Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance–conferring mutations
IntroductionIt is assumed that host defense systems eliminating the pathogen and regulating tissue damage make a strong impact on the outcome of tuberculosis (TB) disease and that these processes are affected by rifampicin (RIF) resistance–conferring mutations of Mycobacterium tuberculosis (Mtb). Ho...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1187390/full |
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| author | Nguyen Thi Le Hang Minako Hijikata Shinji Maeda Pham Huu Thuong Hoang Van Huan Nguyen Phuong Hoang Do Bang Tam Pham Thu Anh Nguyen Thu Huyen Nguyen Thu Huyen Vu Cao Cuong Nobuyuki Kobayashi Keiko Wakabayashi Akiko Miyabayashi Shintaro Seto Naoto Keicho Naoto Keicho |
| author_facet | Nguyen Thi Le Hang Minako Hijikata Shinji Maeda Pham Huu Thuong Hoang Van Huan Nguyen Phuong Hoang Do Bang Tam Pham Thu Anh Nguyen Thu Huyen Nguyen Thu Huyen Vu Cao Cuong Nobuyuki Kobayashi Keiko Wakabayashi Akiko Miyabayashi Shintaro Seto Naoto Keicho Naoto Keicho |
| author_sort | Nguyen Thi Le Hang |
| collection | DOAJ |
| description | IntroductionIt is assumed that host defense systems eliminating the pathogen and regulating tissue damage make a strong impact on the outcome of tuberculosis (TB) disease and that these processes are affected by rifampicin (RIF) resistance–conferring mutations of Mycobacterium tuberculosis (Mtb). However, the host responses to the pathogen harboring different mutations have not been studied comprehensively in clinical settings. We analyzed clinico-epidemiological factors and blood transcriptomic signatures associated with major rpoB mutations conferring RIF resistance in a cohort study.MethodsDemographic data were collected from 295 active pulmonary TB patients with treatment history in Hanoi, Vietnam. When recruited, drug resistance–conferring mutations and lineage-specific variations were identified using whole-genome sequencing of clinical Mtb isolates. Before starting retreatment, total RNA was extracted from the whole blood of HIV-negative patients infected with Mtb that carried either the rpoB H445Y or rpoB S450L mutation, and the total RNA was subjected to RNA sequencing after age-gender matching. The individual RNA expression levels in the blood sample set were also measured using real-time RT-PCR. Logistic and linear regression models were used to assess possible associations.ResultsIn our cohort, rpoB S450L and rpoB H445Y were major RIF resistance–conferring mutations [32/87 (36.8%) and 15/87 (17.2%), respectively]. H445Y was enriched in the ancient Beijing genotype and was associated with nonsynonymous mutations of Rv1830 that has been reported to regulate antibiotic resilience. H445Y was also more frequently observed in genetically clustered strains and in samples from patients who had received more than one TB treatment episode. According to the RNA sequencing, gene sets involved in the interferon-γ and-α pathways were downregulated in H445Y compared with S450L. The qRT-PCR analysis also confirmed the low expression levels of interferon-inducible genes, including BATF2 and SERPING1, in the H445Y group, particularly in patients with extensive lesions on chest X-ray.DiscussionOur study results showed that rpoB mutations as well as Mtb sublineage with additional genetic variants may have significant effects on host response. These findings strengthen the rationale for investigation of host-pathogen interactions to develop countermeasures against epidemics of drug-resistant TB. |
| first_indexed | 2024-03-13T01:27:04Z |
| format | Article |
| id | doaj.art-5569fcbe0edb44bc84f7f724902feaf3 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-03-13T01:27:04Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-5569fcbe0edb44bc84f7f724902feaf32023-07-04T13:59:00ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2023-07-011410.3389/fmicb.2023.11873901187390Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance–conferring mutationsNguyen Thi Le Hang0Minako Hijikata1Shinji Maeda2Pham Huu Thuong3Hoang Van Huan4Nguyen Phuong Hoang5Do Bang Tam6Pham Thu Anh7Nguyen Thu Huyen8Nguyen Thu Huyen9Vu Cao Cuong10Nobuyuki Kobayashi11Keiko Wakabayashi12Akiko Miyabayashi13Shintaro Seto14Naoto Keicho15Naoto Keicho16NCGM-BMH Medical Collaboration Center, Hanoi, VietnamDepartment of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, JATA, Tokyo, JapanFaculty of Pharmaceutical Sciences, Hokkaido University of Science, Sapporo, Hokkaido, JapanMy Duc District General Hospital, Hanoi, VietnamHanoi Lung Hospital, Hanoi, VietnamDepartment of Microbiology, Hanoi Lung Hospital, Hanoi, VietnamDepartment of Biochemistry, Hematology and Blood Transfusion, Hanoi Lung