Journal
JOURNAL OF IMMUNOLOGY
Volume 186, Issue 1, Pages 411-422Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1002175
Keywords
-
Categories
Funding
- Wellcome Trust [081877]
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa no Estado do Rio de Janeiro
- Conselho Nacional de Pesquisas
Ask authors/readers for more resources
Leishmania major is a protozoan parasite that causes skin ulcerations in cutaneous leishmaniasis. In the mammalian host, the parasite resides in professional phagocytes and has evolved to avoid killing by macrophages. We identified L. major genes encoding inhibitors of serine peptidases (ISPs), which are orthologs of bacterial ecotins, and found that ISP2 inhibits trypsin-fold S1A family peptidases. In this study, we show that L. major mutants deficient in ISP2 and ISP3 (Delta isp2/3) trigger higher phagocytosis by macrophages through a combined action of the complement type 3 receptor, TLR4, and unregulated activity of neutrophil elastase ( NE), leading to parasite killing. Whereas all three components are required to mediate enhanced parasite uptake, only TLR4 and NE are necessary to promote parasite killing postinfection. We found that the production of superoxide by macrophages in the absence of ISP2 is the main mechanism controlling the intracellular infection. Furthermore, we show that NE modulates macrophage infection in vivo, and that the lack of ISP leads to reduced parasite burdens at later stages of the infection. Our findings support the hypothesis that ISPs function to prevent the activation of TLR4 by NE during the Leishmania-macrophage interaction to promote parasite survival and growth. The Journal of Immunology, 2011, 186: 411-422.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available