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Article ; Online: Leishmania major-

Ihedioha, Olivia C / Sivakoses, Anutr / Beverley, Stephen M / McMahon-Pratt, Diane / Bothwell, Alfred L M

2023 Volume 14, Page(s) 1257046

Abstract: Background: Platelets are rapidly deployed to infection sites and respond to pathogenic molecules via pattern recognition receptors (TLR, NLRP). Dickkopf1 (DKK1) is a quintessential Wnt antagonist produced by a variety of cell types including platelets, ...

Abstract	Background: Platelets are rapidly deployed to infection sites and respond to pathogenic molecules via pattern recognition receptors (TLR, NLRP). Dickkopf1 (DKK1) is a quintessential Wnt antagonist produced by a variety of cell types including platelets, endothelial cells, and is known to modulate pro-inflammatory responses in infectious diseases and cancer. Moreover, DKK1 is critical for forming leukocyte-platelet aggregates and induction of type 2 cell-mediated immune responses. Our previous publication showed activated platelets release DKK1 following Results: Here we probed the role of the key surface virulence glycoconjugate lipophosphoglycan (LPG), on DKK1 production using null mutants deficient in LPG synthesis ( Conclusion: Thus, LPG is a key virulence factor that induces DKK1 production from activated platelets, and the circulating DKK1 promotes Th2 cell polarization. This suggests that LPG-activated platelets can drive innate and adaptive immune responses to
MeSH term(s)	Leishmania major ; Toll-Like Receptor 1/metabolism ; Endothelial Cells ; Immunity ; Platelet Activation
Chemical Substances	Toll-Like Receptor 1 ; lipophosphonoglycan
Language	English
Publishing date	2023-10-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1257046
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Article ; Online: Identification of connective tissue disease autoantibodies and a novel autoantibody anti-annexin A11 in patients with "idiopathic" interstitial lung disease.

Clinical immunology (Orlando, Fla.)

2024 Volume 262, Page(s) 110201

Abstract: Background: Autoantibodies are a hallmark feature of Connective Tissue Diseases (CTD). Their presence in patients with idiopathic interstitial lung disease (ILD) may suggest covert CTD. We aimed to determine the prevalence of CTD autoantibodies in ... ...

Abstract	Background: Autoantibodies are a hallmark feature of Connective Tissue Diseases (CTD). Their presence in patients with idiopathic interstitial lung disease (ILD) may suggest covert CTD. We aimed to determine the prevalence of CTD autoantibodies in patients diagnosed with idiopathic ILD. Methods: 499 patient sera were analysed: 251 idiopathic pulmonary fibrosis (IPF), 206 idiopathic non-specific interstitial pneumonia (iNSIP) and 42 cryptogenic organising pneumonia (COP). Autoantibody status was determined by immunoprecipitation. Results: 2.4% of IPF sera had a CTD-autoantibody compared to 10.2% of iNSIP and 7.3% of COP. 45% of autoantibodies were anti-synthetases. A novel autoantibody targeting an unknown 56 kDa protein was found in seven IPF patients (2.8%) and two NSIP (1%) patients. This was characterised as anti-annexin A11. Conclusion: Specific guidance on autoantibody testing and interpretation in patients with ILD could improve diagnostic accuracy. Further work is required to determine the clinical significance of anti-annexin A11.
MeSH term(s)	Humans ; Autoantibodies ; Connective Tissue Diseases/diagnosis ; Idiopathic Interstitial Pneumonias/diagnosis ; Idiopathic Pulmonary Fibrosis ; Lung Diseases, Interstitial/diagnosis
Chemical Substances	Autoantibodies
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2024.110201
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Article ; Online: CD4 T cell activation by B cells in human Leishmania (Viannia) infection.

Rodriguez-Pinto, Daniel / Saravia, Nancy Gore / McMahon-Pratt, Diane

BMC infectious diseases

2014 Volume 14, Page(s) 108

Abstract: Background: An effective adaptive immune response requires activation of specific CD4 T cells. The capacity of B cells to activate CD4 T cells in human cutaneous leishmaniasis caused by Leishmania (Viannia) has not been evaluated.: Methods: CD4 T ... ...

