Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis

Hannah E. Cummings, Joseph Barbi, Patrick Reville, Steve Oghumu, Nicholas Zorko, Anasuya Sarkar, Tracy L. Keiser, Bao Lu, Thomas Rückle, Sanjay Varikuti, Claudio Lezama-Davila, Mark D. Wewers, Caroline Whitacre, Danuta Radzioch, Christian Rommel, Stéphanie Seveau, Abhay R. Satoskar

Research output: Contribution to journalArticlepeer-review

Abstract

Obligate intracellular pathogens such as Leishmania specifically target host phagocytes for survival and replication. Phosphoinositide 3-kinase γ (PI3Kγ), a member of the class I PI3Ks that is highly expressed by leukocytes, controls cell migration by initiating actin polymerization and cytoskeletal reorganization, which are processes also critical for phagocytosis. In this study,wedemonstrate that class IB PI3K, PI3Kγ, plays a critical role in pathogenesis of chronic cutaneous leishmaniasis caused by L. mexicana. Using the isoform-selective PI3Kγ inhibitor, AS-605240 and PI3Kγ gene-deficient mice, we show that selective blockade or deficiency of PI3Kγ significantly enhances resistance against L. mexicana that is associated with a significant suppression of parasite entry into phagocytes and reduction in recruitment of host phagocytes as well as regulatory T cells to the site of infection. Furthermore, we demonstrate that AS-605240 is as effective as the standard antileishmanial drug sodium stibogluconate in treatment of cutaneous leishmaniasis caused by L. mexicana. These findings reveal a unique role for PI3Kγ in Leishmania invasion and establishment of chronic infection, and demonstrate that therapeutic targeting of host pathways involved in establishment of infection may be a viable strategy for treating infections caused by obligate intracellular pathogens such as Leishmania.

Original languageEnglish (US)
Pages (from-to)1251-1256
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number4
DOIs
StatePublished - Jan 24 2012
Externally publishedYes

ASJC Scopus subject areas

  • General

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