scholarly journals Deletion of Interleukin-4 Receptor Alpha-Responsive Keratinocytes in BALB/c Mice Does Not Alter Susceptibility to Cutaneous Leishmaniasis

2018 ◽  
Vol 86 (12) ◽  
Author(s):  
Melissa Govender ◽  
Ramona Hurdayal ◽  
Berenice Martinez-Salazar ◽  
Kaya Gqada ◽  
Shandre Pillay ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Interleukin 4 ◽  
High Dose ◽  
Littermate Control ◽  
Content Type ◽  
Receptor Alpha ◽  
Th2 Immune Response

ABSTRACTThe skin microenvironment at the site of infection plays a role in the early events that determine protective T helper 1/type 1 immune responses during cutaneous leishmaniasis (CL) infection. During CL in nonhealing BALB/c mice, early interleukin-4 (IL-4) can instruct dendritic cells for protective Th1 immunity. Additionally, keratinocytes, which are the principal cell type in the skin epidermis, have been shown to secrete IL-4 early afterLeishmania majorinfection. Here, we investigated whether IL-4/IL-13 signaling via the common IL-4 receptor alpha chain (IL-4Rα) on keratinocytes contributes to susceptibility during experimental CL. To address this, keratinocyte-specific IL-4Rα-deficient (KRT14creIL-4Rα−/lox) mice on a BALB/c genetic background were generated by gene targeting and site-specific recombination (Cre/loxP) under the control of the keratinocyte-specifickrt14locus. Following high-dose infection withL. majorIL-81 and LV39 promastigotes subcutaneously in the footpad, footpad swelling, parasite burden, IFN-γ/IL-4/IL-13 cytokine production, and type 1 and type 2 antibody responses were similar between KRT14creIL-4Rα−/loxand littermate control IL-4Rα−/loxBALB/c mice. An intradermal infection with low-doseL. majorIL-81 and LV39 promastigotes in the ear showed results in infected KRT14creIL-4Rα−/loxBALB/c mice similar to those of littermate control IL-4Rα−/loxBALB/c mice, with the exception of a significant decrease observed in parasite burden only at the site of LV39 infection in the ear. Collectively, our results show that autocrine and paracrine signaling of IL-4/IL-13 through the IL-4Rα chain on keratinocytes does not influence the establishment of a nonhealing Th2 immune response in BALB/c mice duringL. majorinfection.

scholarly journals Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania major

2016 ◽  
Vol 60 (5) ◽  
pp. 2932-2940 ◽  
Author(s):  
Douglas R. Rice ◽  
Paola Vacchina ◽  
Brianna Norris-Mullins ◽  
Miguel A. Morales ◽  
Bradley D. Smith
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Coordination Complexes ◽  
Chemotherapeutic Agents ◽  
Selective Toxicity ◽  
Content Type

ABSTRACTCutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. Modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. This study describes the selective targeting of zinc(II)-dipicolylamine (ZnDPA) coordination complexes towardLeishmania major, one of the species responsible for cutaneous leishmaniasis. Fluorescence microscopy ofL. majorpromastigotes treated with a fluorescently labeled ZnDPA probe indicated rapid accumulation of the probe within the axenic promastigote cytosol. The antileishmanial activities of eight ZnDPA complexes were measured using anin vitroassay. All tested complexes exhibited selective toxicity againstL. majoraxenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 μM. Similar toxicity was observed against intracellular amastigotes, but there was almost no effect on the viability of mammalian cells, including mouse peritoneal macrophages.In vivotreatment efficacy studies used fluorescence imaging to noninvasively monitor changes in the red fluorescence produced by an infection of mCherry-L. majorin a mouse model. A ZnDPA treatment regimen reduced the parasite burden nearly as well as the reference care agent, potassium antimony(III) tartrate, and with less necrosis in the local host tissue. The results demonstrate that ZnDPA coordination complexes are a promising new class of antileishmanial agents with potential for clinical translation.

scholarly journals Transgenic Expression of CXCR3 on T Cells Enhances Susceptibility to Cutaneous Leishmania major Infection by Inhibiting Monocyte Maturation and Promoting a Th2 Response