Abstract	Background: An effective adaptive immune response requires activation of specific CD4 T cells. The capacity of B cells to activate CD4 T cells in human cutaneous leishmaniasis caused by Leishmania (Viannia) has not been evaluated. Methods: CD4 T cell activation by B cells of cutaneous leishmaniasis patients was evaluated by culture of PBMCs or purified B cells and CD4 T cells with Leishmania panamensis antigens. CD4 T cell and B cell activation markers were evaluated by flow cytometry and 13 cytokines were measured in supernatants with a bead-based capture assay. The effect of Leishmania antigens on BCR-mediated endocytosis of ovalbumin was evaluated in the Ramos human B cell line by targeting the antigen with anti-IgM-biotin and anti-biotin-ovalbumin-FITC. Results: Culture of PBMCs from cutaneous leishmaniasis patients with Leishmania antigens resulted in upregulation of the activation markers CD25 and CD69 as well as increased frequency of CD25hiCD127- cells among CD4 T cells. Concomitantly, B cells upregulated the costimulatory molecule CD86. These changes were not observed in PBMCs from healthy subjects, indicating participation of Leishmania-specific lymphocytes expanded in vivo. Purified B cells from these patients, when interacting with purified CD4 T cells and Leishmania antigens, were capable of inducing significant increases in CD25 and CD69 expression and CD25hiCD127- frequency in CD4 T cells. These changes were associated with upregulation of CD86 in B cells. Comparison of changes in CD4 T cell activation parameters between PBMC and B cell/CD4 T cell cultures showed no statistically significant differences; further, significant secretion of IFN-γ, TNF-α, IL-6 and IL-13 was induced in both types of cultures. Additionally, culture with Leishmania antigens enhanced BCR-mediated endocytosis of ovalbumin in Ramos human B cells. Conclusions: The capacity of B cells specific for Leishmania antigens in peripheral blood of cutaneous leishmaniasis patients to activate CD4 T cells and induce cytokine secretion is similar to that of all cell populations present in PBMCs. This capacity implicates B cells as a plausible target for modulation of the immune response to Leishmania infection as a therapeutic strategy.
MeSH term(s)	Adult ; Aged ; B-Lymphocytes/immunology ; Biotin/chemistry ; CD4-Positive T-Lymphocytes/immunology ; Colombia/epidemiology ; Female ; Flow Cytometry ; Fluorescein-5-isothiocyanate/chemistry ; Gene Expression Regulation ; Humans ; Immunoglobulin M/chemistry ; Interferon-gamma/immunology ; Interleukin-6/immunology ; Leishmania braziliensis/immunology ; Leishmaniasis, Cutaneous/blood ; Leishmaniasis, Cutaneous/immunology ; Leukocytes, Mononuclear/immunology ; Lymphocyte Activation/immunology ; Male ; Middle Aged ; Ovalbumin/chemistry ; Tumor Necrosis Factor-alpha/immunology ; Young Adult
Chemical Substances	Immunoglobulin M ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Biotin (6SO6U10H04) ; Interferon-gamma (82115-62-6) ; Ovalbumin (9006-59-1) ; Fluorescein-5-isothiocyanate (I223NX31W9)
Language	English
Publishing date	2014-02-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1471-2334
ISSN (online)	1471-2334
DOI	10.1186/1471-2334-14-108
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Article ; Online: The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection.

Wetzel, Dawn M / Rhodes, Emma L / Li, Shaoguang / McMahon-Pratt, Diane / Koleske, Anthony J

Journal of cell science

2016 Volume 129, Issue 16, Page(s) 3130–3143

Abstract: Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. ...

