李斯特菌是一種食源性病原體,，可使人和動物嚴重致病?，F(xiàn)在,，名為GILT (interferon-γ-inducible lysosomal thiol reductase)的酶被發(fā)現(xiàn)是李斯特菌感染的一個關鍵宿主因子。一旦進入體內,，李斯特菌便產(chǎn)生一種能形成孢子的毒素,，即李斯特菌素-O (LLO)，該毒素能將被吞噬的細菌釋放進巨噬細胞的胞液中,，在那里,，它們可以復制。在具有活性之前,，LLO需要被還原,，而調控其還原的是宿主的GILT酶。缺少GILT的小鼠對李斯特菌具有抵抗力,。這項研究工作為一種抗生素抵抗力越來越受到關注的疾病提供了一個新的潛在治療目標,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 455, 1244-1247 (30 October 2008) | doi:10.1038/nature07344
GILT is a critical host factor for Listeria monocytogenes infection
Reshma Singh1,2, Amanda Jamieson1,3 & Peter Cresswell1,2
1 Department of Immunobiology,
2 Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06250-8011, USA
3 Present address: Max F. Perutz Laboratories GmbH, Rennweg 95a, 1030 Wien 3, Landstrae, Wiene A1030, Austria.
Listeria monocytogenes is a Gram-positive, intracellular, food-borne pathogen that can cause severe illness in humans and animals. On infection, it is actively phagocytosed by macrophages1; it then escapes from the phagosome, replicates in the cytosol, and subsequently spreads from cell to cell by a non-lytic mechanism driven by actin polymerization2. Penetration of the phagosomal membrane is initiated by the secreted haemolysin listeriolysin O (LLO), which is essential for vacuolar escape in vitro and for virulence in animal models of infection3. Reduction is required to activate the lytic activity of LLO in vitro 4, 5, 6, and we show here that reduction by the enzyme -interferon-inducible lysosomal thiol reductase (GILT, also called Ifi30) is responsible for the activation of LLO in vivo. GILT is a soluble thiol reductase expressed constitutively within the lysosomes of antigen-presenting cells7, 8, and it accumulates in macrophage phagosomes as they mature into phagolysosomes9. The enzyme is delivered by a mannose-6-phosphate receptor-dependent mechanism to the endocytic pathway, where amino- and carboxy-terminal pro-peptides are cleaved to generate a 30-kDa mature enzyme7, 8, 10. The active site of GILT contains two cysteine residues in a CXXC motif that catalyses the reduction of disulphide bonds7, 8. Mice lacking GILT are deficient in generating major histocompatibility complex class-II-restricted CD4+ T-cell responses to protein antigens that contain disulphide bonds11, 12. Here we show that these mice are resistant to L. monocytogenes infection. Replication of the organism in GILT-negative macrophages, or macrophages expressing an enzymatically inactive GILT mutant, is impaired because of delayed escape from the phagosome. GILT activates LLO within the phagosome by the thiol reductase mechanism shared by members of the thioredoxin family. In addition, purified GILT activates recombinant LLO, facilitating membrane permeabilization and red blood cell lysis. The data show that GILT is a critical host factor that facilitates L. monocytogenes infection.
