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Expression of multiple CPB genes encoding cysteine proteases is required for Leishmania mexicana virulence in vivo

Hubert Denise1, Kathryn McNeil, Darren R Brooks

  • 1Wellcome Centre for Molecular Parasitology, The Anderson College, University of Glasgow, United Kingdom.

Infection and Immunity
|May 23, 2003
PubMed

Insights

Leishmania mexicana cysteine proteases (CPB) are crucial virulence factors. Multiple CPB genes are needed to restore virulence and induce a Th2 immune response in mice.

Area of Science:

  • Parasitology
  • Immunology
  • Molecular Biology

Background:

  • Leishmania mexicana causes cutaneous leishmaniasis.
  • The parasite possesses a multicopy gene array for cysteine proteases (CPB).
  • CPB are implicated as virulence factors in Leishmania.

Purpose of the Study:

  • To investigate the role of CPB gene copy number in Leishmania mexicana virulence.
  • To determine if single CPB genes can restore virulence in deficient mutants.
  • To understand the relationship between CPB expression, virulence, and host immune response.

Main Methods:

  • Generating Leishmania mexicana mutants deficient in the CPB gene array.
  • Reintroducing specific CPB genes (CPB2.8, CPB2) or multiple CPB genes via cosmids.
  • Assessing parasite virulence by measuring lesion growth in BALB/c mice.
  • Evaluating host immune response by measuring Th1/Th2 cytokine production (interleukin-4) and immunoglobulin levels (IgG1, IgE).

Main Results:

  • CPB-deficient mutants exhibited reduced virulence, poor lesion growth, and a Th1 response.
  • Reinsertion of single CPB genes failed to restore virulence or a Th2 response.
  • Re-expression of multiple CPB genes significantly restored virulence, parasite growth, and induced a Th2 response.
  • A Th2 response was indicated by increased interleukin-4, IgG1, and IgE levels.

Conclusions:

  • Leishmania mexicana cysteine proteases (CPB) are essential virulence factors.
  • The multicopy nature of the CPB gene array is critical for full virulence and induction of a Th2-biased immune response.
  • These findings explain the evolutionary advantage of maintaining multiple CPB genes in tandem arrays.

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