Abstract	Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis. Amastigotes, the life cycle stage found in the human host, bind Fc receptors and enter macrophages primarily through immunoglobulin-mediated phagocytosis. However, the host machinery that mediates amastigote uptake is poorly understood. We have previously shown that the Arg (also known as Abl2) non-receptor tyrosine kinase facilitates L. amazonensis amastigote uptake by macrophages. Using small-molecule inhibitors and primary macrophages lacking specific Src family kinases, we now demonstrate that the Hck, Fgr and Lyn kinases are also necessary for amastigote uptake by macrophages. Src-mediated Arg activation is required for efficient uptake. Interestingly, the dual Arg and Src kinase inhibitor bosutinib, which is approved to treat cancer, not only decreases amastigote uptake, but also significantly reduces disease severity and parasite burden in Leishmania-infected mice. Our results suggest that leishmaniasis could potentially be treated with host-cell-active agents such as kinase inhibitors.
MeSH term(s)	Aniline Compounds/pharmacology ; Animals ; Cytokines/secretion ; Disease Models, Animal ; Imatinib Mesylate/pharmacology ; Immunoglobulin G/metabolism ; Leishmania/drug effects ; Leishmania/pathogenicity ; Leishmaniasis/enzymology ; Leishmaniasis/parasitology ; Macrophages/drug effects ; Macrophages/enzymology ; Macrophages/parasitology ; Mice ; Models, Biological ; Nitriles/pharmacology ; Parasites/drug effects ; Parasites/parasitology ; Phagocytosis/drug effects ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-hck/metabolism ; Pyrimidines/pharmacology ; Quinolines/pharmacology ; RAW 264.7 Cells ; Signal Transduction/drug effects ; src-Family Kinases/metabolism
Chemical Substances	AG 1879 ; Aniline Compounds ; Cytokines ; Immunoglobulin G ; Nitriles ; Proto-Oncogene Proteins ; Pyrimidines ; Quinolines ; bosutinib (5018V4AEZ0) ; Imatinib Mesylate (8A1O1M485B) ; ARG tyrosine kinase (EC 2.7.1.-) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Hck protein, mouse (EC 2.7.10.2) ; Proto-Oncogene Proteins c-hck (EC 2.7.10.2) ; lyn protein-tyrosine kinase (EC 2.7.10.2) ; proto-oncogene proteins c-fgr (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2016-08-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.185595
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Article ; Online: Profiles of Local and Systemic Inflammation in the Outcome of Treatment of Human Cutaneous Leishmaniasis Caused by

Navas, Adriana / Fernández, Olga / Gallego-Marín, Carolina / Castro, María Del Mar / Rosales-Chilama, Mariana / Murillo, Julieth / Cossio, Alexandra / McMahon-Pratt, Diane / Saravia, Nancy Gore / Gómez, María Adelaida

Infection and immunity

2020 Volume 88, Issue 3

Abstract: The immune mechanisms that contribute to the efficacy of treatment of cutaneous leishmaniasis (CL) are not fully understood. The aim of this study was to define immune correlates of the outcome of treatment of CL caused ... ...

Abstract	The immune mechanisms that contribute to the efficacy of treatment of cutaneous leishmaniasis (CL) are not fully understood. The aim of this study was to define immune correlates of the outcome of treatment of CL caused by
MeSH term(s)	Antiprotozoal Agents/therapeutic use ; Cytokines/metabolism ; Gene Expression Profiling ; Humans ; Immunity, Innate/physiology ; Leishmania/immunology ; Leishmaniasis/drug therapy ; Leishmaniasis/immunology ; Leishmaniasis/metabolism ; Leukocytes, Mononuclear/metabolism ; Meglumine Antimoniate/therapeutic use ; Monocyte Chemoattractant Proteins/metabolism ; Monocytes/metabolism
Chemical Substances	Antiprotozoal Agents ; Cytokines ; Monocyte Chemoattractant Proteins ; Meglumine Antimoniate (75G4TW236W)
Language	English
Publishing date	2020-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.00764-19
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Article ; Online: Ex vivo host and parasite response to antileishmanial drugs and immunomodulators.

Gonzalez-Fajardo, Laura / Fernández, Olga Lucía / McMahon-Pratt, Diane / Saravia, Nancy Gore

PLoS neglected tropical diseases

2015 Volume 9, Issue 5, Page(s) e0003820

Abstract: Background: Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, ... ...

