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Ex vivo host and parasite response to antileishmanial drugs and immunomodulators.
PLoS Negl Trop Dis. 2015 May; 9(5):e0003820.PN

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.

Authors+Show Affiliations

Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia.Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia.Yale University School of Public Health, New Haven, Connecticut, United States of America.Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26024228

Citation

Gonzalez-Fajardo, Laura, et al. "Ex Vivo Host and Parasite Response to Antileishmanial Drugs and Immunomodulators." PLoS Neglected Tropical Diseases, vol. 9, no. 5, 2015, pp. e0003820.
Gonzalez-Fajardo L, Fernández OL, McMahon-Pratt D, et al. Ex vivo host and parasite response to antileishmanial drugs and immunomodulators. PLoS Negl Trop Dis. 2015;9(5):e0003820.
Gonzalez-Fajardo, L., Fernández, O. L., McMahon-Pratt, D., & Saravia, N. G. (2015). Ex vivo host and parasite response to antileishmanial drugs and immunomodulators. PLoS Neglected Tropical Diseases, 9(5), e0003820. https://doi.org/10.1371/journal.pntd.0003820
Gonzalez-Fajardo L, et al. Ex Vivo Host and Parasite Response to Antileishmanial Drugs and Immunomodulators. PLoS Negl Trop Dis. 2015;9(5):e0003820. PubMed PMID: 26024228.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ex vivo host and parasite response to antileishmanial drugs and immunomodulators. AU - Gonzalez-Fajardo,Laura, AU - Fernández,Olga Lucía, AU - McMahon-Pratt,Diane, AU - Saravia,Nancy Gore, Y1 - 2015/05/29/ PY - 2014/07/28/received PY - 2015/05/10/accepted PY - 2015/5/30/entrez PY - 2015/5/30/pubmed PY - 2016/4/1/medline SP - e0003820 EP - e0003820 JF - PLoS neglected tropical diseases JO - PLoS Negl Trop Dis VL - 9 IS - 5 N2 - 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. SN - 1935-2735 UR - https://www.unboundmedicine.com/medline/citation/26024228/Ex_vivo_host_and_parasite_response_to_antileishmanial_drugs_and_immunomodulators_ L2 - https://dx.plos.org/10.1371/journal.pntd.0003820 DB - PRIME DP - Unbound Medicine ER -