Neonatal RSV infection and alteration of allergic immune responses

摘要 婴儿免疫反应的发展是建立一个平衡系统的核心， 适合于感染性刺激，但不诱导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种临床相关病原体， 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 和哮喘。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，这似乎在生命早期起着特别重要的作用 在我们的研究中RSV感染后改变。我们的初步数据显示，新生儿早期感染RSV 在4周龄时改变了骨髓来源的树突状细胞（DC），表明先天性 免疫表型由于早期RSV感染。当新生RSV感染小鼠对 在4周龄的小鼠中，与那些 没有被感染后一组数据反映了新生儿重度RSV风险增加的临床结果 感染和那些感染最严重的人在感染期间发生过敏性疾病的发病率增加， 童年.我们的初步数据还强调，DC功能的变化与以下方面的重大转变有关： 新生儿RSV诱导的肠道细菌群落组成和血浆代谢产物的变化 谱，最显著的是黄嘌呤/尿酸代谢物。在目前的建议中，我们的假设是， RSV感染通过改变微生物组来改变局部和全身免疫应答 这与全身代谢产物产生谱的变化一致， DC的编程导致变应性疾病发展的易感性增加。我们 已经提供了强有力的初步数据，证明早期肺部RSV感染改变了 新生儿全身免疫反应的发展，导致肠道微生物组的改变， 新生儿的全身代谢情况。特别是，我们的数据表明，黄嘌呤/尿酸 导致炎性小体活化的代谢途径高度上调，并与炎症相关。 在RSV感染期间改变微生物组。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期的炎症反应。 对免疫系统的长期影响。这些早期事件改变影响过敏反应的进展 通过免疫细胞表型的长期改变，在以后的生活中全身性地发生。的调查 控制这些反应的机制将建立新的范式，在患者群体中进行测试， 代表了我们对传染性生物如何改变发育中的新生儿的理解的一个重大差距 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.