Abstract	Background: Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania infection and antileishmanial drugs can themselves modulate drug transport, metabolism and/or immune responses, immunotherapeutic approaches require integrated assessment of host and parasite responses. Methodology: To achieve an integrated assessment of current and innovative therapeutic strategies, we determined host and parasite responses to miltefosine and meglumine antimoniate alone and in combination with pentoxifylline or CpG 2006 in peripheral blood mononuclear cells (PBMCs) of cutaneous leishmaniasis patients. Parasite survival and secretion of TNF-α, IFN-γ, IL-10 and IL-13 were evaluated concomitantly in PBMCs infected with Luc-L. (V.) panamensis exposed to meglumine antimoniate (4, 8, 16, 32 and 64 μg SbV/mL) or miltefosine (2, 4, 8, 16 and 32 μM HePC). Concentrations of 4 μM of miltefosine and 8 μg SbV/mL were selected for evaluation in combination with immunomodulators based on the high but partial reduction of parasite burden by these antileishmanial concentrations without affecting cytokine secretion of infected PBMCs. Intracellular parasite survival was determined by luminometry and cytokine secretion measured by ELISA and multiplex assays. Principal findings: Anti- and pro-inflammatory cytokines characteristic of L. (V.) panamensis infection were evaluable concomitantly with viability of Leishmania within monocyte-derived macrophages present in PBMC cultures. Both antileishmanial drugs reduced the parasite load of macrophages; miltefosine also suppressed IL-10 and IL-13 secretion in a dose dependent manner. Pentoxifylline did not affect parasite survival or alter antileishmanial effects of miltefosine or meglumine antimoniate. However, pentoxifylline diminished secretion of TNF-α, IFN-γ and IL-13, cytokines associated with the outcome of infection by species of the Viannia subgenus. Exposure to CpG diminished the leishmanicidal effect of meglumine antimoniate, but not miltefosine, and significantly reduced secretion of IL-10, alone and in combination with either antileishmanial drug. IL-13 increased in response to CpG plus miltefosine. Conclusions and significance: Human PBMCs allow integrated ex vivo assessment of antileishmanial treatments, providing information on host and parasite determinants of therapeutic response that may be used to tailor therapeutic strategies to optimize clinical resolution.
MeSH term(s)	Adolescent ; Animals ; Antiprotozoal Agents/pharmacology ; Antiprotozoal Agents/therapeutic use ; Female ; Humans ; Immunologic Factors/pharmacology ; Immunologic Factors/therapeutic use ; Interferon-alpha/metabolism ; Interleukin-10/metabolism ; Interleukin-13/metabolism ; Leishmania/drug effects ; Leishmaniasis/drug therapy ; Leukocytes, Mononuclear/metabolism ; Macrophages/parasitology ; Male ; Meglumine/pharmacology ; Meglumine/therapeutic use ; Meglumine Antimoniate ; Organometallic Compounds/pharmacology ; Organometallic Compounds/therapeutic use ; Phosphorylcholine/analogs & derivatives ; Phosphorylcholine/pharmacology ; Phosphorylcholine/therapeutic use ; Tumor Necrosis Factor-alpha/metabolism ; Young Adult
Chemical Substances	Antiprotozoal Agents ; IL10 protein, human ; IL13 protein, human ; Immunologic Factors ; Interferon-alpha ; Interleukin-13 ; Organometallic Compounds ; TNF protein, human ; Tumor Necrosis Factor-alpha ; Phosphorylcholine (107-73-3) ; Interleukin-10 (130068-27-8) ; miltefosine (53EY29W7EC) ; Meglumine (6HG8UB2MUY) ; Meglumine Antimoniate (75G4TW236W)
Language	English
Publishing date	2015-05-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2727
ISSN (online)	1935-2735
ISSN	1935-2727
DOI	10.1371/journal.pntd.0003820
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Article ; Online: Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility.

Barrera, Maria Claudia / Rojas, Laura Jimena / Weiss, Austin / Fernandez, Olga / McMahon-Pratt, Diane / Saravia, Nancy G / Gomez, Maria Adelaida

Acta tropica

2017 Volume 176, Page(s) 355–363

Abstract: The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. ... ...

Abstract	The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. Being an intracellular parasite, the activity of antileishmanials is dependent on internalization of drugs into host cells and effective delivery to the intracellular compartments inhabited by the parasite. In this study we quantified and comparatively analyzed the gene expression of nine molecules involved in mechanisms of xenobiotic detoxification and Leishmania resistance to antimonial drugs in resistant and susceptible laboratory derived and clinical L.(Viannia) panamensis strains(n=19). In addition, we explored the impact of Leishmania susceptibility to antimonials on the expression of macrophage gene products having putative functions in transport, accumulation and metabolism of antimonials. As previously shown for other Leishmania species, a trend of increased abcc3 and lower aqp-1 expression was observed in the laboratory derived Sb-resistant L.(V.) panamensis line. However, this was not found in clinical strains, in which the expression of abca2 was significantly higher in resistant strains as both, promastigotes and intracellular amastigotes. The effect of drug susceptibility on host cell gene expression was evaluated on primary human macrophages from patients with cutaneous leishmaniasis (n=17) infected ex-vivo with the matched L.(V.) panamensis strains isolated at diagnosis, and in THP-1 cells infected with clinical strains (n=6) and laboratory adapted L.(V.) panamensis lines. Four molecules, abcb1 (p-gp), abcb6, aqp-9 and mt2a were differentially modulated by drug resistant and susceptible parasites, and among these, a consistent and significantly increased expression of the xenobiotic scavenging molecule mt2a was observed in macrophages infected with Sb-susceptible L. (V.) panamensis. Our results substantiate that different mechanisms of drug resistance operate in laboratory adapted and clinical Leishmania strains, and provide evidence that parasite-mediated modulation of host cell gene expression of molecules involved in drug transport and metabolism could contribute to the mechanisms of drug resistance and susceptibility in Leishmania.
Language	English
Publishing date	2017-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	210415-5
ISSN	1873-6254 ; 0001-706X
ISSN (online)	1873-6254
ISSN	0001-706X
DOI	10.1016/j.actatropica.2017.08.017
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Article ; Online: The Abl and Arg kinases mediate distinct modes of phagocytosis and are required for maximal Leishmania infection.

