Philipson Casandra W, Bassaganya-Riera Josep, Viladomiu Monica, Kronsteiner Barbara, Abedi Vida, Hoops Stefan, Michalak Pawel, Kang Lin, Girardin Stephen E, Hontecillas Raquel
Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA, United States of America; Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA, United States of America.
Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA, United States of America; Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, VA, United States of America; Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, VA, United States of America.
PLoS One. 2015 Sep 14;10(9):e0137839. doi: 10.1371/journal.pone.0137839. eCollection 2015.
Helicobacter pylori colonizes half of the world's population as the dominant member of the gastric microbiota resulting in a lifelong chronic infection. Host responses toward the bacterium can result in asymptomatic, pathogenic or even favorable health outcomes; however, mechanisms underlying the dual role of H. pylori as a commensal versus pathogenic organism are not well characterized. Recent evidence suggests mononuclear phagocytes are largely involved in shaping dominant immunity during infection mediating the balance between host tolerance and succumbing to overt disease. We combined computational modeling, bioinformatics and experimental validation in order to investigate interactions between macrophages and intracellular H. pylori. Global transcriptomic analysis on bone marrow-derived macrophages (BMDM) in a gentamycin protection assay at six time points unveiled the presence of three sequential host response waves: an early transient regulatory gene module followed by sustained and late effector responses. Kinetic behaviors of pattern recognition receptors (PRRs) are linked to differential expression of spatiotemporal response waves and function to induce effector immunity through extracellular and intracellular detection of H. pylori. We report that bacterial interaction with the host intracellular environment caused significant suppression of regulatory NLRC3 and NLRX1 in a pattern inverse to early regulatory responses. To further delineate complex immune responses and pathway crosstalk between effector and regulatory PRRs, we built a computational model calibrated using time-series RNAseq data. Our validated computational hypotheses are that: 1) NLRX1 expression regulates bacterial burden in macrophages; and 2) early host response cytokines down-regulate NLRX1 expression through a negative feedback circuit. This paper applies modeling approaches to characterize the regulatory role of NLRX1 in mechanisms of host tolerance employed by macrophages to respond to and/or to co-exist with intracellular H. pylori.
幽门螺杆菌作为胃微生物群的主要成员，定植于全球一半的人口中，导致终身慢性感染。宿主对该细菌的反应可能导致无症状、致病甚至有益的健康结果；然而，幽门螺杆菌作为共生菌与致病菌双重作用的潜在机制尚未得到充分表征。最近的证据表明，单核吞噬细胞在很大程度上参与了感染期间主导免疫的形成，介导宿主耐受与患上显性疾病之间的平衡。我们结合了计算建模、生物信息学和实验验证，以研究巨噬细胞与细胞内幽门螺杆菌之间的相互作用。在庆大霉素保护试验中，对六个时间点的骨髓来源巨噬细胞（BMDM）进行全局转录组分析，揭示了存在三个连续的宿主反应波：一个早期短暂调节基因模块，随后是持续和晚期效应反应。模式识别受体（PRR）的动力学行为与时空反应波的差异表达相关，并通过细胞外和细胞内检测幽门螺杆菌来诱导效应免疫。我们报告说，细菌与宿主细胞内环境的相互作用导致调节性NLRC3和NLRX1的显著抑制，其模式与早期调节反应相反。为了进一步描绘效应性和调节性PRR之间复杂的免疫反应和信号通路串扰，我们构建了一个使用时间序列RNAseq数据校准的计算模型。我们经过验证的计算假设是：1）NLRX1表达调节巨噬细胞中的细菌负荷；2）早期宿主反应细胞因子通过负反馈回路下调NLRX1表达。本文应用建模方法来表征NLRX1在巨噬细胞用于应对和/或与细胞内幽门螺杆菌共存的宿主耐受机制中的调节作用。
