Neonatal RSV infection and alteration of allergic immune responses

摘要 婴儿发育中的免疫反应是建立平衡的反应系统的核心。 对感染性刺激适当，但不会引起具有潜在长期后遗症的改变的疾病状态。 呼吸道合胞病毒(RSV)通常是生活中遇到的第一个与临床相关的病原体，并且已经 建议改变免疫系统，影响未来的反应，如导致儿童过敏的反应 还有哮喘。其他早期生命过程也有助于免疫反应的发展，包括 微生物组的组装，这似乎在生命早期具有特别重要的作用 在我们的研究中，RSV感染后发生了改变。我们的初步数据显示，早期新生儿感染RSV 4周龄时骨髓来源的树突状细胞(DC)发生改变，提示先天改变时间延长 早期RSV感染所致的免疫表型。当新生的RSV感染小鼠对 过敏原在4周龄时，小鼠表现出严重的过敏性疾病表型 都没有被感染。后一组数据反映了新生儿患严重呼吸道合胞病毒风险增加的临床结果。 感染和感染最严重的人患过敏性疾病的几率在 童年。我们的初步数据也强调了DC功能的变化与 新生儿呼吸道合胞病毒感染后肠道细菌群落组成及血浆代谢物的变化 最显著的是黄嘌呤/尿酸代谢物。在目前的提议中，我们的假设是新生儿 呼吸道合胞病毒感染通过改变微生物群改变局部和系统免疫反应 这与全身性代谢物产生谱的变化是一致的，这种变化促进了 DC的规划导致过敏性疾病发展的易感性增加。我们 提供了强有力的初步数据，表明早期生命的呼吸道合胞病毒感染会改变肺部的 新生儿全身免疫反应的发展，导致肠道微生物群的改变和改变 新生儿的全身性代谢特征。特别是，我们的数据表明黄嘌呤/尿酸 进入炎症体激活的代谢途径被高度上调，并与 呼吸道合胞病毒感染过程中微生物群的改变。由于尿酸促进炎性小体激活和上调 IL-1、β和其他炎症介质，我们认为这一途径将显著促进长时间的 对免疫系统的长期影响。这些早期事件会影响过敏反应的进展 在晚年生活中通过免疫细胞表型的长期变化来系统地改变。对这一事件的调查 管理这些反应的机制将建立新的范例，在患者群体和 代表着我们对感染性生物如何改变发育中的新生儿的理解上的一个重大差距 免疫系统。

Abstract The developing immune response in infants is central to establishing a balanced system that reacts appropriately to infectious stimuli but does not induce altered disease states with potential long term sequelae. Respiratory syncytial virus (RSV) is often the first clinically relevant pathogen encountered in life and has been suggested to alter the immune system, affecting future responses, such as those leading to childhood allergies and asthma. Other early life processes also contribute to the development of immune responses including assembly of the microbiome, which appears to have a particularly important role early in life and significantly altered after RSV infection in our studies. Our preliminary data show that early neonatal infection with RSV alters bone marrow-derived dendritic cells (DC) at 4 weeks of age suggesting an prolonged altered innate immune phenotype due to the early RSV infection. When neonatal RSV infected mice are sensitized to allergens at 4 weeks of age, mice show an exacerbated allergic disease phenotype compared to those that were not infected. These latter data reflect clinical findings where neonates have increased risk of severe RSV infection and those most severely infected have an increased incidence to develop allergic disease during childhood. Our preliminary data also highlight that the change in DC function is associated with major shifts in the neonatal RSV-induced bacterial community composition of the gut and changes in plasma metabolite profiles, most notably xanthine/uric acid metabolites. In the present proposal our hypothesis is that neonatal RSV infection alters the local and systemic immune responses through alteration of the microbiome that is coincident with changes in systemic metabolite production profiles that promote altered programming of DC leading to increased susceptibility for the development of allergic disease. We have provided strong preliminary data that demonstrate that early life RSV infection of the lungs alters the development of the systemic immune responses in neonates, leads to gut microbiome alteration, and changes the systemic metabolic profile of the neonate. In particular, our data suggest that the xanthine/uric acid metabolic pathway that feeds into inflammasome activation is highly upregulated and is associated with the altered microbiome during RSV infection. As uric acid promotes inflammasome activation and upregulation of IL-1β and other inflammatory mediators we propose that this pathway will significantly contribute to the long- term effects on the immune system. These early events modify impact the progression of allergic responses systemically later in life through the long-term alteration of immune cell phenotypes. The investigation of the mechanisms that govern these responses will establish new paradigms to be tested in patient populations and represent a significant gap in our understanding of how infectious organisms alter the developing neonatal immune system.