Hospital, Hanoi, VietnamTuberculosis Network Management Office, Hanoi Lung Hospital, Hanoi, VietnamNCGM-BMH Medical Collaboration Center, Hanoi, VietnamDepartment of Health Policy and Economics, Hanoi University of Public Health, Hanoi, Vietnam0Hanoi Department of Health, Hanoi, Vietnam1Department of Internal Medicine, Fureai Machida Hospital, Tokyo, JapanDepartment of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, JATA, Tokyo, JapanDepartment of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, JATA, Tokyo, JapanDepartment of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, JATA, Tokyo, Japan2The Research Institute of Tuberculosis, JATA, Tokyo, Japan3National Center for Global Health and Medicine, Tokyo, JapanIntroductionIt is assumed that host defense systems eliminating the pathogen and regulating tissue damage make a strong impact on the outcome of tuberculosis (TB) disease and that these processes are affected by rifampicin (RIF) resistance–conferring mutations of Mycobacterium tuberculosis (Mtb). However, the host responses to the pathogen harboring different mutations have not been studied comprehensively in clinical settings. We analyzed clinico-epidemiological factors and blood transcriptomic signatures associated with major rpoB mutations conferring RIF resistance in a cohort study.MethodsDemographic data were collected from 295 active pulmonary TB patients with treatment history in Hanoi, Vietnam. When recruited, drug resistance–conferring mutations and lineage-specific variations were identified using whole-genome sequencing of clinical Mtb isolates. Before starting retreatment, total RNA was extracted from the whole blood of HIV-negative patients infected with Mtb that carried either the rpoB H445Y or rpoB S450L mutation, and the total RNA was subjected to RNA sequencing after age-gender matching. The individual RNA expression levels in the blood sample set were also measured using real-time RT-PCR. Logistic and linear regression models were used to assess possible associations.ResultsIn our cohort, rpoB S450L and rpoB H445Y were major RIF resistance–conferring mutations [32/87 (36.8%) and 15/87 (17.2%), respectively]. H445Y was enriched in the ancient Beijing genotype and was associated with nonsynonymous mutations of Rv1830 that has been reported to regulate antibiotic resilience. H445Y was also more frequently observed in genetically clustered strains and in samples from patients who had received more than one TB treatment episode. According to the RNA sequencing, gene sets involved in the interferon-γ and-α pathways were downregulated in H445Y compared with S450L. The qRT-PCR analysis also confirmed the low expression levels of interferon-inducible genes, including BATF2 and SERPING1, in the H445Y group, particularly in patients with extensive lesions on chest X-ray.DiscussionOur study results showed that rpoB mutations as well as Mtb sublineage with additional genetic variants may have significant effects on host response. These findings strengthen the rationale for investigation of host-pathogen interactions to develop countermeasures against epidemics of drug-resistant TB.https://www.frontiersin.org/articles/10.3389/fmicb.2023.1187390/fullMycobacterium tuberculosisrecurrencerifampicin resistancerpoB variantswhole genome sequencingblood transcriptomic signatures |
| spellingShingle | Nguyen Thi Le Hang Minako Hijikata Shinji Maeda Pham Huu Thuong Hoang Van Huan Nguyen Phuong Hoang Do Bang Tam Pham Thu Anh Nguyen Thu Huyen Nguyen Thu Huyen Vu Cao Cuong Nobuyuki Kobayashi Keiko Wakabayashi Akiko Miyabayashi Shintaro Seto Naoto Keicho Naoto Keicho Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance–conferring mutations Frontiers in Microbiology Mycobacterium tuberculosis recurrence rifampicin resistance rpoB variants whole genome sequencing blood transcriptomic signatures |
| title | Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance–conferring mutations |
| title_full | Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance–conferring mutations |
| title_fullStr | Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance–conferring mutations |
| title_full_unstemmed | Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance–conferring mutations |
| title_short | Host-pathogen relationship in retreated tuberculosis with major rifampicin resistance–conferring mutations |
| title_sort | host pathogen relationship in retreated tuberculosis with major rifampicin resistance conferring mutations |
| topic | Mycobacterium tuberculosis recurrence rifampicin resistance rpoB variants whole genome sequencing blood transcriptomic signatures |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2023.1187390/full |
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