Premium
Targeting phosphoinositide 3‐kinase γ (PI3Kγ) in the treatment of cutaneous leishmaniasis caused by L. mexicana.
Author(s) -
Cummings Hannah Elizabeth,
Barbi J.,
Keiser T.,
Zorko N.,
Lu B.,
Gerard C.,
Ruckle T.,
Seveau S.,
Rommel C.,
Whitacre C.,
Satoskar A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.674.2
Subject(s) - pi3k/akt/mtor pathway , leishmania mexicana , leishmania , phosphoinositide 3 kinase , immunology , leishmaniasis , lesion , biology , kinase , cutaneous leishmaniasis , cancer research , parasite hosting , medicine , apoptosis , microbiology and biotechnology , pathology , biochemistry , world wide web , computer science
Class I PI3Ks are dual‐specificity lipid and protein kinases controlling cell growth, proliferation, survival, adhesion and motility. They include class IA (PI3Kα, PI3Kβ and PI3Kδ) and class IB (PI3Kγ). In this study, we examined the role of PI3Kγ in the development of cutaneous leishmaniasis caused by L. mexicana using a PI3Kγ‐specific inhibitor (PI3Kγ inh ) as well as PI3Kγ −/‐ mice. We found that daily treatment of L. mexicana‐ infected C57BL/6 mice with the PI3Kγ inh inhibited lesion growth and reduced parasite burdens without significant changes in host T cell responses. PI3Kγ inh reduced the early adherence of L. mexicana to BMDMs and inhibited uptake in both macrophages and neutrophils in vitro, indicating that PI3Kγ is critical for L. mexicana to enter these cells. PI3Kγ −/‐ mice were resistant to L mexicana infection , developing smaller lesions with fewer parasites than WT mice. PI3Kγ −/‐ had fewer macrophages and neutrophils within the lesions. Parasite uptake was also reduced in PI3Kγ −/‐ BMDMs. These data show that PI3Kγ mediates susceptibility to L. mexicana by 1) promoting the migration of neutrophils and macrophages to the lesion and 2) by facilitating entry of the parasite into these cells, which is critical for parasite survival. These data suggest that PI3Kγ is a therapeutic target for treatment of cutaneous L. mexicana infection.