群体感应信号分子对免疫系统的影响

Effects of Quorum Sensing Molecules on The Immune System

近年来,宿主导向的抗菌药物研发逐步成为抗感染领域的热点。通过研究宿主和病原菌的相互作用机制,发现免疫系统是宿主导向抗菌药物的关键靶点之一。在以细菌为首的微生物种群中存在一种通讯交流系统,称为群体感应系统,其主要用于调整多微生物群落结构并协调群体行为。当微生物分泌的群体感应信号分子达到阈值浓度时,激活了群体感应系统并引起微生物整体基因表达变化。除了对微生物自身密度的调控外,群体感应信号分子还可以作为病原微生物与宿主之间的纽带进入宿主免疫系统并发挥作用,在影响免疫细胞形态结构、细胞因子分泌以及诱导细胞凋亡等方面导致宿主免疫损伤,造成宿主免疫功能失常。因此以宿主免疫系统为作用靶点,以群体感应信号分子为目标开发抗菌药物,可以有效抑制病原菌对宿主免疫功能的侵袭并协助宿主抗菌。本文对重要群体感应信号分子引发的宿主免疫应答反应机制进行综述,深入探究宿主导向抗菌药物的可能作用靶点,以期为预防或治疗病原体感染以及相关药物研发提供新方向。

In recent years,the development of host-acting antibacterial compounds has gradually become a hotspot in the field of anti-infection.Through research on the interaction mechanism between hosts and pathogenic bacteria,it has been found that the immune system is one of the key targets of host-acting antibacterial compounds.There is a communication system called the quorum sensing system in microorganisms,which mainly adjusts the structure of multi-microbial community and coordinates the group behavior.When the quorum sensing molecules secreted by microorganisms reach a threshold concentration,the quorum sensing system is activated and the overall gene expression of the microorganism is changed.In addition to regulating the density of microorganisms,quorum sensing molecules can also act as a link between pathogenic microorganisms and hosts,entering the host immune system and playing a role in affecting the morphological structure of immune cells,secreting cytokines,and inducing apoptosis,leading to host immune injury and causing host immune dysfunction.The key mechanism of 3-oxo-C12-HSL and other acyl-homoserine lactone(AHL)molecules in the innate immune system has been extensively studied.The lipid solubility allows AHLs to pass through the plasma membrane of host immune cells easily and induce dissolution of lipid domains.Then,it acts through signaling pathways such as p38MAPK and JAK-STAT,further influencing the immune cell’s defense response to bacteria and potentially leading to cell apoptosis.Additionally,the human lactonase paraoxonase 2,which can degrade 3-oxo-C12-HSL,has been found in macrophage.It acts as an immune regulator that promotes macrophage phagocytosis of pathogens and is hypothesized to have the ability to reduce bacterial resistance.The mechanism of quorum sensing molecules in the adaptive immune system is less studied,the current results suggest that 3-oxo-C12-HSL is closely related to the mitochondrial pathway in host immune cells.For example,3-oxo-C12-HSL induces apoptosis of Jurkat cells by inhibiting the expression of three mitochondrial electron transport chain proteins;it can also trigger mitochondrial dysfunction and induce mast cell apoptosis through Ca2+signaling.Among the quorum sensing molecules,the AHLs have the greatest impact on plant immune system.The different effects on plant resistance depends on the chain lengths of acyl groups in bacterial-produced AHLs.Short-chain AHLs(C4-HSL and C8-HSL)induce plant resistance to pathogenic bacteria mainly through the auxin pathway and jasmonic acid pathway.Long-chain AHL(3-oxo-C14-HSL)is commonly used in hosts against fungal pathogens by inducing stomata defense responses,and the reaction process is related to salicylic acid.Diffusible signal factor molecules also interfere with the stomatal immunity caused by pathogens.It may act through the formin nanoclustering-mediated actin assembly and MPK3 pathway to inhibit the innate immunity of Arabidopsis.In summary,AHLs induced different plant pathways and affects the plant-bacteria interactions to trigger plant immunity.As a quorum sensing molecule of fungi,farnesol has similar effects on host immunity as AHLs,such as stimulating cytokine secretion and activating an inflammatory response.It also plays a unique role on dendritic cell differentiation and maturation.In addition,studies have found that farnesol has a protective effect on autoimmune encephalomyelitis,which may be related to its effect on the composition of intestinal microorganisms of the host.Therefore,targeting the host immune system and quorum sensing molecules to develop antibacterial compounds can effectively inhibit the invasion of pathogens and subserve the host to resist the influence of pathogenic bacteria.This article will review the mechanism of host immune responses triggered by important quorum sensing molecules,aiming to explore the targets of host-acting antibacterial compounds and provide new directions for the prevention or treatment of causative infectious sources and the development of related drugs.