Wetzel, Dawn M / McMahon-Pratt, Diane / Koleske, Anthony J

Molecular and cellular biology

2012 Volume 32, Issue 15, Page(s) 3176–3186

Abstract: Leishmania, an obligate intracellular parasite, binds several receptors to trigger engulfment by phagocytes, leading to cutaneous or visceral disease. These receptors include complement receptor 3 (CR3), used by promastigotes, and the Fc receptor (FcR), ... ...

Abstract	Leishmania, an obligate intracellular parasite, binds several receptors to trigger engulfment by phagocytes, leading to cutaneous or visceral disease. These receptors include complement receptor 3 (CR3), used by promastigotes, and the Fc receptor (FcR), used by amastigotes. The mechanisms mediating uptake are not well understood. Here we show that Abl family kinases mediate both phagocytosis and the uptake of Leishmania amazonensis by macrophages (Ms). Imatinib, an Abl/Arg kinase inhibitor, decreases opsonized polystyrene bead phagocytosis and Leishmania uptake. Interestingly, phagocytosis of IgG-coated beads is decreased in Arg-deficient Ms, while that of C3bi-coated beads is unaffected. Conversely, uptake of C3bi-coated beads is decreased in Abl-deficient Ms, but that of IgG-coated beads is unaffected. Consistent with these results, Abl-deficient Ms are inefficient at C3bi-opsonized promastigote uptake, and Arg-deficient Ms are defective in IgG1-opsonized amastigote uptake. Finally, genetic loss of Abl or Arg reduces infection severity in murine cutaneous leishmaniasis, and imatinib treatment results in smaller lesions with fewer parasites than in controls. Our studies are the first to demonstrate that efficient phagocytosis and maximal Leishmania infection require Abl family kinases. These results highlight Abl family kinase-mediated signaling pathways as potential therapeutic targets for leishmaniasis.
MeSH term(s)	Animals ; Benzamides ; Cell Line ; Complement C3b/immunology ; Imatinib Mesylate ; Immunoglobulin G/immunology ; Leishmania mexicana/immunology ; Leishmania mexicana/metabolism ; Leishmania mexicana/pathogenicity ; Leishmaniasis/drug therapy ; Leishmaniasis/immunology ; Leishmaniasis/metabolism ; Leishmaniasis/parasitology ; Macrophage-1 Antigen/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/parasitology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microspheres ; Phagocytosis ; Piperazines/pharmacology ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Proto-Oncogene Proteins c-abl/antagonists & inhibitors ; Proto-Oncogene Proteins c-abl/genetics ; Proto-Oncogene Proteins c-abl/metabolism ; Pyrimidines/pharmacology
Chemical Substances	Benzamides ; Immunoglobulin G ; Macrophage-1 Antigen ; Piperazines ; Pyrimidines ; Complement C3b (80295-43-8) ; Imatinib Mesylate (8A1O1M485B) ; ARG tyrosine kinase (EC 2.7.1.-) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins c-abl (EC 2.7.10.2)
Language	English
Publishing date	2012-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00086-12
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Article: Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility

Barrera, Maria Claudia / Rojas, Laura Jimena / Weiss, Austin / Fernandez, Olga / McMahon-Pratt, Diane / Saravia, Nancy G / Gomez, Maria Adelaida

