Leishmania amazonensis Amastigotes Highly Express a Tryparedoxin Peroxidase Isoform That Increases Parasite Resistance to Macrophage Antimicrobial Defenses and Fosters Parasite Virulence

Calvin A. Henard, Eric D. Carlsen, Christie Hay, Peter E. Kima, Lynn Soong

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Professional phagocytes generate a myriad of antimicrobial molecules to kill invading microorganisms, of which nitrogen oxides are integral in controlling the obligate intracellular pathogen Leishmania. Although reactive nitrogen species produced by the inducible nitric oxide synthase (iNOS) can promote the clearance of intracellular parasites, some Leishmania species/stages are relatively resistant to iNOS-mediated antimicrobial activity. The underlying mechanism for this resistance remains largely uncharacterized. Here, we show that the amastigote form of L. amazonensis is hyper-resistant to the antimicrobial actions of cytokine-activated murine and human macrophages as compared to its promastigote counterpart. Amastigotes exhibit a marked ability to directly counter the cytotoxicity of peroxynitrite (ONOO-), a leishmanicidal oxidant that is generated during infection through the combined enzymatic activities of NADPH oxidase and iNOS. The enhanced antinitrosative defense of amastigotes correlates with the increased expression of a tryparedoxin peroxidase (TXNPx) isoform that is also upregulated in response to iNOS enzymatic activity within infected macrophages. Accordingly, ectopic over-expression of the TXNPx isoform by L. amazonensis promastigotes significantly enhances parasite resistance against ONOO- cytotoxicity. Moreover, TXNPx-overexpressing parasites exhibit greater intra-macrophage survival, and increased parasite growth and lesion development in a murine model of leishmaniasis. Our investigations indicate that TXNPx isoforms contribute to Leishmania's ability to adapt to and antagonize the hostile microenvironment of cytokine-activated macrophages, and provide a mechanistic explanation for persistent infection in experimental and human leishmaniasis.

Original languageEnglish (US)
Article numbere3000
JournalPLoS Neglected Tropical Diseases
Volume8
Issue number7
DOIs
StatePublished - 2014

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Leishmania
Nitric Oxide Synthase Type II
Virulence
Protein Isoforms
Parasites
Macrophages
Leishmaniasis
Nitrogen Oxides
Cytokines
L Forms
Reactive Nitrogen Species
Peroxynitrous Acid
NADPH Oxidase
Phagocytes
Infection
Growth and Development
Oxidants
tryparedoxin peroxidase

ASJC Scopus subject areas

  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Leishmania amazonensis Amastigotes Highly Express a Tryparedoxin Peroxidase Isoform That Increases Parasite Resistance to Macrophage Antimicrobial Defenses and Fosters Parasite Virulence. / Henard, Calvin A.; Carlsen, Eric D.; Hay, Christie; Kima, Peter E.; Soong, Lynn.

In: PLoS Neglected Tropical Diseases, Vol. 8, No. 7, e3000, 2014.

Research output: Contribution to journalArticle

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