Integrated Analysis Reveals That miR-193b, miR-671, and TREM-1 Correlate With a Good Response to Treatment of Human Localized Cutaneous Leishmaniasis Caused by Leishmania braziliensis

Leishmania braziliensis is the most important cause of cutaneous leishmaniasis (CL) in the Americas. A Th1-type immune response is required to control Leishmania infection, but an exaggerated inflammatory response leads to the development of ulcers seen in CL. Infection with intestinal helminths has the potential to inhibit the Th1 response in a manner that depends both on the species of helminth present as well as the burden of helminthiasis. We conducted a prospective cohort study of CL patients from an endemic area between January and December 2017 with either negative or high intestinal helminth burden to characterize relationships between helminth burden, L. braziliensis quantification within CL lesions, clinical aspects of CL, and therapeutic response. Of 234 participants with leishmaniasis who underwent stool examination at the time of diagnosis, 45% had detectable helminth infection. The overall cure rate after 90 days was 66%, with a median time to resolution of disease of 40 days (interquartile range: 30–65 days). There was no significant association between the type of helminth infection or the magnitude of intestinal helminth burden at the time of diagnosis and L. braziliensis genomic DNA (gDNA) detected in biopsies from CL lesions. Likewise, there was no association between helminth burden and response to treatment after 90 days. Considering quantification of parasite DNA in CL lesions, participants who were cured at 90 days had a median of 0.017 ng/mg gDNA, and participants who failed therapy had a median of 0.091 ng/mg gDNA (P = 0.03). The results indicate that cutaneous Leishmania load may influence therapeutic response in CL.

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Efficacy and Tolerability of Miltefosine in the Treatment of Cutaneous Leishmaniasis

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1238 ◽

2020 ◽

Author(s):

JeanAnne M Ware ◽

Elise M O’Connell ◽

Thomas Brown ◽

Lauren Wetzler ◽

Kawsar R Talaat ◽

...

Keyword(s):

Adverse Events ◽

Cutaneous Leishmaniasis ◽

Leishmania Major ◽

Standard Of Care ◽

Leishmania Species ◽

Response To Treatment ◽

Prior History ◽

Leishmania Braziliensis ◽

Alternative Treatment Option ◽

Leishmania Panamensis

Abstract Background Cutaneous leishmaniasis (CL) is a neglected tropical disease causing an estimated 1 million new cases annually. While antimonial compounds are the standard of care worldwide, they are associated with significant adverse effects. Miltefosine, an oral medication, is United States (US) Food and Drug Administration approved to treat CL caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis. Evidence of efficacy in other species and side-effect profiles in CL has been limited. Methods Twenty-six patients with CL were treated with miltefosine at the US National Institutes of Health. Species included L. braziliensis (n = 7), L. panamensis (n = 5), Leishmania mexicana (n = 1), Leishmania infantum (n = 3), Leishmania aethiopica (n = 4), Leishmania tropica (n = 2), Leishmania major (n = 1), and unspeciated (n = 3). Demographic and clinic characteristics of the participants, response to treatment, and associated adverse events were analyzed. Results Treatment with miltefosine resulted in cure in 77 % (20/26) of cases, with cures among all species. Common adverse events included nausea/vomiting (97%) and lack of appetite (54%). Clinical management or dose reduction was required in a third of cases. Gout occurred in 3 individuals with a prior history of gout. Most laboratory abnormalities, including elevated creatinine and aminotransferases, were mild and normalized after treatment. Conclusions Our data suggest that miltefosine has good but imperfect efficacy to a wide variety of Leishmania species. While side effects were common and mostly mild to moderate, some resulted in discontinuation of therapy. Due to oral administration, broad efficacy, and manageable toxicities, miltefosine is a viable alternative treatment option for CL, though cost and lack of local availability may limit its widespread use.