2014 ◽  
Vol 83 (1) ◽  
pp. 67-76 ◽  
Author(s):  
Steve Oghumu ◽  
James C. Stock ◽  
Sanjay Varikuti ◽  
Ran Dong ◽  
Cesar Terrazas ◽  
...  
Keyword(s):  
T Cells ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Critical Role ◽  
Sand Fly ◽  
Interleukin 4 ◽  
Th2 Response ◽  
Content Type ◽  
Transgenic Expression ◽  
Inflammatory Monocytes

Cutaneous leishmaniasis, caused mainly byLeishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused byLeishmania major. Furthermore, T cells fromL. major-susceptible BALB/c but notL. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance toL. majorinfection in susceptible BALB/c mice. We generated BALB/c and C57BL/6 transgenic mice, which constitutively overexpressed CXCR3 under a CD2 promoter, and then examined the outcomes withL. majorinfection. Contrary to our hypothesis, transgenic expression of CXCR3 (CXCR3Tg) on T cells of BALB/c mice resulted in increased lesion sizes and parasite burdens compared to wild-type (WT) littermates afterL. majorinfection. Restimulated lymph node cells fromL. major-infected BALB/c-CXCR3Tgmice produced more interleukin-4 (IL-4) and IL-10 and less gamma interferon (IFN-γ). Cells in draining lymph nodes from BALB/c-CXCR3Tgmice showed enhanced Th2 and reduced Th1 cell accumulation associated with increased neutrophils and inflammatory monocytes. However, monocytes displayed an immature phenotype which correlated with increased parasite burdens. Interestingly, transgenic expression of CXCR3 on T cells did not impact the outcome ofL. majorinfection in C57BL/6 mice, which mounted a predominantly Th1 response and spontaneously resolved their infection similar to WT littermates. Our findings demonstrate that transgenic expression of CXCR3 on T cells increases susceptibility of BALB/c mice toL. major.

scholarly journals Local Delivery of the Toll-Like Receptor 9 Ligand CpG Downregulates Host Immune and Inflammatory Responses, Ameliorating Established Leishmania (Viannia) panamensis Chronic Infection

2017 ◽  
Vol 85 (3) ◽  
Author(s):  
Allison K. Ehrlich ◽  
Olga L. Fernández ◽  
Daniel Rodriguez-Pinto ◽  
Tiago M. Castilho ◽  
Maria J. Corral Caridad ◽  
...  
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
Cutaneous Leishmaniasis ◽  
Transforming Growth Factor ◽  
Parasite Burden ◽  
Cell Populations ◽  
High Dose ◽  
Toll Like Receptor ◽  
Content Type ◽  
Ifn Γ

ABSTRACT Infection by Leishmania (Viannia) panamensis, the predominant etiologic agent for cutaneous leishmaniasis in Colombia, is characterized by a chronic mixed inflammatory response. Current treatment options are plagued by toxicity, lengthy treatment regimens, and growing evidence of drug resistance. Immunotherapy, modulating the immune system to mount a protective response, may provide an alternate therapeutic approach. We investigated the ability of the Toll-like receptor 9 (TLR9) ligand CpG to modulate established disease in the L. (V.) panamensis mouse model. Treatment of established infection with a high dose (50 μg) of CpG ameliorated disease and lowered parasite burden. Interestingly, immediately after treatment there was a significant increase in transforming growth factor β (TGF-β) and concomitantly an increase in T regulatory cell (Treg) function. Although a general reduction in cell-mediated immune cytokine and chemokine (gamma interferon [IFN-γ], interleukin 10 [IL-10], IL-13, IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-4, and MIP-1α) responses of the treated mice was observed, certain chemokines (RANTES, monocyte chemoattractant protein 1[MCP-1], and IP-10) were increased. Further, in peripheral blood mononuclear cells (PBMCs) from patients with cutaneous leishmaniasis, CpG treatment similarly exhibited a dose-response effect on the production of IFN-γ, IL-17, IL-10, and IL-13, with reductions observed at higher doses. To further understand the underlying mechanisms and cell populations driving the CpG mediated response, we examined the ex vivo dose effects mediated by the TLR9+ cell populations (dendritic cells, macrophages, and B cells) found to accumulate labeled CpG in vivo. Notably, B cells altered the production of IL-17, IL-13, and IFN-γ, supporting a role for B cells functioning as antigen-presenting cells (APCs) and/or regulatory cells during infection. Interestingly, B cells have been previously demonstrated as a primary type of APC in patients infected with L. (V.) panamensis and thus may be useful targets of immunotherapy. Collectively, our results show that CpG-induced immune regulation leads to a dampening of the host immune response and healing in the mouse model, and it may provide an alternate approach to treatment of cutaneous leishmaniasis caused by L. (V.) panamensis.

