PMID- 30133440
OWN - NLM
STAT- MEDLINE
DCOM- 20181221
LR  - 20211204
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Print)
IS  - 1935-2727 (Linking)
VI  - 12
IP  - 8
DP  - 2018 Aug
TI  - Therapeutic control of leishmaniasis by inhibitors of the mammalian target of 
      rapamycin.
PG  - e0006701
LID - 10.1371/journal.pntd.0006701 [doi]
LID - e0006701
AB  - Leishmaniasis is a serious global health problem affecting many people worldwide. 
      While patients with leishmaniasis can be treated with several agents, drug 
      toxicicty and the emergence of resistant strains render available treatments 
      ineffective in the long run. Inhibitors of the mammalian target of rapamycin 
      (mTOR) have been demonstrated to exert anti-pathogen properties. In this study, 
      we tested the therapeutic efficacy of several mTOR inhibitors in controlling 
      infection with Leishmania major. Rapamycin, GSK-2126458 and KU-0063794 were 
      administered to BALB/c mice, which had received an intrafootpad injection of the 
      parasite. Footpad swelling and parasite burden were assessed, and cytokine 
      production by mouse splenocytes and phenotypic changes in draining lymph node 
      cells were evaluated. Treatment with a clinically relevant dose of rapamycin or 
      with GSK-2126458, but not with KU-0063794, dramatically lowered both the footpad 
      swelling and the parasite load in the draining lymph node. Importantly, the 
      employed dose of rapamycin did not kill the promastigotes in vitro as judged by 
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and 
      electron microscopy. Moreover, the IL-4 production capacity of splenocytes 
      harvested from infected mice that were treated with rapamycin was significantly 
      reduced. Consequently, the IFN-gamma:IL-4 production ratio was elevated, suggesting a 
      T helper-type 1 (Th1)-skewed cytokine profile. Finally, the expression level of 
      CD69, an early activation marker, on splenic and lymph node CD4+ and CD8+ T cells 
      was enhanced in rapamycin-treated mice. Taken together, our findings suggest that 
      select mTOR inhibitors may be used in therapeutic settings for the management of 
      leishmaniasis. We propose that the beneficial effects of such inhibitors stem 
      from their immunomodulatory properties. Therefore, the adjuvanticity of mTOR 
      inhibitors may also be considered in vaccination strategies against Leishmania 
      species.
FAU - Khadir, Fatemeh
AU  - Khadir F
AUID- ORCID: 0000-0001-9969-9322
AD  - Department of Pathology, School of Veterinary Medicine, Shiraz University, 
      Shiraz, Iran.
AD  - Department of Microbiology and Immunology, Western University, London, Ontario, 
      Canada.
AD  - Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of 
      Iran, Tehran, Iran.
FAU - Shaler, Christopher R
AU  - Shaler CR
AD  - Department of Microbiology and Immunology, Western University, London, Ontario, 
      Canada.
FAU - Oryan, Ahmad
AU  - Oryan A
AD  - Department of Pathology, School of Veterinary Medicine, Shiraz University, 
      Shiraz, Iran.
FAU - Rudak, Patrick T
AU  - Rudak PT
AD  - Department of Microbiology and Immunology, Western University, London, Ontario, 
      Canada.
FAU - Mazzuca, Delfina M
AU  - Mazzuca DM
AD  - Department of Microbiology and Immunology, Western University, London, Ontario, 
      Canada.
FAU - Taheri, Tahereh
AU  - Taheri T
AD  - Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of 
      Iran, Tehran, Iran.
FAU - Dikeakos, Jimmy D
AU  - Dikeakos JD
AD  - Department of Microbiology and Immunology, Western University, London, Ontario, 
      Canada.
FAU - Haeryfar, S M Mansour
AU  - Haeryfar SMM
AD  - Department of Microbiology and Immunology, Western University, London, Ontario, 
      Canada.
AD  - Centre for Human Immunology, Western University, London, Ontario, Canada.
AD  - Lawson Health Research Institute, London, Ontario, Canada.
AD  - Division of Clinical Immunology and Allergy, Department of Medicine, Western 
      University, London, Ontario, Canada.
FAU - Rafati, Sima
AU  - Rafati S
AUID- ORCID: 0000-0002-7221-1320
AD  - Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of 
      Iran, Tehran, Iran.
LA  - eng
GR  - MOP-130465/Canadian Institutes of Health Research/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180822
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
RN  - 0 (Antiprotozoal Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Pyridazines)
RN  - 0 (Pyrimidines)
RN  - 0 (Quinolines)
RN  - 0 (Sulfonamides)
RN  - 1X8F5A3NA0 (omipalisib)
RN  - 81HJG228AB (Ku 0063794)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antiprotozoal Agents/therapeutic use
MH  - Enzyme Inhibitors/therapeutic use
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Inhibitory Concentration 50
MH  - Leishmaniasis/*drug therapy
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Morpholines/*therapeutic use
MH  - Pyridazines
MH  - Pyrimidines/*therapeutic use
MH  - Quinolines/*therapeutic use
MH  - Sirolimus/pharmacology
MH  - Sulfonamides/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC6122837
COIS- The authors have declared that no competing interests exist.
EDAT- 2018/08/23 06:00
MHDA- 2018/12/24 06:00
PMCR- 2018/08/22
CRDT- 2018/08/23 06:00
PHST- 2018/04/30 00:00 [received]
PHST- 2018/07/18 00:00 [accepted]
PHST- 2018/09/04 00:00 [revised]
PHST- 2018/08/23 06:00 [pubmed]
PHST- 2018/12/24 06:00 [medline]
PHST- 2018/08/23 06:00 [entrez]
PHST- 2018/08/22 00:00 [pmc-release]
AID - PNTD-D-18-00697 [pii]
AID - 10.1371/journal.pntd.0006701 [doi]
PST - epublish
SO  - PLoS Negl Trop Dis. 2018 Aug 22;12(8):e0006701. doi: 
      10.1371/journal.pntd.0006701. eCollection 2018 Aug.