Acta tropica. 2017 Dec., v. 176

2017

Abstract	The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. Being an intracellular parasite, the activity of antileishmanials is dependent on internalization of drugs into host cells and effective delivery to the intracellular compartments inhabited by the parasite. In this study we quantified and comparatively analyzed the gene expression of nine molecules involved in mechanisms of xenobiotic detoxification and Leishmania resistance to antimonial drugs in resistant and susceptible laboratory derived and clinical L.(Viannia) panamensis strains(n=19). In addition, we explored the impact of Leishmania susceptibility to antimonials on the expression of macrophage gene products having putative functions in transport, accumulation and metabolism of antimonials. As previously shown for other Leishmania species, a trend of increased abcc3 and lower aqp-1 expression was observed in the laboratory derived Sb-resistant L.(V.) panamensis line. However, this was not found in clinical strains, in which the expression of abca2 was significantly higher in resistant strains as both, promastigotes and intracellular amastigotes. The effect of drug susceptibility on host cell gene expression was evaluated on primary human macrophages from patients with cutaneous leishmaniasis (n=17) infected ex-vivo with the matched L.(V.) panamensis strains isolated at diagnosis, and in THP-1 cells infected with clinical strains (n=6) and laboratory adapted L.(V.) panamensis lines. Four molecules, abcb1 (p-gp), abcb6, aqp-9 and mt2a were differentially modulated by drug resistant and susceptible parasites, and among these, a consistent and significantly increased expression of the xenobiotic scavenging molecule mt2a was observed in macrophages infected with Sb-susceptible L. (V.) panamensis. Our results substantiate that different mechanisms of drug resistance operate in laboratory adapted and clinical Leishmania strains, and provide evidence that parasite-mediated modulation of host cell gene expression of molecules involved in drug transport and metabolism could contribute to the mechanisms of drug resistance and susceptibility in Leishmania.
Keywords	Leishmania ; P-glycoproteins ; amastigotes ; antileishmanials ; antimony ; cutaneous leishmaniasis ; drug resistance ; drugs ; gene expression ; genes ; humans ; macrophages ; metabolism ; parasites ; patients ; phenotype ; promastigotes ; xenobiotics
Language	English
Dates of publication	2017-12
Size	p. 355-363.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	210415-5
ISSN	1873-6254 ; 0001-706X
ISSN (online)	1873-6254
ISSN	0001-706X
DOI	10.1016/j.actatropica.2017.08.017
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Article ; Online: Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence.

Holowka, Thomas / Castilho, Tiago M / Garcia, Alvaro Baeza / Sun, Tiffany / McMahon-Pratt, Diane / Bucala, Richard

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2016 Volume 30, Issue 6, Page(s) 2249–2265

Abstract: Leishmania major encodes 2 orthologs of the cytokine macrophage migration inhibitory factor (MIF), whose functions in parasite growth or in the host-parasite interaction are unknown. To determine the importance of Leishmania-encoded MIF, both LmMIF genes ...

Abstract	Leishmania major encodes 2 orthologs of the cytokine macrophage migration inhibitory factor (MIF), whose functions in parasite growth or in the host-parasite interaction are unknown. To determine the importance of Leishmania-encoded MIF, both LmMIF genes were removed to produce an mif(-/-) strain of L. major This mutant strain replicated normally in vitro but had a 2-fold increased susceptibility to clearance by macrophages. Mice infected with mif(-/-) L. major, when compared to the wild-type strain, also showed a 3-fold reduction in parasite burden. Microarray and functional analyses revealed a reduced ability of mif(-/-) L. major to activate antigen-presenting cells, resulting in a 2-fold reduction in T-cell priming. In addition, there was a reduction in inflammation and effector CD4 T-cell formation in mif(-/-) L. major-infected mice when compared to mice infected with wild-type L. major Notably, effector CD4 T cells that developed during infection with mif(-/-) L. major demonstrated statistically significant differences in markers of functional exhaustion, including increased expression of IFN-γ and IL-7R, reduced expression of programmed death-1, and decreased apoptosis. These data support a role for LmMIF in promoting parasite persistence by manipulating the host response to increase the exhaustion and depletion of protective CD4 T cells.-Holowka, T., Castilho, T. M., Baeza Garcia, A., Sun, T., McMahon-Pratt, D., Bucala, R. Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence.
MeSH term(s)	Animals ; Antigens, Differentiation, B-Lymphocyte/genetics ; Antigens, Differentiation, B-Lymphocyte/metabolism ; Apoptosis/physiology ; CD4-Positive T-Lymphocytes/physiology ; Cloning, Molecular ; Gene Deletion ; Gene Expression Regulation/physiology ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/metabolism ; Leishmania major/metabolism ; Leishmaniasis, Cutaneous/immunology ; Leishmaniasis, Cutaneous/parasitology ; Macrophage Migration-Inhibitory Factors/genetics ; Macrophage Migration-Inhibitory Factors/metabolism ; Macrophages ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, SCID ; Organisms, Genetically Modified ; Protein Array Analysis ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism
Chemical Substances	Antigens, Differentiation, B-Lymphocyte ; Histocompatibility Antigens Class II ; Macrophage Migration-Inhibitory Factors ; Protozoan Proteins ; invariant chain
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201500189R
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