Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis
Critical role for phosphoinositide 3-kinase gamma in parasite invasion and disease progression of cutaneous leishmaniasis
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DOI：
10.1073/pnas.1110339109
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发表时间：
2012-01-24
影响因子：
11.1
通讯作者：
Satoskar, Abhay R.
中科院分区：
文献类型：
--
作者：
Cummings, Hannah E.;Barbi, Joseph;Satoskar, Abhay R.
专性细胞内病原体如利什曼原虫特异性靶向宿主吞噬细胞以存活和复制。磷酸肌醇3-激酶γ（PI 3 K γ）是由白细胞高度表达的I类PI 3 K的成员，通过启动肌动蛋白聚合和细胞骨架重组来控制细胞迁移，这也是吞噬作用的关键过程。在这项研究中，我们证明了IB类PI 3 K，PI 3 K γ，在由L.墨西哥人。使用亚型选择性PI 3 K γ抑制剂AS-605240和PI 3 K γ基因缺陷小鼠，我们发现选择性阻断或PI 3 K γ缺陷显著增强对L. mexicana，其与寄生虫进入吞噬细胞的显著抑制和宿主吞噬细胞以及调节性T细胞向感染部位的募集减少相关。此外，我们证明AS-605240在治疗由利什曼原虫引起的皮肤利什曼病方面与标准抗利什曼病药物葡萄糖酸锑钠一样有效。墨西哥人。这些发现揭示了PI 3 K γ在利什曼原虫侵袭和建立慢性感染中的独特作用，并证明了治疗靶向参与建立感染的宿主途径可能是治疗由专性细胞内病原体如利什曼原虫引起的感染的可行策略。
Obligate intracellular pathogens such as Leishmania specifically target host phagocytes for survival and replication. Phosphoinositide 3-kinase gamma (PI3K gamma), 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, we demonstrate that class IB PI3K, PI3K gamma, plays a critical role in pathogenesis of chronic cutaneous leishmaniasis caused by L. mexicana. Using the isoform-selective PI3K gamma inhibitor, AS-605240 and PI3K gamma gene-deficient mice, we show that selective blockade or deficiency of PI3K gamma 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 PI3K gamma 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.