Epithelial regulation of innate immunity to respiratory syncytial virus
Epithelial regulation of innate immunity to respiratory syncytial virus
复制标题
DOI：
10.1165/ajrcmb.23.5.f204
复制
发表时间：
2000-11-01
影响因子：
6.4
通讯作者：
Haeberle, H
中科院分区：
文献类型：
--
作者：
Garofalo, RP;Haeberle, H
在2001年，我们将纪念呼吸道合胞病毒（RSV）研究45周年，该病毒被发现是黑猩猩感冒“医院爆发”的原因（1）。尽管进行了近半个世纪的积极临床和基础研究，但仍无法获得有效的疫苗，仅在美国，每年约有100，000名婴儿因RSV疾病住院（2）。此外，与严重RSV感染相关的长期发病率导致医疗保健负担和成本远远高于仅基于治疗急性原发性感染的住院费用估计的医疗保健负担和成本。具有免疫原性、保护性和非反应原性特性的RSV疫苗目前正在研究中，但其开发的一个重大障碍仍然是我们对决定病毒引起的下呼吸道感染严重程度的致病机制的理解不足。讽刺的是，第一种RSV福尔马林灭活疫苗（3）的不幸经历推动了密集的研究工作，这极大地促进了我们对免疫介导机制的理解，这些机制导致了接种疫苗的婴儿亚组中发生的疾病增强，但尚未完全确定自然获得性原发感染中的免疫致病成分。尽管如此，越来越多的实验证据表明，“先天”宿主反应的早期炎症和免疫事件特征可能是决定急性RSV感染的结果及其长期后果（哮喘和反复喘息）的关键。呼吸道粘膜的上皮是RSV的主要靶标，其主要功能是提供保护性物理屏障以抵抗有害的吸入刺激。在吸入或自身接种病毒进入鼻粘膜并感染局部呼吸道上皮后，RSV沿呼吸道传播沿着，主要通过病毒沿着胞质内桥的细胞间转移发生（4）。已经描述了由人上皮细胞产生的作为RSV感染的结果的许多分子。其中包括强效免疫调节和炎症介质，包括细胞因子（白细胞介素[IL]-1、肿瘤坏死因子[TNF]-α、IL-6、IL-11）、趋化因子（IL-8、GRO、MCP-1、MIP-1α、RANTES）、干扰素（IFN-γ/α）和生长因子（GM-CSF、G-CSF）（综述见[5]）。RSV感染后，这些分子中的一些似乎仅在下呼吸道呼吸道中选择性表达（6，7）。此外，II型肺泡上皮细胞能够产生调理素，如补体（8）和表面活性蛋白（9），负责中性粒细胞、单核细胞和巨噬细胞对病原体的血清非依赖性吞噬作用。因此，呼吸道上皮细胞似乎是理想的定位和武装作为宿主防御机制的启动子，通过调节先天免疫系统的原型细胞元件。在这方面，我们将简要回顾已知参与RSV感染的先天免疫系统的一些组成部分，特别是表面活性蛋白-A（SP-A），肺泡巨噬细胞，嗜酸性粒细胞，中性粒细胞和NK细胞，所有这些都可能受到感染的呼吸道粘膜上皮细胞的显着影响。
In the year 2001, we will mark the 45th anniversary of research on respiratory syncytial virus (RSV), the agent that was discovered as the cause of a “nosocomial outbreak” of colds in chimpanzees (1). Despite almost a half century of active clinical and basic investigations, an effective vaccine is still not available, and each year approximately 100,000 infants are hospitalized with RSV disease in the United States only (2). Moreover, the long-term morbidity that is associated with severe RSV infections results in health care burden and costs that are disproportionally higher than those estimated based only on hospitalization costs to treat acute primary infections. RSV vaccines with immunogenic, protective, and nonreactogenic properties are currently under investigation, but a significant obstacle to their development is still our poor understanding of the pathogenetic mechanisms that determine the severity of lower respiratory tract infections caused by the virus. Paradoxically, intense research efforts boosted by the unfortunate experience with the first RSV formalin-inactivated vaccine (3) has significantly contributed to our understanding of the immune-mediated mechanisms responsible for the enhanced disease that occurred in a subset of vaccinated infants, but has incompletely identified the immunopathogenic components in naturally acquired primary infection. Nonetheless, mounting experimental evidence suggests that early inflammatory and immune events characteristic of the “innate” host response may be crucial in determining the outcome of acute RSV infection as well as its long-term consequences (asthma and recurrent wheezing). The epithelium of the respiratory mucosa, the main function of which is to provide a protective physical barrier against injurious inhaled stimuli, is the main target of RSV. Following inhalation or self-inoculation of the virus into the nasal mucosa and infection of the local respiratory epithelium, RSV spreading along the respiratory tract occurs mainly by cell-to-cell transfer of the virus along the intracytoplasmic bridges (4). A number of molecules that are produced by human epithelial cells as a consequence of RSV infection have been described. Among them are potent immunomodulatory and inflammatory mediators, including cytokines (interleukin [IL]-1, tumor necrosis factor [TNF]-α, IL-6, IL-11), chemokines (IL-8, GRO, MCP-1, MIP-1α, RANTES), interferons (IFN-ß/α) and growth factors (GM-CSF, G-CSF)(reviewed in [5]). Some of these molecules appear to be selectively expressed only in the lower airway respiratory tract, following RSV infection (6, 7). In addition, type II alveolar epithelial cells are able to produce opsonins such as complement (8) and surfactant proteins (9) responsible for serum-independent phagocytosis of pathogens by neutrophils, monocytes, and macrophages. Therefore, respiratory epithelial cells appear to be ideally located and armed to function as initiators of host defense mechanisms by regulating the prototypic cellular elements of the innate immune system. In this Perspective we will briefly review some of the components of the innate immune system known to be involved in RSV infection, in particular surfactant protein-A (SP-A), alveolar macrophages, eosinophils, neutrophils, and NK cells, all of which may be significantly affected by the infected respiratory mucosa epithelium.