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Influence of Obesity on Clinical Manifestations and Response to Therapy in Cutaneous Leishmaniasis caused by Leishmania braziliensis

Clinical Infectious Diseases ◽

10.1093/cid/ciab236 ◽

2021 ◽

Author(s):

Tainã Lago ◽

Lucas Carvalho ◽

Mauricio Nascimento ◽

Luiz H Guimarães ◽

Jamile Lago ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Clinical Presentation ◽

Clinical Manifestations ◽

Healing Time ◽

Response To Therapy ◽

Leishmania Braziliensis ◽

Cutaneous Lesions ◽

Cytokine Levels ◽

Cure Rates ◽

The Impact

Abstract Background Cutaneous leishmaniasis (CL) caused by L. braziliensis is characterized by a single ulcer or multiple cutaneous lesions with raised borders. Cure rates below 60% are observed in response to meglumine antimoniate therapy. We investigated the impact of obesity on CL clinical presentation and therapeutic response. Methods A total of 90 age-matched CL patients were included (30 obese, 30 overweight and 30 with normal BMI). CL was diagnosed through documentation of L. braziliensis DNA by PCR or identification of amastigotes in biopsied skin lesion samples. Serum cytokine levels were determined by chemiluminescence. Antimony therapy with Glucantime (20mg/kg/day) was administered for 20 days. Results Obese CL patients may present hypertrophic ulcers rather than typical oval, ulcerated lesions. A direct correlation between BMI and healing time was noted. After one course of Antimony, cure was achieved in 73% of patients with normal BMI, 37% of overweight subjects, yet just 18% of obese CL patients (p<0.01). Obese CL cases additionally presented higher leptin levels than overweight patients or those with normal BMI (p<0.05). Conclusions Obesity modifies the clinical presentation of CL and host immune response, and is associated with greater failure to therapy.

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Low Plasma Membrane Expression of the Miltefosine Transport Complex Renders Leishmania braziliensis Refractory to the Drug

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01694-08 ◽

2009 ◽

Vol 53 (4) ◽

pp. 1305-1313 ◽

Cited By ~ 54

Author(s):

María P. Sánchez-Cañete ◽

Luís Carvalho ◽

F. Javier Pérez-Victoria ◽

Francisco Gamarro ◽

Santiago Castanys

Keyword(s):

Plasma Membrane ◽

Cutaneous Leishmaniasis ◽

Oral Drug ◽

Leishmania Braziliensis ◽

Β Subunit ◽

Membrane Expression ◽

Plasma Membrane Expression ◽

Highly Sensitive ◽

P Type ◽

Transport Complex

ABSTRACT Miltefosine (hexadecylphosphocholine, MLF) is the first oral drug with recognized efficacy against both visceral and cutaneous leishmaniasis. However, some clinical studies have suggested that MLF shows significantly less efficiency against the cutaneous leishmaniasis caused by Leishmania braziliensis. In this work, we have determined the cellular and molecular basis for the natural MLF resistance observed in L. braziliensis. Four independent L. braziliensis clinical isolates showed a marked decrease in MLF sensitivity that was due to their inability to internalize the drug. MLF internalization in the highly sensitive L. donovani species requires at least two proteins in the plasma membrane, LdMT, a P-type ATPase involved in phospholipid translocation, and its β subunit, LdRos3. Strikingly, L. braziliensis parasites showed highly reduced levels of this MLF translocation machinery at the plasma membrane, mainly because of the low expression levels of the β subunit, LbRos3. Overexpression of LbRos3 induces increased MLF sensitivity not only in L. braziliensis promastigotes but also in intracellular amastigotes. These results further highlight the importance of the MLF translocation machinery in determining MLF potency and point toward the development of protocols to routinely monitor MLF susceptibility in geographic areas where L. braziliensis might be prevalent.

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Case Report: Miltefosine Failure and Spontaneous Resolution of Cutaneous Leishmaniasis braziliensis

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.20-1642 ◽

2021 ◽

Author(s):

Sheridan Joseph ◽

Timothy J. Whitman ◽

Frederick S. Buckner ◽

Anna L. Cogen

Keyword(s):

Case Report ◽

South America ◽

Treatment Failure ◽

Cutaneous Leishmaniasis ◽

Young Woman ◽

Spontaneous Resolution ◽

Clinical Monitoring ◽

Leishmania Braziliensis ◽

Oral Medications ◽

Mucocutaneous Leishmaniasis

Cutaneous leishmaniasis (CL) is often caused by Leishmania braziliensis (L. braziliensis) in South America. Because of the risk for mucocutaneous leishmaniasis, L. braziliensis is frequently treated with parenteral or oral medications. Here, we present a case of a young woman with L. braziliensis (CL) that did not respond to miltefosine but eventually experienced spontaneous resolution. This case highlights the potential for treatment failure and the importance of clinical monitoring in the setting of cutaneous leishmaniasis caused by L. braziliensis.

