The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection

Dawn M. Wetzel, Emma L. Rhodes, Shaoguang Li, Diane McMahon-Pratt, Anthony J. Koleske

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis. Amastigotes, the life cycle stage found in the human host, bind Fc receptors and enter macrophages primarily through immunoglobulin-mediated phagocytosis. However, the host machinery that mediates amastigote uptake is poorly understood.We have previously shown that the Arg (also known as Abl2) nonreceptor tyrosine kinase facilitates L. amazonensis amastigote uptake by macrophages. Using small-molecule inhibitors and primary macrophages lacking specific Src family kinases, we now demonstrate that the Hck, Fgr and Lyn kinases are also necessary for amastigote uptake by macrophages. Src-mediated Arg activation is required for efficient uptake. Interestingly, the dual Arg and Src kinase inhibitor bosutinib, which is approved to treat cancer, not only decreases amastigote uptake, but also significantly reduces disease severity and parasite burden in Leishmania-infected mice. Our results suggest that leishmaniasis could potentially be treated with host-cellactive agents such as kinase inhibitors.

Original languageEnglish (US)
Pages (from-to)3130-3143
Number of pages14
JournalJournal of cell science
Volume129
Issue number16
DOIs
StatePublished - 2016

Keywords

  • Abl
  • Kinase
  • Leishmania
  • Macrophage
  • Phagocytosis
  • Src

ASJC Scopus subject areas

  • Cell Biology

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