Lauzon-Joset Jean-Francois, Mincham Kyle T, Scott Naomi M, Khandan Yasmine, Stumbles Philip A, Holt Patrick G, Strickland Deborah H
Centre de Recherche Institut Universitaire de Cardiologie et de Pneumologie de Québec Université Laval Québec QC Canada.
Telethon Kids Institute University of Western Australia Nedlands WA Australia.
Clin Transl Immunology. 2021 Jul 1;10(7):e1303. doi: 10.1002/cti2.1303. eCollection 2021.
Incomplete maturation of immune regulatory functions at birth is antecedent to the heightened risk for severe respiratory infections during infancy. Our forerunner animal model studies demonstrated that maternal treatment with the microbial-derived immune training agent OM-85 during pregnancy promotes accelerated postnatal maturation of mechanisms that regulate inflammatory processes in the offspring airways. Here, we aimed to provide proof of concept for a novel solution to reduce the burden and potential long-term sequelae of severe early-life respiratory viral infection through maternal oral treatment during pregnancy with OM-85, already in widespread human clinical use.
In this study, we performed flow cytometry and targeted gene expression (RT-qPCR) analysis on lungs from neonatal offspring whose mothers received oral OM-85 treatment during pregnancy. We next determined whether neonatal offspring from OM-85 treated mothers demonstrate enhanced protection against lethal lower respiratory infection with mouse-adapted rhinovirus (vMC), and associated lung immune changes.
Offspring from mothers treated with OM-85 during pregnancy display accelerated postnatal seeding of lung myeloid populations demonstrating upregulation of function-associated markers. Offspring from OM-85 mothers additionally exhibit enhanced expression of TLR4/7 and the IL-1β/NLRP3 inflammasome complex within the lung. These treatment effects were associated with enhanced capacity to clear an otherwise lethal respiratory viral infection during the neonatal period, with concomitant regulation of viral-induced IFN response intensity.
These results demonstrate that maternal OM-85 treatment protects offspring against lethal neonatal respiratory viral infection by accelerating development of innate immune mechanisms crucial for maintenance of local immune homeostasis in the face of pathogen challenge.
出生时免疫调节功能的不完全成熟是婴儿期严重呼吸道感染风险增加的前提。我们之前的动物模型研究表明，孕期用微生物衍生的免疫训练剂OM-85对母体进行治疗，可促进后代气道中调节炎症过程的机制在出生后加速成熟。在此，我们旨在为一种新的解决方案提供概念验证，即通过孕期对母体进行口服OM-85治疗（OM-85已在广泛的人类临床应用中），来减轻严重的早期生命期呼吸道病毒感染的负担及其潜在的长期后遗症。
在本研究中，我们对孕期接受口服OM-85治疗的母亲所生的新生后代的肺组织进行了流式细胞术和靶向基因表达（RT-qPCR）分析。接下来，我们确定了OM-85治疗的母亲所生的新生后代是否对适应小鼠的鼻病毒（vMC）致死性下呼吸道感染具有增强的抵抗力，以及相关的肺部免疫变化。
孕期接受OM-85治疗的母亲所生的后代，其出生后肺髓系细胞群体的定植加速，功能相关标志物上调。OM-85治疗的母亲所生的后代在肺内还表现出TLR4/7和IL-1β/NLRP3炎性小体复合物的表达增强。这些治疗效果与新生儿期清除原本致死性呼吸道病毒感染的能力增强相关，并伴有对病毒诱导的IFN反应强度的调节。
这些结果表明，孕期母体OM-85治疗可通过加速先天性免疫机制的发育来保护后代免受致死性新生儿呼吸道病毒感染，这些机制对于面对病原体挑战时维持局部免疫稳态至关重要。
