Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
PLoS Comput Biol. 2012 Jan;8(1):e1002345. doi: 10.1371/journal.pcbi.1002345. Epub 2012 Jan 12.
Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations.
合并感染会改变宿主的免疫反应，但感染部位的全身和局部过程如何相互作用仍不清楚。大多数关于合并感染的研究都集中在一种感染物种、一种免疫功能或一组细胞上，并且经常侧重于感染的初始阶段。在这里，我们结合实验和数学建模来研究针对呼吸道细菌博德特氏菌（Bordetella bronchiseptica）和胃肠道蠕虫旋毛虫（Trichostrongylus retortaeformis）的单一和合并感染的免疫反应网络。我们的目标是确定可以代表整个宿主免疫反应本质的代表性介质和功能，并评估它们的相对贡献如何随时间和在单一和合并感染个体之间动态变化。使用细菌和寄生虫免疫学的现有知识构建了单一感染的基于网络的离散动态模型；将两个单一感染模型组合成一个合并感染模型，然后用我们的经验结果对其进行验证。模拟结果表明，辅助性 T 细胞介导的抗体和中性粒细胞反应导致博德特氏菌从肺部被吞噬和清除。在单一和合并感染中均如此，寄生虫没有导致明显的延迟。相比之下，当与细菌合并感染时，旋毛虫的强度下降更快。模拟表明，在合并感染中，中性粒细胞的大量募集，加上 IgG 的激活和嗜酸性粒细胞驱动的幼虫减少，这些在单一感染中也发挥了重要作用，有助于快速清除。通过对模型进行节点（免疫细胞）剔除的干扰分析，确定了在单一和合并感染中对寄生虫持续存在和清除至关重要的细胞。我们的综合方法捕捉到了细菌-寄生虫感染的体内免疫动力学，并确定了在自然种群中解释单一和合并感染个体间变异性的关键组成部分。
