Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response
It is uncertain whether differences in Mycobacterium tuberculosis (Mtb) virulence defined in vitro influence clinical tuberculosis pathogenesis, transmission, and mortality. We primarily used a macrophage lysis model to characterize the virulence of Mtb isolates collected from 153 Vietnamese adults...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcimb.2018.00417/full |
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| author | Trinh T. B. Tram Hoang N. Nhung Srinivasan Vijay Srinivasan Vijay Hoang T. Hai Do D. A. Thu Vu T. N. Ha Tran D. Dinh Philip M. Ashton Philip M. Ashton Nguyen T. Hanh Nguyen H. Phu Guy E. Thwaites Guy E. Thwaites Nguyen T. T. Thuong |
| author_facet | Trinh T. B. Tram Hoang N. Nhung Srinivasan Vijay Srinivasan Vijay Hoang T. Hai Do D. A. Thu Vu T. N. Ha Tran D. Dinh Philip M. Ashton Philip M. Ashton Nguyen T. Hanh Nguyen H. Phu Guy E. Thwaites Guy E. Thwaites Nguyen T. T. Thuong |
| author_sort | Trinh T. B. Tram |
| collection | DOAJ |
| description | It is uncertain whether differences in Mycobacterium tuberculosis (Mtb) virulence defined in vitro influence clinical tuberculosis pathogenesis, transmission, and mortality. We primarily used a macrophage lysis model to characterize the virulence of Mtb isolates collected from 153 Vietnamese adults with pulmonary tuberculosis. The virulence phenotypes were then investigated for their relationship with sputum bacterial load, bacterial lineages, bacterial growth, and cytokine responses in macrophages. Over 6 days of infection, 34 isolates (22.2%) showed low virulence (< 5% macrophages lysed), 46 isolates (30.1%) showed high virulence (≥90% lysis of macrophages), and 73 isolates (47.7%) were of intermediate virulence (5–90% macrophages lysed). Highly virulent isolates were associated with an increased bacterial load in patients' sputum before anti-tuberculosis therapy (P = 0.02). Isolate-dependent virulence phenotype was consistent in both THP-1 and human monocyte-derived macrophages. High virulence isolates survived better and replicated in macrophages one hundred fold faster than those with low virulence. Macrophages infected with high virulence isolates produced lower concentrations of TNF-α and IL-6 (P = 0.002 and 0.0005, respectively), but higher concentration of IL-1β (P = 5.1 × 10−5) compared to those infected with low virulence isolates. High virulence was strongly associated with East Asian/Beijing lineage [P = 0.002, Odd ratio (OR) = 4.32, 95% confident intervals (CI) 1.68–11.13]. The association between virulence phenotypes, bacterial growth, and proinflammatory cytokines in macrophages suggest the suppression of certain proinflammatory cytokines (TNF-α and IL-6) but not IL-1β allows better intracellular survival of highly virulent Mtb. This could result in rapid macrophage lysis and higher bacterial load in sputum of patients infected with high virulence isolates, which may contribute to the pathogenesis and success of the Beijing lineage. |
| first_indexed | 2024-12-22T21:21:02Z |
| format | Article |
| id | doaj.art-18fbb6cf8fbc415186c7c6748f21dbb1 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-22T21:21:02Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-18fbb6cf8fbc415186c7c6748f21dbb12022-12-21T18:12:12ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882018-11-01810.3389/fcimb.2018.00417422142Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine ResponseTrinh T. B. Tram0Hoang N. Nhung1Srinivasan Vijay2Srinivasan Vijay3Hoang T. Hai4Do D. A. Thu5Vu T. N. Ha6Tran D. Dinh7Philip M. Ashton8Philip M. Ashton9Nguyen T. Hanh10Nguyen H. Phu11Guy E. Thwaites12Guy E. Thwaites13Nguyen T. T. Thuong14Oxford University Clinical Research Unit, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Ho Chi Minh City, VietnamNuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United KingdomOxford University Clinical Research Unit, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Ho Chi Minh City, VietnamNuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United KingdomOxford University Clinical Research Unit, Ho Chi Minh City, VietnamHospital for Tropical Diseases, Ho Chi Minh City, VietnamOxford University Clinical Research Unit, Ho Chi Minh City, VietnamNuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United KingdomOxford University Clinical Research Unit, Ho Chi Minh City, VietnamIt is uncertain whether differences in Mycobacterium tuberculosis (Mtb) virulence defined in vitro influence clinical tuberculosis pathogenesis, transmission, and mortality. We primarily used a macrophage lysis model to characterize the virulence of Mtb isolates collected from 153 Vietnamese adults with pulmonary tuberculosis. The virulence phenotypes were then investigated for their relationship with sputum bacterial load, bacterial lineages, bacterial growth, and cytokine responses in macrophages. Over 6 days of infection, 34 isolates (22.2%) showed low virulence (< 5% macrophages lysed), 46 isolates (30.1%) showed high virulence (≥90% lysis of macrophages), and 73 isolates (47.7%) were of intermediate virulence (5–90% macrophages lysed). Highly virulent isolates were associated with an increased bacterial load in patients' sputum before anti-tuberculosis therapy (P = 0.02). Isolate-dependent virulence phenotype was consistent in both THP-1 and human monocyte-derived macrophages. High virulence isolates survived better and replicated in macrophages one hundred fold faster than those with low virulence. Macrophages infected with high virulence isolates produced lower concentrations of TNF-α and IL-6 (P = 0.002 and 0.0005, respectively), but higher concentration of IL-1β (P = 5.1 × 10−5) compared to those infected with low virulence isolates. High virulence was strongly associated with East Asian/Beijing lineage [P = 0.002, Odd ratio (OR) = 4.32, 95% confident intervals (CI) 1.68–11.13]. The association between virulence phenotypes, bacterial growth, and proinflammatory cytokines in macrophages suggest the suppression of certain proinflammatory cytokines (TNF-α and IL-6) but not IL-1β allows better intracellular survival of highly virulent Mtb. This could result in rapid macrophage lysis and higher bacterial load in sputum of patients infected with high virulence isolates, which may contribute to the pathogenesis and success of the Beijing lineage.https://www.frontiersin.org/article/10.3389/fcimb.2018.00417/fullMycobacterium tuberculosisclinical isolatesvirulencesputumbacterial growthcytokine response |
| spellingShingle | Trinh T. B. Tram Hoang N. Nhung Srinivasan Vijay Srinivasan Vijay Hoang T. Hai Do D. A. Thu Vu T. N. Ha Tran D. Dinh Philip M. Ashton Philip M. Ashton Nguyen T. Hanh Nguyen H. Phu Guy E. Thwaites Guy E. Thwaites Nguyen T. T. Thuong Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response Frontiers in Cellular and Infection Microbiology Mycobacterium tuberculosis clinical isolates virulence sputum bacterial growth cytokine response |
| title | Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response |
| title_full | Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response |
| title_fullStr | Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response |
| title_full_unstemmed | Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response |
| title_short | Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response |
| title_sort | virulence of mycobacterium tuberculosis clinical isolates is associated with sputum pre treatment bacterial load lineage survival in macrophages and cytokine response |
| topic | Mycobacterium tuberculosis clinical isolates virulence sputum bacterial growth cytokine response |
| url | https://www.frontiersin.org/article/10.3389/fcimb.2018.00417/full |
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