Effect of BMAP-28 antimicrobial peptides on Leishmania major promastigote and amastigote growth: Role of leishmanolysin in parasite survival

Miriam A. Lynn, Jason Kindrachuk, Alexandra K. Marr, Håvard Jenssen, Nelly Panté, Melissa R. Elliott, Scott Napper, Robert E. Hancock, W. Robert McMaster

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Background: Protozoan parasites, such as Leishmania, still pose an enormous public health problem in many countries throughout the world. Current measures are outdated and have some associated drug resistance, prompting the search into novel therapies. Several innovative approaches are under investigation, including the utilization of host defence peptides (HDPs) as emerging anti-parasitic therapies. HDPs are characterised by their small size, amphipathic nature and cationicity, which induce permeabilization of cell membranes, whilst modulating the immune response of the host. Recently, members of the cathelicidin family of HDPs have demonstrated significant antimicrobial activities against various parasites including Leishmania. The cathelicidin bovine myeloid antimicrobial peptide 28 (BMAP-28) has broad antimicrobial activities and confers protection in animal models of bacterial infection or sepsis. We tested the effectiveness of the use of BMAP-28 and two of its isomers the D-amino acid form (D-BMAP-28) and the retro-inverso form (RI-BMAP-28), as anti-leishmanial agents against the promastigote and amastigote intracellular Leishmania major lifecycle stages. Methodology/Principal Findings: An MTS viability assay was utilized to show the potent antiparasitic activity of BMAP-28 and its protease resistant isomers against L. major promastigotes in vitro. Cell membrane permeability assays, caspase 3/7, Tunel assays and morphologic studies suggested that this was a late stage apoptotic cell death with early osmotic cell lysis caused by the antimicrobial peptides. Furthermore, BMAP-28 and its isomers demonstrated anti-leishmanial activities against intracellular amastigotes within a macrophage infection model. Conclusions/Significance: Interestingly, D-BMAP-28 appears to be the most potent antiparasitic of the three isomers against wild type L. major promastigotes and amastigotes. These exciting results suggest that BMAP-28 and its protease resistant isomers have significant therapeutic potential as novel anti-leishmanials.

LanguageEnglish
Article numbere1141
JournalPLoS Neglected Tropical Diseases
Volume5
Issue number5
DOIs
Publication statusPublished - 1 May 2011

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Lynn, Miriam A. ; Kindrachuk, Jason ; Marr, Alexandra K. ; Jenssen, Håvard ; Panté, Nelly ; Elliott, Melissa R. ; Napper, Scott ; Hancock, Robert E. ; McMaster, W. Robert. / Effect of BMAP-28 antimicrobial peptides on Leishmania major promastigote and amastigote growth : Role of leishmanolysin in parasite survival. In: PLoS Neglected Tropical Diseases. 2011 ; Vol. 5, No. 5.
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abstract = "Background: Protozoan parasites, such as Leishmania, still pose an enormous public health problem in many countries throughout the world. Current measures are outdated and have some associated drug resistance, prompting the search into novel therapies. Several innovative approaches are under investigation, including the utilization of host defence peptides (HDPs) as emerging anti-parasitic therapies. HDPs are characterised by their small size, amphipathic nature and cationicity, which induce permeabilization of cell membranes, whilst modulating the immune response of the host. Recently, members of the cathelicidin family of HDPs have demonstrated significant antimicrobial activities against various parasites including Leishmania. The cathelicidin bovine myeloid antimicrobial peptide 28 (BMAP-28) has broad antimicrobial activities and confers protection in animal models of bacterial infection or sepsis. We tested the effectiveness of the use of BMAP-28 and two of its isomers the D-amino acid form (D-BMAP-28) and the retro-inverso form (RI-BMAP-28), as anti-leishmanial agents against the promastigote and amastigote intracellular Leishmania major lifecycle stages. Methodology/Principal Findings: An MTS viability assay was utilized to show the potent antiparasitic activity of BMAP-28 and its protease resistant isomers against L. major promastigotes in vitro. Cell membrane permeability assays, caspase 3/7, Tunel assays and morphologic studies suggested that this was a late stage apoptotic cell death with early osmotic cell lysis caused by the antimicrobial peptides. Furthermore, BMAP-28 and its isomers demonstrated anti-leishmanial activities against intracellular amastigotes within a macrophage infection model. Conclusions/Significance: Interestingly, D-BMAP-28 appears to be the most potent antiparasitic of the three isomers against wild type L. major promastigotes and amastigotes. These exciting results suggest that BMAP-28 and its protease resistant isomers have significant therapeutic potential as novel anti-leishmanials.",
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Effect of BMAP-28 antimicrobial peptides on Leishmania major promastigote and amastigote growth : Role of leishmanolysin in parasite survival. / Lynn, Miriam A.; Kindrachuk, Jason; Marr, Alexandra K.; Jenssen, Håvard; Panté, Nelly; Elliott, Melissa R.; Napper, Scott; Hancock, Robert E.; McMaster, W. Robert.

In: PLoS Neglected Tropical Diseases, Vol. 5, No. 5, e1141, 01.05.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of BMAP-28 antimicrobial peptides on Leishmania major promastigote and amastigote growth

T2 - PLoS Neglected Tropical Diseases

AU - Lynn, Miriam A.

AU - Kindrachuk, Jason

AU - Marr, Alexandra K.

AU - Jenssen, Håvard

AU - Panté, Nelly

AU - Elliott, Melissa R.

AU - Napper, Scott

AU - Hancock, Robert E.

AU - McMaster, W. Robert

PY - 2011/5/1

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N2 - Background: Protozoan parasites, such as Leishmania, still pose an enormous public health problem in many countries throughout the world. Current measures are outdated and have some associated drug resistance, prompting the search into novel therapies. Several innovative approaches are under investigation, including the utilization of host defence peptides (HDPs) as emerging anti-parasitic therapies. HDPs are characterised by their small size, amphipathic nature and cationicity, which induce permeabilization of cell membranes, whilst modulating the immune response of the host. Recently, members of the cathelicidin family of HDPs have demonstrated significant antimicrobial activities against various parasites including Leishmania. The cathelicidin bovine myeloid antimicrobial peptide 28 (BMAP-28) has broad antimicrobial activities and confers protection in animal models of bacterial infection or sepsis. We tested the effectiveness of the use of BMAP-28 and two of its isomers the D-amino acid form (D-BMAP-28) and the retro-inverso form (RI-BMAP-28), as anti-leishmanial agents against the promastigote and amastigote intracellular Leishmania major lifecycle stages. Methodology/Principal Findings: An MTS viability assay was utilized to show the potent antiparasitic activity of BMAP-28 and its protease resistant isomers against L. major promastigotes in vitro. Cell membrane permeability assays, caspase 3/7, Tunel assays and morphologic studies suggested that this was a late stage apoptotic cell death with early osmotic cell lysis caused by the antimicrobial peptides. Furthermore, BMAP-28 and its isomers demonstrated anti-leishmanial activities against intracellular amastigotes within a macrophage infection model. Conclusions/Significance: Interestingly, D-BMAP-28 appears to be the most potent antiparasitic of the three isomers against wild type L. major promastigotes and amastigotes. These exciting results suggest that BMAP-28 and its protease resistant isomers have significant therapeutic potential as novel anti-leishmanials.

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