scholarly journals Antileishmanial Effects of Synthetic EhPIb Analogs Derived from the Entamoeba histolytica Lipopeptidephosphoglycan

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Helena Fehling ◽  
Siew Ling Choy ◽  
Frederic Ting ◽  
Dirk Landschulze ◽  
Hannah Bernin ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Entamoeba Histolytica ◽  
Murine Model ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
Intestinal Protozoan ◽  
Cutaneous Lesions ◽  
Content Type ◽  
Arginase 1

ABSTRACT With an estimated number of new cases annually of approximately 1.4 million, leishmaniasis belongs to the most important parasitic diseases in the world. Nevertheless, existing drugs against leishmaniasis in general have several drawbacks that urgently necessitate new drug development. A glycolipid molecule of the intestinal protozoan parasite Entamoeba histolytica and its synthetic analogs previously showed considerable immunotherapeutic effects against Leishmania major infection. Here, we designed and synthesized a series of new immunostimulatory compounds derived from the phosphatidylinositol b anchor of Entamoeba histolytica (EhPIb) subunit of the native compound and investigated their antileishmanial activity in vitro and in vivo in a murine model of cutaneous leishmaniasis. The new synthetic EhPIb analogs showed almost no toxicity in vitro. Treatment with the analogs significantly decreased the parasite load in murine and human macrophages in vitro. In addition, topical application of the EhPIb analog Eh-1 significantly reduced cutaneous lesions in the murine model, correlating with an increase in the production of selected Th1 cytokines. In addition, we could show in in vitro experiments that treatment with Eh-1 led to a decrease in mRNA expression of arginase-1 (Arg1) and interleukin 4 (IL-4), which are required by the parasites to circumvent their elimination by the immune response. The use of the host-targeting synthetic EhPIb compounds, either alone or in combination therapy with antiparasitic drugs, shows promise for treating cutaneous leishmaniasis and therefore might improve the current unsatisfactory status of chemotherapy against this infectious disease.

scholarly journals IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

2017 ◽  
Vol 114 (40) ◽  
pp. E8430-E8439 ◽  
Author(s):  
Ramona Hurdayal ◽  
Hlumani H. Ndlovu ◽  
Mélanie Revaz-Breton ◽  
Suraj P. Parihar ◽  
Justin Komguep Nono ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
T Helper ◽  
Type 2 Immune Response

Interleukin-4 (IL-4)–induced T helper (Th) 2 cells promote susceptibility to the protozoan parasite Leishmania major, while conferring immunity to the intestinal trematode Schistosoma mansoni. Here, we report that abrogation of IL-4 receptor alpha (IL-4Rα) signaling on B cells in BALB/c mice (mb1creIL-4Rα–/lox) transformed nonhealer BALB/c to a healer phenotype with an early type 1 and dramatically reduced type 2 immune response and an absence of ulceration and necrosis during cutaneous leishmaniasis. From adoptive reconstitution and mixed bone-marrow chimera studies in B cell-deficient (µMT) mice, we reveal a central role for B cell-derived IL-4 and IL-4Rα in the optimal induction of the susceptible type 2 phenotype to L. major infection. We further demonstrate that the absence of IL-4Rα signaling on B cells exacerbated S. mansoni-induced mortality and pathology in BALB/c mice, due to a diminished type 2 immune response. In both disease models, IL-4Rα–responsive B cells displayed increased IL-4 production as early as day 1 after infection. Together, these results demonstrate that IL-4–producing and IL-4Rα–responsive B cells are critical in regulating and assisting early T helper dichotomy toward Th2 responses, which are detrimental in cutaneous leishmaniasis but beneficial in acute schistosomiasis.

scholarly journals Foxp3+ T Regulatory Cells as a Potential Target for Immunotherapy against Primary Infection with Echinococcus multilocularis Eggs

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Junhua Wang ◽  
Rita Cardoso ◽  
Nelson Marreros ◽  
Norbert Müller ◽  
Britta Lundström-Stadelmann ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Echinococcus Multilocularis ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Expression Profiles ◽  
Growth Potential ◽  
Interleukin 4 ◽  
Content Type ◽  
Hepatic Expression ◽  
Th2 Immune Response

