Passive case detection and treatment constitute the principal, often the sole measure of control for cutaneous leishmaniasis (CL) in Central and South America yet first line therapies (pentavalent antimonials, pentamidine and miltefosine) are often ineffective (overall non response is of the order of 24% based on a recent meta analysis [1]) and poorly tolerated. Since pathogenesis of dermal leishmaniasis is mediated by the immune and inflammatory responses, resolution of disease and control of infection are intimately linked to the host response. Consequently, antileishmanial drugs alone are often insufficient to clinically resolve disease even in immunocompetent individuals, and furthermore, do not eliminate infection [2-6]. Although immune mechanisms underlying the outcome of infection differ among Leishmania species [7], non-healing phenotypes of infection by different species can be converted to healing phenotypes and vice versa by intervention of the host immune response [8-12]. In experimental models, a wide range of interventions (including deletion of T cell populations, neutralization or genetic depletion of cytokines that drive T cell differentiation, down regulate macrophage activation, or modulate T regulatory cell function) invert susceptibility and resistance. Importantly, these interventions have broadly targeted immune function rather than responses to specific parasite antigens. The feasibility of translating this experience with murine models to human leishmaniasis is supported by the clinical resolution of cutaneous and mucosal disease unresponsive to chemotherapy alone, by co-adjuvant immunotherapy [13-17]. However, neither the immunological basis of the healing response enabled by these interventions, the mechanisms involved nor the generalizability of any immunotherapeutic intervention (to different species of Leishmania or for the spectrum of clinical outcomes) has been determined. Local as well as systemic and combined therapies have recently been recommended as alternatives for New World cutaneous leishmaniasis by the WHO Expert Committee on Leishmaniasis. Risk/benefit considerations of the toxicity of current systemic treatment regimens, persistence of infection following treatment, and evidence of the effectiveness of various local therapies compelled the amplification of therapeutic options to include local and combined strategies. Such strategies may be optimized through innovative delivery of antileishmanial drugs and immunomodulators via nanoparticle technology. This project seeks to identify the immunologic bases of healing of cutaneous leishmaniasis caused by Leishmania Viannia species, and to discern the mechanisms of immunomodulation that together with chemotherapy, improve clinical outcome, reduce parasite burden and persistence, and preserve the effective life of antileishmanial drugs.

Public Health Relevance

Cutaneous leishmaniasis (CL) is a parasitic disease of global importance effecting 12 million people in 88 countries worldwide;current treatments involve drugs that are toxic, with severe side reactions. In Colombia and parts of South America, this disease is increasingly a disease of children. This project is focused on the development of effective topic treatment for CL through the targeted stimulation of the host immune response that should avoid toxicity and adverse side reactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093775-02
Application #
8247683
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Wali, Tonu M
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$661,652
Indirect Cost
$157,627
Name
Yale University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wetzel, Dawn M; Rhodes, Emma L; Li, Shaoguang et al. (2016) The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection. J Cell Sci 129:3130-43
Chae, Wook-Jin; Ehrlich, Allison K; Chan, Pamela Y et al. (2016) The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity 44:246-58
Saldarriaga, Omar A; Castellanos-Gonzalez, Alejandro; Porrozzi, Renato et al. (2016) An Innovative Field-Applicable Molecular Test to Diagnose Cutaneous Leishmania Viannia spp. Infections. PLoS Negl Trop Dis 10:e0004638
Holowka, Thomas; Castilho, Tiago M; Garcia, Alvaro Baeza et al. (2016) Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence. FASEB J 30:2249-65
Siefert, Alyssa L; Ehrlich, Allison; Corral, María Jesús et al. (2016) Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model. Biomaterials 108:168-76
Di-Blasi, Tatiana; Lobo, Amanda R; Nascimento, Luanda M et al. (2015) The flagellar protein FLAG1/SMP1 is a candidate for Leishmania-sand fly interaction. Vector Borne Zoonotic Dis 15:202-9
Gonzalez-Fajardo, Laura; Fernández, Olga Lucía; McMahon-Pratt, Diane et al. (2015) Ex vivo host and parasite response to antileishmanial drugs and immunomodulators. PLoS Negl Trop Dis 9:e0003820
Rosales-Chilama, Mariana; Gongora, Rafael E; Valderrama, Liliana et al. (2015) Parasitological Confirmation and Analysis of Leishmania Diversity in Asymptomatic and Subclinical Infection following Resolution of Cutaneous Leishmaniasis. PLoS Negl Trop Dis 9:e0004273
Gómez, Maria Adelaida; Navas, Adriana; Márquez, Ricardo et al. (2014) Leishmania panamensis infection and antimonial drugs modulate expression of macrophage drug transporters and metabolizing enzymes: impact on intracellular parasite survival. J Antimicrob Chemother 69:139-49
Obonaga, Ricardo; Fernández, Olga Lucía; Valderrama, Liliana et al. (2014) Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by Leishmania subgenus Viannia species. Antimicrob Agents Chemother 58:144-52

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