PMID- 37200402
OWN - NLM
STAT- MEDLINE
DCOM- 20230602
LR  - 20231102
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 19
IP  - 5
DP  - 2023 May
TI  - The host-directed therapeutic imatinib mesylate accelerates immune responses to 
      Mycobacterium marinum infection and limits pathology associated with granulomas.
PG  - e1011387
LID - 10.1371/journal.ppat.1011387 [doi]
LID - e1011387
AB  - Infections caused by members of the mycobacterium tuberculosis complex [MTC] and 
      nontuberculous mycobacteria [NTM] can induce widespread morbidity and mortality 
      in people. Mycobacterial infections cause both a delayed immune response, which 
      limits rate of bacterial clearance, and formation of granulomas, which contain 
      bacterial spread, but also contribute to lung damage, fibrosis, and morbidity. 
      Granulomas also limit access of antibiotics to bacteria, which may facilitate 
      development of resistance. Bacteria resistant to some or all antibiotics cause 
      significant morbidity and mortality, and newly developed antibiotics readily 
      engender resistance, highlighting the need for new therapeutic approaches. 
      Imatinib mesylate, a cancer drug used to treat chronic myelogenous leukemia [CML] 
      that targets Abl and related tyrosine kinases, is a possible host-directed 
      therapeutic [HDT] for mycobacterial infections, including those causing TB. Here, 
      we use the murine Mycobacterium marinum [Mm] infection model, which induces 
      granulomatous tail lesions. Based on histological measurements, imatinib reduces 
      both lesion size and inflammation of surrounding tissue. Transcriptomic analysis 
      of tail lesions indicates that imatinib induces gene signatures indicative of 
      immune activation and regulation at early time points post infection that 
      resemble those seen at later ones, suggesting that imatinib accelerates but does 
      not substantially alter anti-mycobacterial immune responses. Imatinib likewise 
      induces signatures associated with cell death and promotes survival of bone 
      marrow-derived macrophages [BMDMs] in culture following infection with Mm. 
      Notably, the capacity of imatinib to limit formation and growth of granulomas in 
      vivo and to promote survival of BMDMs in vitro depends upon caspase 8, a key 
      regulator of cell survival and death. These data provide evidence for the utility 
      of imatinib as an HDT for mycobacterial infections in accelerating and regulating 
      immune responses, and limiting pathology associated with granulomas, which may 
      mitigate post-treatment morbidity.
CI  - Copyright: (c) 2023 Cleverley et al. This is an open access article distributed 
      under the terms of the Creative Commons Attribution License, which permits 
      unrestricted use, distribution, and reproduction in any medium, provided the 
      original author and source are credited.
FAU - Cleverley, Tesia L
AU  - Cleverley TL
AUID- ORCID: 0000-0002-5141-2764
AD  - Department of Pathology and Laboratory Medicine, Emory University School of 
      Medicine, Atlanta, Georgia, United States of America.
AD  - Immunology and Molecular Pathogenesis Graduate Program, Emory University School 
      of Medicine, Atlanta, Georgia, United States of America.
FAU - Peddineni, Siri
AU  - Peddineni S
AD  - Department of Pathology and Laboratory Medicine, Emory University School of 
      Medicine, Atlanta, Georgia, United States of America.
FAU - Guarner, Jeannette
AU  - Guarner J
AD  - Department of Pathology and Laboratory Medicine, Emory University School of 
      Medicine, Atlanta, Georgia, United States of America.
FAU - Cingolani, Francesca
AU  - Cingolani F
AD  - Department of Pathology and Laboratory Medicine, Emory University School of 
      Medicine, Atlanta, Georgia, United States of America.
FAU - Garcia, Pamela K
AU  - Garcia PK
AD  - Immunology and Molecular Pathogenesis Graduate Program, Emory University School 
      of Medicine, Atlanta, Georgia, United States of America.
FAU - Koehler, Heather
AU  - Koehler H
AD  - Department of Pathology and Laboratory Medicine, Emory University School of 
      Medicine, Atlanta, Georgia, United States of America.
FAU - Mocarski, Edward S
AU  - Mocarski ES
AD  - Department of Microbiology and Immunology, Emory University School of Medicine, 
      Atlanta, Georgia, United States of America.
FAU - Kalman, Daniel
AU  - Kalman D
AUID- ORCID: 0000-0003-0693-2928
AD  - Department of Pathology and Laboratory Medicine, Emory University School of 
      Medicine, Atlanta, Georgia, United States of America.
LA  - eng
GR  - R01 DK074731/DK/NIDDK NIH HHS/United States
GR  - UH3 AI122320/AI/NIAID NIH HHS/United States
GR  - R56 DK074731/DK/NIDDK NIH HHS/United States
GR  - UH2 AI122320/AI/NIAID NIH HHS/United States
GR  - R21 AG054903/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20230518
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - 0 (Pyrimidines)
RN  - 0 (Piperazines)
RN  - 0 (Benzamides)
RN  - 0 (Anti-Bacterial Agents)
RN  - Infection with Mycobacterium marinum
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - Imatinib Mesylate/pharmacology
MH  - *Pyrimidines/pharmacology
MH  - *Piperazines/pharmacology
MH  - Benzamides
MH  - Anti-Bacterial Agents/therapeutic use
MH  - Granuloma/drug therapy
PMC - PMC10231790
COIS- The authors have declared that no competing interests exist.
EDAT- 2023/05/18 19:12
MHDA- 2023/06/02 06:43
PMCR- 2023/05/18
CRDT- 2023/05/18 13:54
PHST- 2022/10/13 00:00 [received]
PHST- 2023/04/25 00:00 [accepted]
PHST- 2023/05/31 00:00 [revised]
PHST- 2023/06/02 06:43 [medline]
PHST- 2023/05/18 19:12 [pubmed]
PHST- 2023/05/18 13:54 [entrez]
PHST- 2023/05/18 00:00 [pmc-release]
AID - PPATHOGENS-D-22-01763 [pii]
AID - 10.1371/journal.ppat.1011387 [doi]
PST - epublish
SO  - PLoS Pathog. 2023 May 18;19(5):e1011387. doi: 10.1371/journal.ppat.1011387. 
      eCollection 2023 May.