ABSTRACT Alveolar echinococcosis (AE) is a lethal disease caused by infection with the metacestode stage of the helminth Echinococcus multilocularis, which develops into a tumorlike mass in susceptible intermediate hosts. The growth potential of this parasite stage is directly linked to the nature of the surrounding periparasitic immune-mediated processes. In a first step (experiment 1), mice were orally infected with E. multilocularis eggs, to be used for assessing the hepatic expression profiles of 15 selected cytokine and chemokine genes related to acquired immunity from 21 to 120 days postinfection. The early stage of infection in immunocompetent animals was marked by a mixed Th1/Th2 immune response, as characterized by the concomitant presence of gamma interferon (IFN-γ) and interleukin-4 (IL-4) and their related chemokines. At the late stage of AE, the profile extended to a combined tolerogenic mode including Foxp3, IL-10, and transforming growth factor beta (TGF-β) as key components. In a second step (experiment 2), the effect of T regulatory cell (Treg) deficiency on metacestode growth was assessed in E. multilocularis-infected DEREG (depletion of regulatory T cells) mice upon induction of Treg deficiency with diphtheria toxin (DT). The parasite lesions were significantly smaller in the livers of treated mice than in corresponding control groups. Foxp3+ Tregs appear to be one of the key players in immune-regulatory processes favoring metacestode survival by affecting antigen presentation and suppressing Th1-type immune responses. For these reasons, we suggest that affecting Foxp3+ Tregs could offer an attractive target in the development of an immunotherapy against AE.

scholarly journals Expression of Inducible Nitric Oxide Synthase in Skin Lesions of Patients with American Cutaneous Leishmaniasis

2002 ◽  
Vol 70 (8) ◽  
pp. 4638-4642 ◽  
Author(s):  
Muna Qadoumi ◽  
Inge Becker ◽  
Norbert Donhauser ◽  
Martin Röllinghoff ◽  
Christian Bogdan
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Skin Lesions ◽  
And Function ◽  
Oxide Synthase

ABSTRACT Cytokine-inducible (or type 2) nitric oxide synthase (iNOS) is indispensable for the resolution of Leishmania major or Leishmania donovani infections in mice. In contrast, little is known about the expression and function of iNOS in human leishmaniasis. Here, we show by immunohistological analysis of skin biopsies from Mexican patients with local (LCL) or diffuse (DCL) cutaneous leishmaniasis that the expression of iNOS was most prominent in LCL lesions with small numbers of parasites whereas lesions with a high parasite burden (LCL or DCL) contained considerably fewer iNOS-positive cells. This is the first study to suggest an antileishmanial function of iNOS in human Leishmania infections in vivo.

scholarly journals The Levels and Patterns of Cytokines Produced by CD4 T Lymphocytes of BALB/c Mice Infected with Leishmania major by Inoculation into the Ear Dermis Depend on the Infectiousness and Size of the Inoculum

2003 ◽  
Vol 71 (5) ◽  
pp. 2674-2683 ◽  
Author(s):  
Thierry Lang ◽  
Nathalie Courret ◽  
Jean-Hervé Colle ◽  
Geneviève Milon ◽  
Jean-Claude Antoine
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
High Dose ◽  
Cutaneous Lesions ◽  
Cell Reactivity ◽  
Ifn Γ ◽  
T Cell Reactivity ◽  
Parasite Populations

