rong Sun (ORCID: https://orcid.org/0009-0008-4644-0729)
Institutions
- University of North Carolina at Chapel Hill (US)
- Shanghai Medical College of Fudan University (CN)
- Harvard University (US)
- Chinese Academy of Sciences (CN)
- Institute of Microbiology (BY)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- Institute of Microbiology (CN)
Publication Details
- Journal
- mSystems
- Published
- 2025-10-09
- DOI
- https://doi.org/10.1128/msystems.00972-25
- Primary Topic
- Mycobacterium research and diagnosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00