病原体感染的天然免疫防御效应

Innate immune defense effects of pathogenic microorganism infection

机体的天然免疫系统是古老的、保守的和重要的抗感染防御体系.脊椎动物、无脊椎动物甚至植物受到病原微生物攻击时,均可以活化并产生不同的天然免疫防御应答.天然免疫系统如何防御病原体微生物感染,一直是免疫学甚至生命科学领域的重要课题.因此,哺乳动物(小鼠(Mus musculus)和人)的天然免疫防御效应和机制研究成为目前免疫学领域的研究热点和重点.研究主要集中在病原体的免疫识别、免疫细胞集聚和病原体免疫清除等不同阶段的天然免疫防御效应和机制.本文主要从以上3个方面简要评述了近年来在天然免疫细胞防御病原微生物感染的效应及机制方面的研究进展.针对某一热点研究主题,也引用了较为详尽的文献综述.这将有助于研究者从整体上认识天然免疫系统、天然免疫细胞和分子对病原体感染的防御效应.

The innate immune system is old, conservative and important anti-infection defense system. How does the innate immune system defend against an array of invading microbial pathogens including bacteria, viruses, parasites and fungi, which becomes an important research topic in the immunological fields. This article just summarized the different stages of immune defense against pathogenic microorganism, including the innate immune recognition, the recruitment of innate immune cells, and the pathogen immune clearance. The innate immune system comprises various immune cells including DCs, macrophages and neutrophils that sense and respond rapidly to aid in the elimination of microbial pathogens, thereby providing the first line of host defense against infection. This early innate microbial sensing is achieved via the recognition of distinct molecular motifs, termed pathogen-associated molecular patterns（PAMPs）, of microbial components, such as proteins, lipids, nucleic acids and carbohydrates, by evolutionarily conserved host germline encoded pattern recognition receptors（PRRs）. The interactions between the various PRRs and their cognate PAMPs trigger a complex cascade of intracellular signaling pathways leading to the production of cytokines and chemokines that mediate the induction of antimicrobial and inflammatory responses. There are several distinct families of PRRs including Toll-like receptors（TLRs）, nucleotide-binding oligomerization domain（NOD）-like receptors（NLRs） and the retinoic acid-inducible gene-I（RIG-I）-like receptors（RLRs） are involved during this course. Macrophages and DCs engulf microbes by detecting PRRs. The result of pathogen recognition is activation of resident phagocytes and mast cells and the release of proinflammatory cytokines. Proinflammatory cytokines induce changes in local blood vessel endothelial cells that promote the conversion of the infected tissue to an inflamed state. In particular, TNF-a and IL-1 cause a series of morphological and molecular changes that collectively lead to increased migration of leukocytes and flow of plasma to the infected site. In most cases, neutrophils arrive within hours followed by a later influx of monocytes. After entering the site of inflammation, neutrophils phagocytose any available microbes and direct the contents of their granules toward these phagosomes. If neutrophils detect TNF-a, but do not directly encounter any microbial particles after entering the tissues, they release their granules into the extracellular space in an effort to create an inhospitable environment for nearby pathogens. All options for neutrophils, however, result in the same eventual fate： their death by apoptosis and clearance by macrophages. Macrophages enter the site of inflammation after neutrophils, called by many of the same signals. In addition to the clearance of apoptotic neutrophils, macrophages also contribute to the killing of microbial organisms. They engulf and degrade microbes using proteases, antimicrobial peptides. Depending on the inflammatory microenvironment, macrophages can also be programmed to various distinct subsets and the heterogeneity of circulating monocytes may predefine their polarization fate once they arrive at tissues. The innate immune system is also responsible for initiating an adaptive immune response specifically tailored to the invading microbe. DCs play a critical role in translating the appropriate signals from the innate to adaptive immune system to mediate the regulation of adaptive immunity. The adaptive immune system consists of B and T cells that express highly diverse repertoires of B- and T-cell receptors, respectively, and generates specificity in antibody and cellular responses and long-term memory. Our previously studies have demonstrated that sirtuin 1（SIRT1）, a histone deacetylase, plays an essential role in mediating proinflammatory signaling in DCs, consequentially modulating the balance of proinflammatory T helper type 1（TH1） cells and anti-inflammatory Foxp3~＋ regulatory T cells（T_（reg） cells）. And, it implicates a DC-based SIRT1-HIF1a metabolic checkpoint controls T cell specification in anti-infection immunity. Recently, SIRT1 also plays important effects in controlling differentiation of myeloid-derived suppressor cells（MDSCs） and Th9 cell differentiation in infectious inflammation.