ABSTRACT The production of cytokines by CD4 lymph node T lymphocytes derived from BALB/c mice recently infected in the ear dermis with high (106 parasites) or low (103 parasites) doses of Leishmania major metacyclic promastigotes (MP) was examined over a 3-week period following inoculation. Results were compared with those obtained when mice were injected with less infectious parasite populations, namely, stationary-phase or log-phase promastigotes (LP). Cells were purified 16 h and 3, 8, and 19 days after inoculation, and the amounts of gamma interferon (IFN-γ) and interleukin-4 (IL-4) released in response to LACK (Leishmania homolog of receptors for activated C kinase) or total L. major antigens were assessed. We found that LACK-reactive T cells from mice inoculated with a high dose of parasites first produced IFN-γ and later on IL-4; the level of IFN-γ produced early by these cells was dependent upon the stage of the promastigotes inoculated, the highest level being reached with cells recovered from mice inoculated with the least infectious parasites, LP; sequential production of IFN-γ and then of IL-4 also characterized L. major antigen-reactive CD4 T cells, suggesting that the early production of IFN-γ does not impede the subsequent rise of IL-4 and finally the expansion of the parasites; after low-dose inoculation of MP, cutaneous lesions developed with kinetics similar to that of lesions induced after inoculation of 106 LP, but in this case CD4 T lymphocytes did not release IFN-γ or IL-4 in the presence of LACK and neither cytokine was produced in response to L. major antigens before the onset of lesion signs. These results suggest the existence of a discreet phase in terms of CD4 T-cell reactivity for at least the first 8 days following inoculation, a time period during which parasites are able to grow moderately. In conclusion, the levels and profiles of cytokines produced by Leishmania-specific CD4 T lymphocytes clearly depend on both the stage of differentiation and number of parasites used for inoculation.

scholarly journals Leishmania-Derived Trimannose Modulates the Inflammatory Response To Significantly Reduce Leishmania major-Induced Lesions

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Tara L. Grinnage-Pulley ◽  
Daniel E. K. Kabotso ◽  
Chelsea L. Rintelmann ◽  
Rajarshi Roychoudhury ◽  
Robert G. Schaut ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Parasite Load ◽  
Mannose Receptor ◽  
Lesion Size ◽  
Wild Type ◽  
Cutaneous Lesions ◽  
Content Type ◽  
Latex Beads

ABSTRACTLeishmanialipophosphoglycan (LPG) is a key virulence factor, initiating inflammation resulting in cutaneous lesions. LPG is capped by various oligosaccharides. How these glycans are recognized and how they alter the course ofLeishmaniainfection are poorly understood. Previous studies synthesized α-1,2-trimannose cap sugars on latex beads and demonstrated that C57BL/6 mice coinoculated withLeishmania majorand trimannose-coated beads produced significantly higher levels of interleukin-12p40 (IL-12p40) and other proinflammatory, type 1 cytokines than mice inoculated withL. majoralone within the first 48 h of infection. However, asL. majorinfection typically progress over weeks to months, the role of trimannose in altering disease progression over the course of infection was unknown. Wild-type mice were inoculated with either trimannose-coated or carrier (uncoated) beads, infected withL. majoralone, coinoculated with carrier beads andL. major, or coinoculated with trimannose-coated beads andL. major. Trimannose treatment ofL. major-infected mice decreased the parasite load and significantly decreased the lesion size at 14 days postinfection (p.i.) compared to results for nontreated, infected mice. Infected, trimannose-treated mice had decreased IL-12p40 and IL-10 secretion and increased interferon gamma secretion at 14 days p.i. Mannose receptor knockout (MR−/−) mice lack the ability to detect trimannose. When MR−/−mice were infected withL. majorand treated with trimannose beads, they did not have decreased lesion size.Leishmania-derived trimannose represents a novel immunomodulator that provides early type 1-skewed cytokine production to control the parasite load and alter the course of cutaneous leishmaniasis.

scholarly journals Evaluation of α,β-Unsaturated Ketones as Antileishmanial Agents

2015 ◽  
Vol 59 (6) ◽  
pp. 3598-3601 ◽  
Author(s):  
Miguel A. Vasquez ◽  
Eva Iniguez ◽  
Umashankar Das ◽  
Stephen M. Beverley ◽  
Linda J. Herrera ◽  
...  
Keyword(s):  
Murine Model ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Effective Concentration ◽  
Bioluminescent Imaging ◽  
Content Type ◽  
Unsaturated Ketones ◽  
Parasite Replication ◽  
20 Nm

ABSTRACTIn this study, we assessed the antileishmanial activity of 126 α,β-unsaturated ketones. The compounds NC901, NC884, and NC2459 showed high leishmanicidal activity for both the extracellular (50% effective concentration [EC50], 456 nM, 1,122 nM, and 20 nM, respectively) and intracellular (EC50, 1,870 nM, 937 nM, and 625 nM, respectively) forms ofLeishmania majorpropagated in macrophages, with little or no toxicity to mammalian cells. Bioluminescent imaging of parasite replication showed that all three compounds reduced the parasite burden in the murine model, with no apparent toxicity.

Sign in / Sign up

Export Citation Format

Share Document