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Front. Microbiol. | doi: 10.3389/fmicb.2017.02296

Influence of stress and antibiotic resistance on cell length distribution in Mycobacterium tuberculosis clinical isolates

 Vijay Srinivasan1, 2,  Dao N. Vinh1, Hoang T. Hai1, Vu T. Ha1, Vu T. Dung1, Tran D. Dinh1,  Hoang N. Nhung1,  Trinh T. Tram1, Bree Aldridge3, 4, 5, Nguyen T. Hanh1, Do D. Thu1, Nguyen H. Phu6, Guy Thwaites1, 2 and  Nguyen T. Thuong Thuong1, 2*
  • 1Oxford University Clinical Research Unit in Vietnam (OUCRU), Vietnam
  • 2University of Oxford, United Kingdom
  • 3Tufts University School of Medicine, United States
  • 4School of Engineering, Tufts University, United States
  • 5Harvard Medical School, Harvard University, United States
  • 6Hospital for Tropical Diseases (HTD), Vietnam

Mycobacterial cellular variations in growth and division increase heterogeneity in cell length, possibly contributing to cell-to-cell variation in host and antibiotic stress tolerance. This may be one of the factors influencing Mycobacterium tuberculosis persistence to antibiotics. Tuberculosis is a major public health problem in developing countries, antibiotic persistence and emergence of antibiotic resistance further complicates this problem. We wanted to investigate the factors influencing cell length distribution in clinical M. tuberculosis strains. In parallel we examined M. tuberculosis cell length distribution in a large set of clinical strains (n = 158) from ex-vivo sputum samples, in-vitro macrophage models, and in-vitro cultures. Our aim was to understand the influence of clinically relevant factors such as host stresses, M. tuberculosis lineages, antibiotic resistance, antibiotic concentrations and disease severity on the cell size distribution in clinical M. tuberculosis strains. Increased cell size and cell-to-cell variation in cell length were associated with bacteria in sputum and infected macrophages rather than liquid culture. Multidrug resistant (MDR) strains displayed increased cell length heterogeneity compared to sensitive strains in infected macrophages and also during growth under rifampicin treatment. Importantly, increased cell length was also associated with pulmonary tuberculosis disease severity. Supporting these findings, individual host stresses, such as oxidative stress and iron deficiency, increased cell length heterogeneity of M. tuberculosis strains. In addition we also observed synergism between host stress and rifampicin treatment in increasing cell length in MDR-TB strains. This study has identified the important clinical factors contributing to cell length heterogeneity in clinical M. tuberculosis strains. The role of these cellular adaptations to host and antibiotic tolerance needs further investigation.

Keywords: Mycobacterium tuberculosis, cell length variation, macrophage infection, Sputum, multi drug resistance, Oxidative Stress, rifampicin, iron deficiency

Received: 28 Aug 2017; Accepted: 07 Nov 2017.

Edited by:

Frank Schreiber, Bundesanstalt für Materialforschung und prüfung (BAM), Germany

Reviewed by:

Giulia MANINA, Institut Pasteur, France
Hesper Rego, Yale School of Medicine, Yale University, United States  

Copyright: © 2017 Srinivasan, Vinh, Hai, Ha, Dung, Dinh, Nhung, Tram, Aldridge, Hanh, Thu, Phu, Thwaites and Thuong Thuong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Nguyen T. Thuong Thuong, Oxford University Clinical Research Unit in Vietnam (OUCRU), Ho Chi Minh City, Vietnam,