Defensins enable macrophages to inhibit the intracellular proliferation of Listeria monocytogenes
Defensins enable macrophages to inhibit the intracellular proliferation of Listeria monocytogenes
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DOI：
10.1111/j.1462-5822.2010.01563.x
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发表时间：
2011-04-01
影响因子：
3.4
通讯作者：
Seveau, Stephanie
中科院分区：
文献类型：
--
作者：
Arnett, Eusondia;Lehrer, Robert I.;Seveau, Stephanie
P>；单核细胞增生性李斯特菌是一种兼性胞内病原体，可感染多种宿主细胞，包括巨噬细胞。为了避开吞噬小体杀菌环境，单核细胞增生性李氏杆菌分泌一种致孔毒素(李斯特菌素O，LLO)，将细菌释放到细胞质中。我们假设分别由人和非人灵长类中性粒细胞产生的α-防御素(HNPs)和/或人源化的Theta-Defensin(RC-1)多肽与巨噬细胞合作控制单核细胞增多性李斯特菌感染。我们的结果表明，HNP-1和RC-1通过抑制吞噬小体逃逸，使巨噬细胞能够控制单核细胞增多性李斯特菌在细胞内的生长，因此，细菌仍然被困在LAMP-1阳性的吞噬小体中。重要的是，HNP-1与巨噬细胞的相互作用和RC-1与细菌的相互作用是预防巨噬细胞感染所必需的。根据这些结果，RC-1是一种比HNP-1更有效的抗李斯特菌肽，HNP-1被巨噬细胞获取并运输到吞噬细菌。最后，HNP-1和RC-1的抗微生物活性得到了补充，它们通过两种机制防止LLO功能，阻止LLO依赖的巨噬细胞膜穿孔和LLO从细菌中释放。总之，在感染部位，抗菌肽，如HNP-1，与巨噬细胞之间的合作可能在针对单核细胞增多性李斯特菌的天然免疫防御中发挥关键作用。
P>Listeria monocytogenes is a facultative intracellular pathogen that infects a large diversity of host cells, including macrophages. To avoid the phagosome microbicidal environment, L. monocytogenes secretes a pore-forming toxin (listeriolysin O, LLO) that releases the bacterium into the cytoplasm. We hypothesized that the alpha-defensins (HNPs) and/or humanized theta-defensin (RC-1) peptides produced by human and non-human primate neutrophils, respectively, cooperate with macrophages to control L. monocytogenes infection. Our results establish that HNP-1 and RC-1 enable macrophages to control L. monocytogenes intracellular growth by inhibiting phagosomal escape, as a consequence, bacteria remain trapped in a LAMP-1-positive phagosome. Importantly, HNP-1 interaction with macrophages and RC-1 interaction with bacteria are required to prevent macrophage infection. In accordance with these results, RC-1 is a more potent anti-listerial peptide than HNP-1 and HNP-1 is acquired by macrophages and trafficked to the phagocytosed bacteria. Finally, HNP-1 and RC-1 antimicrobial activity is complemented by their ability to prevent LLO function through two mechanisms, blocking LLO-dependent perforation of macrophage membranes and the release of LLO from the bacteria. In conclusion, at the site of infection the cooperation between antimicrobial peptides, such as HNP-1, and macrophages likely plays a critical role in the innate immune defence against L. monocytogenes.