Department of Pharmacy, Uppsala University, Uppsala, Sweden.
CPT Pharmacometrics Syst Pharmacol. 2023 Dec;12(12):1972-1987. doi: 10.1002/psp4.13046. Epub 2023 Oct 16.
Neutrophil granulocytes are key components of the host response against pathogens, and severe neutropenia, with neutrophil counts below 0.5 × 10 cells/mL, renders patients increasingly vulnerable to infections. Published in vitro (n = 7) and in vivo (n = 5) studies with time-course information on bacterial and neutrophil counts were digitized to characterize the kinetics of neutrophil-mediated bacterial killing and inform on the immune systems' contribution to the clearance of bacterial infections. A mathematical model for the in vitro dynamics of bacteria and the kinetics of neutrophil-mediated phagocytosis and digestion was developed, which was extended to in vivo studies in immune-competent and immune-compromised mice. Neutrophil-mediated bacterial killing was described by two first-order processes-phagocytosis and digestion-scaled by neutrophil concentration, where 50% of the maximum was achieved at neutrophil counts of 1.19 × 10 cells/mL (phagocytosis) and 6.55 × 10 cells/mL (digestion). The process efficiencies diminished as the phagocytosed bacteria to total neutrophils ratio increased (with 50% reduction at a ratio of 3.41). Neutrophil in vivo dynamics were captured through the characterization of myelosuppressive drug effects and postinoculation neutrophil influx into lungs and by system differences (27% bacterial growth and 9.3% maximum capacity, compared with in vitro estimates). Predictions showed how the therapeutically induced reduction of neutrophil counts enabled bacterial growth, especially when falling below 0.5 × 10 cells/mL, whereas control individuals could deal with all tested bacterial burdens (up to 10 colony forming units/g lung). The model-based characterization of neutrophil-mediated bacterial killing simultaneously predicted data across in vitro and in vivo studies and may be used to inform the capacity of host-response at the individual level.
中性粒细胞是宿主抵御病原体的关键组成部分，严重中性粒细胞减少症（中性粒细胞计数低于 0.5×10 个细胞/mL）使患者越来越容易受到感染。发表的具有细菌和中性粒细胞计数时间过程信息的体外（n=7）和体内（n=5）研究被数字化，以描述中性粒细胞介导的细菌杀伤动力学，并了解免疫系统对清除细菌感染的贡献。开发了一种用于体外细菌动力学和中性粒细胞介导的吞噬和消化动力学的数学模型，该模型扩展到免疫功能正常和免疫功能低下的小鼠的体内研究。中性粒细胞介导的细菌杀伤由两个一级过程描述——吞噬和消化，其规模由中性粒细胞浓度决定，其中最大杀伤效率在中性粒细胞计数为 1.19×10 个细胞/mL（吞噬）和 6.55×10 个细胞/mL（消化）时达到 50%。随着被吞噬的细菌与总中性粒细胞的比例增加（比例为 3.41 时减少 50%），过程效率降低。通过描述骨髓抑制药物的作用以及接种后中性粒细胞进入肺部的流入情况，并通过系统差异（与体外估计值相比，细菌生长 27%和最大能力 9.3%），捕捉到了中性粒细胞在体内的动力学。预测结果表明，中性粒细胞计数的治疗性降低如何使细菌生长，尤其是当计数降至 0.5×10 个细胞/mL 以下时，而对照个体可以处理所有测试的细菌负担（高达 10 个菌落形成单位/g 肺）。基于模型的中性粒细胞介导的细菌杀伤特性同时预测了体外和体内研究的数据，可用于告知个体水平宿主反应的能力。
