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Human cutaneous leishmaniasis: interferon-dependent expression of double-stranded RNA-dependent protein kinase (PKR)

Aislan de Carvalho Vivarini1, Renata de Meirelles Santos Pereira, Karina Luiza Dias Teixeira

  • 1Laboratório de Parasitologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, RJ, Brazil.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|August 18, 2011
PubMed

Insights

The type I interferon (IFN-1)/PKR pathway is crucial in Leishmania amazonensis infections. This axis, triggered by TLR2, sustains infection and influences disease severity in humans.

Area of Science:

  • Immunology
  • Molecular Biology
  • Parasitology

Background:

  • Leishmania amazonensis infection impacts immune responses.
  • The type I interferon (IFN-1) and Protein Kinase R (PKR) signaling pathway's role in leishmaniasis is not fully understood.

Purpose of the Study:

  • To investigate the type I interferon (IFN-1)/PKR axis in Leishmania amazonensis infection.
  • To elucidate the mechanisms triggering and sustaining this pathway.
  • To correlate pathway activity with disease manifestation in humans.

Main Methods:

  • Reporter assays in macrophages and HEK-293T cells.
  • Infection of Toll-like receptor 2 (TLR2)-knockout and IFN receptor (IFNR)-knockout mouse macrophages.
  • Analysis of PKR, IFN-1, and superoxide dismutase 1 (SOD1) transcript levels.
  • Immunohistochemical analysis of human leishmaniasis lesions.

Main Results:

  • Leishmania infection upregulated PKR and IFN-β expression, dependent on TLR2 engagement.
  • PKR signaling is essential for Leishmania-induced IFN-1 expression, sustaining PKR levels and enhancing infection.
  • SOD1 transcript levels increased during infection and were further enhanced by IFN-1, but abrogated by dominant-negative PKR.
  • Human lesions from anergic diffuse cutaneous leishmaniasis showed higher PKR/IFN-1 expression than localized cutaneous leishmaniasis.

Conclusions:

  • The IFN-1/PKR axis is a key player in Leishmania amazonensis infection outcome.
  • TLR2 engagement initiates the IFN-1/PKR pathway, which sustains infection and influences disease severity.
  • This pathway represents a potential target for therapeutic interventions in leishmaniasis.

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