病原微生物入侵中枢神经系统机制的研究进展

Advances in the Study of Mechanisms of Pathogen Invasion into Central Nervous System

新冠疫情后,亚健康人群数量迅速增加,加之近年来全球旅行、气候变化和接触野生动物等频率升高可能导致人兽共患病原体现象增加,中枢神经系统(Central nervous system,CNS)感染的发病率持续上升,已成为导致人类伤残调整寿命年增加的主要原因之一。由于CNS感染病死率高,且给机体造成严重的后遗症,其也是目前最严峻的全球公共卫生挑战之一。为抵御病原体入侵,宿主在体表和体内构筑了一系列屏障结构,包括皮肤屏障、血肺屏障、血睾屏障及血脑屏障(Blood-brain barrier,BBB)等。其中,BBB是一种复杂的屏障结构,由多种细胞和非细胞成分组成。作为机体内隔离中枢与外周的生物屏障,BBB能够阻止绝大多数有害物质侵入脑部,从而保证脑部内环境的动态平衡与CNS的正常运转。然而,病原微生物经过长时间的进化,已经开发出多种途径来穿越BBB以实现入侵CNS。现今,已有5种入侵途径被研究人员所证实,包括感染或破坏脑内皮细胞;通过转胞吞作用穿过BBB;以“特洛伊木马”的形式,通过被感染的白细胞浸润而穿过BBB;通过细胞旁间隙进入CNS;以及通过轴突运输由外周绕过BBB进入CNS。CNS感染性疾病的严重程度和复杂性受到病原本身、宿主BBB结构和功能及神经侵袭途径的多样性影响。此外,随着研究的深入,病原体利用蛋白互作、调节BBB通透性及利用胞吞作用入侵CNS的分子机制被详细解析,这使得一些药物的CNS递送成为可能,也为开发全新的CNS药物递送系统奠定了一定的理论基础。因此,充分了解BBB结构和病原微生物入侵CNS途径,将有助于研发控制病原入侵、新型脑靶向药物及新的递送系统以减轻宿主CNS中已建立感染的策略。

In post-pandemic period of COVID-19,the increase in the number of sub-healthy population,coupled with factors such as global travel,climate change,and increased contact with wildlife,may lead to a rise in the incidence of central nervous system(Central nervous system,CNS)infections by potential zoonotic pathogens,which has become one of the main reasons for the increase in adjusted life years lost due to human disability.Due to the high case fatality rate of CNS infection and the severe sequelae of the body,it is also one of the most serious global public health challenges at present.To resist pathogen invasion,hosts have constructed a series of barrier structures on their surfaces and within their bodies,including skin barrier,blood-lung barrier,blood-testis barrier and blood-brain barrier(BBB).Among these,the BBB is a complex barrier structure composed of various cellular and non-cellular components.As a biological barrier isolating the CNS from the periphery,BBB can prevent a vast majority of harmful substances from entering the brain,thus ensuring the dynamic equilibrium of the brain’s internal environment and the normal functioning of the CNS.However,through long-term evolution,pathogens have developed multiple pathways to cross the BBB and invade the CNS.Currently,five invasion pathways have been confirmed by researchers,including infection or disruption of brain endothelial cells;crossing the BBB through transcellular migration;infiltrating through the BBB as a“Trojan horse”via infected leukocytes;entering the CNS through paracellular spaces;and bypassing the BBB and entering the CNS through axonal transport from the periphery.The severity and complexity of CNS infectious diseases are influenced by the nature of the pathogen itself,the structure and function of the host BBB and the diversity of neural invasion pathways.Furthermore,the molecular mechanisms by which pathogens utilize protein interactions,regulate BBB permeability,and invade the CNS through phagocytosis have been elucidated in detail.This has made CNS delivery of certain drugs possible and also laid a theoretical foundation for the development of entirely new CNS drug delivery systems.Therefore,a comprehensive understanding of the structure of the BBB and the pathways through which pathogens invade the CNS will contribute to the development of strategies to control pathogen invasion,novel brain-targeted drugs,and new delivery systems to mitigate established infections in the host CNS.