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 #
5R01AI093775-03
Application #
8438476
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
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$627,013
Indirect Cost
$150,625
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
Martínez-Valencia, Alvaro J; Daza-Rivera, Carlos Frisherald; Rosales-Chilama, Mariana et al. (2017) Clinical and parasitological factors in parasite persistence after treatment and clinical cure of cutaneous leishmaniasis. PLoS Negl Trop Dis 11:e0005713
Castro, Maria Del Mar; Cossio, Alexandra; Velasco, Carlos et al. (2017) Risk factors for therapeutic failure to meglumine antimoniate and miltefosine in adults and children with cutaneous leishmaniasis in Colombia: A cohort study. PLoS Negl Trop Dis 11:e0005515
Ehrlich, Allison K; Fernández, Olga L; Rodriguez-Pinto, Daniel et al. (2017) Local Delivery of the Toll-Like Receptor 9 Ligand CpG Downregulates Host Immune and Inflammatory Responses, Ameliorating Established Leishmania (Viannia) panamensis Chronic Infection. Infect Immun 85:
Castro, María Del Mar; Gomez, Maria Adelaida; Kip, Anke E et al. (2017) Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis. Antimicrob Agents Chemother 61:
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
Siefert, Alyssa L; Caplan, Michael J; Fahmy, Tarek M (2016) Artificial bacterial biomimetic nanoparticles synergize pathogen-associated molecular patterns for vaccine efficacy. Biomaterials 97:85-96
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
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
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

Showing the most recent 10 out of 25 publications