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Inflammasome Activation by CD8+ T Cells from Patients with Cutaneous Leishmaniasis Caused by Leishmania braziliensis in the Immunopathogenesis of the Disease

Journal of Investigative Dermatology ◽

10.1016/j.jid.2020.05.106 ◽

2021 ◽

Vol 141 (1) ◽

pp. 209-213.e2

Author(s):

Thiago Marconi Cardoso ◽

Jonilson B. Lima ◽

Ícaro Bonyek-Silva ◽

Sara Nunes ◽

Daniel Feijó ◽

...

Keyword(s):

T Cells ◽

Cutaneous Leishmaniasis ◽

Cd8 T Cells ◽

Leishmania Braziliensis ◽

Inflammasome Activation

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Potential Use of Interleukin-10 Blockade as a Therapeutic Strategy in Human Cutaneous Leishmaniasis

Journal of Immunology Research ◽

10.1155/2015/152741 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 8

Author(s):

Lucio Roberto Castellano ◽

Laurent Argiro ◽

Helia Dessein ◽

Alain Dessein ◽

Marcos Vinícius da Silva ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Therapeutic Strategy ◽

Interleukin 10 ◽

Leishmania Braziliensis ◽

Soluble Antigen ◽

Innovative Strategies ◽

Host Protection ◽

Human Cutaneous Leishmaniasis ◽

Potential Use ◽

Worse Prognosis

Interleukin-10 overproduction has been associated with worse prognosis in human cutaneous leishmaniasis, while IFN-γ-dependent responses are associated with parasite killing and host protection. Innovative strategies are needed to overcome therapeutic failure observed in endemic areas. The use of monoclonal antibody-based immunotherapy targeting IL-10 cytokine was evaluated here. Partial IL-10 blockade inLeishmania braziliensiswhole soluble antigen-stimulated cells from endemic area CL patients with active or healed lesions and asymptomatic controls was evaluated. Overall decrease in IL-10, IL-4, and TNF-αproduction was observed in all groups of subjects. Only patients with active lesions still produced some levels of TNF-αafter anti-IL-10 stimulation in association withLeishmaniaantigens. Moreover, this strategy showed limited modulatory effects on IFN-γ-dependent chemokine CXCL10 production. Results suggest the potential immunotherapeutic use of partial IL-10 blockade in localized cutaneous leishmaniasis.

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A Double-blind, Randomized Trial to Evaluate Miltefosine and Topical Granulocyte Macrophage Colony-stimulating Factor in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis in Brazil

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1337 ◽

2020 ◽

Author(s):

Paulo R L Machado ◽

Fernanda V O Prates ◽

Viviane Boaventura ◽

Tainã Lago ◽

Luiz H Guimarães ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Combined Treatment ◽

Healing Time ◽

Leishmania Braziliensis ◽

Colony Stimulating Factor ◽

Double Blind ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Abstract Background The treatment of cutaneous leishmaniasis (CL) in Brazil using pentavalent antimony (Sbv) is associated with a high rate of failure. Miltefosine has proven efficacy for CL caused by L. braziliensis, with a cure rate (CR) of 75%. A combined treatment with granulocyte macrophage colony-stimulating factor (GM-CSF) and miltefosine could increase CR and decrease healing time. Methods A randomized, double-blind clinical trial to evaluate the efficacy of miltefosine combined with topical GM-CSF (M + GM) vs miltefosine and placebo (M + P) vs Sbv in 133 patients with CL caused by L. braziliensis in Bahia, Brazil. Results The final CR at 180 days after the initiation of treatment was 44.4% in the Sbv group, 76.6% in the M + P group (P = .003 vs Sbv), and 75.6% in the M + GM group (P = .004 vs Sbv). The median healing time for cure was 102 days for the Sbv group and 60 days for both miltefosine groups (P = .0009). During the 6-month follow-up period, 4 relapses were documented: 1 in the Sbv group, 1 in the M + P group, and 2 in the M + GM group. Mild adverse events occurred in 65% of patients from the Sbv group, 76% and 79% from the M + P and M + GM groups respectively. Conclusions Miltefosine is more effective than Sbv for the treatment of CL caused by L. braziliensis in Brazil and accelerates the healing time. Association with GM-CSF does not improve therapeutic outcome. Clinical Trials Registration NCT03023111.

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