Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois, USA.
mBio. 2013 Mar 19;4(2):e00617-12. doi: 10.1128/mBio.00617-12.
Environmental pathogens survive and replicate within the outside environment while maintaining the capacity to infect mammalian hosts. For some microorganisms, mammalian infection may be a relatively rare event. Understanding how environmental pathogens retain their ability to cause disease may provide insight into environmental reservoirs of disease and emerging infections. Listeria monocytogenes survives as a saprophyte in soil but is capable of causing serious invasive disease in susceptible individuals. The bacterium secretes virulence factors that promote cell invasion, bacterial replication, and cell-to-cell spread. Recently, an L. monocytogenes chitinase (ChiA) was shown to enhance bacterial infection in mice. Given that mammals do not synthesize chitin, the function of ChiA within infected animals was not clear. Here we have demonstrated that ChiA enhances L. monocytogenes survival in vivo through the suppression of host innate immunity. L. monocytogenes ΔchiA mutants were fully capable of establishing bacterial replication within target organs during the first 48 h of infection. By 72 to 96 h postinfection, however, numbers of ΔchiA bacteria diminished, indicative of an effective immune response to contain infection. The ΔchiA-associated virulence defect could be complemented in trans by wild-type L. monocytogenes, suggesting that secreted ChiA altered a target that resulted in a more permissive host environment for bacterial replication. ChiA secretion resulted in a dramatic decrease in inducible nitric oxide synthase (iNOS) expression, and ΔchiA mutant virulence was restored in NOS2(-/-) mice lacking iNOS. This work is the first to demonstrate modulation of a specific host innate immune response by a bacterial chitinase.
Bacterial chitinases have traditionally been viewed as enzymes that either hydrolyze chitin as a food source or serve as a defense mechanism against organisms containing structural chitin (such as fungi). Recent evidence indicates that bacterial chitinases and chitin-binding proteins contribute to pathogenesis, primarily via bacterial adherence to chitin-like molecules present on the surface of mammalian cells. In contrast, mammalian chitinases have been linked to immunity via inflammatory immune responses that occur outside the context of infection, and since mammals do not produce chitin, the targets of these mammalian chitinases have remained elusive. This work demonstrates that a Listeria monocytogenes-secreted chitinase has distinct functional roles that include chitin hydrolysis and suppression of host innate immunity. The established link between chitinase and the inhibition of host inducible nitric oxide synthase (iNOS) expression may help clarify the thus far elusive relationship observed between mammalian chitinase enzymes and host inflammatory responses occurring in the absence of infection.
环境病原体在外部环境中生存和复制，同时保持感染哺乳动物宿主的能力。对于某些微生物来说，哺乳动物感染可能是一种相对罕见的事件。了解环境病原体如何保持致病能力，可以深入了解疾病的环境储库和新发感染。李斯特菌在土壤中作为腐生物生存，但能够在易感个体中引起严重的侵袭性疾病。该细菌分泌促进细胞入侵、细菌复制和细胞间传播的毒力因子。最近，研究表明李斯特菌的一种几丁质酶（ChiA）可增强小鼠的细菌感染。由于哺乳动物不合成几丁质，因此 ChiA 在感染动物体内的功能尚不清楚。在这里，我们证明 ChiA 通过抑制宿主固有免疫来增强李斯特菌在体内的存活能力。李斯特菌ΔchiA 突变株在感染后 48 小时内完全能够在靶器官内建立细菌复制。然而，在感染后 72 至 96 小时，ΔchiA 细菌数量减少，表明宿主对感染的免疫反应有效。通过野生型李斯特菌的转染可补充ΔchiA 相关的毒力缺陷，这表明分泌的 ChiA 改变了一个靶标，从而为细菌复制提供了一个更允许的宿主环境。ChiA 的分泌导致诱导型一氧化氮合酶（iNOS）表达的显著下降，并且缺乏 iNOS 的 NOS2(-/-) 小鼠中的ΔchiA 突变体毒力得到恢复。这项工作首次证明了细菌几丁质酶对特定宿主固有免疫反应的调节。
细菌几丁质酶传统上被视为水解几丁质作为食物来源的酶，或作为抵御含有结构几丁质（如真菌）的生物体的防御机制。最近的证据表明，细菌几丁质酶和几丁质结合蛋白主要通过细菌与存在于哺乳动物细胞表面的几丁质样分子的粘附作用而促进发病机制。相比之下，哺乳动物几丁质酶已通过发生在感染背景之外的炎症免疫反应与免疫联系在一起，由于哺乳动物不产生几丁质，这些哺乳动物几丁质酶的靶标仍然难以捉摸。这项工作表明，李斯特菌分泌的一种几丁质酶具有独特的功能作用，包括几丁质水解和抑制宿主固有免疫。几丁质酶与宿主诱导型一氧化氮合酶（iNOS）表达抑制之间已建立的联系可能有助于阐明迄今为止观察到的哺乳动物几丁质酶与感染缺失时发生的宿主炎症反应之间难以捉摸的关系。
