Means Shawn A, Ali Md A, Ho Harvey
Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.
Department Mathematics and Physics, Kansas Wesleyan University, Salina, KS, United States.
Front Syst Biol. 2023 Feb 20;3:1045754. doi: 10.3389/fsysb.2023.1045754. eCollection 2023.
Unfortunately for the estimated 250 million sufferers of chronic hepatitis-B viral (HBV) infection worldwide, the liver terrain is typically ignored. An immuno-tolerant environment attractive for pathogens, the essential metabolic roles and structural features of the liver are aligned with distinctive gradients of oxygen and nutrients established along blood flows through fundamental hepatic processing units known as sinusoids. Capillaries surrounded by banks of hepatocytes, sinusoids express spatial configurations and concentrations of not only metabolic roles but also immune cell localisations, blood filtering and transporter specialisations: the liver terrain. HBV targets proteins regulating gluconeogenesis, a crucial liver function of blood glucose management, highly active at blood entry points-the periportal sites of sinusoids. Meanwhile, at these same sites, specialised liver macrophages, Kupffer cells (KC), aggregate and perform critical pathogen capture, detection and signaling for modulating immune responses. In tandem with KC, liver sinusoidal endothelial cells (LSECs) complement KC blood filtration and capture of pathogens as well as determine KC aggregation at the periportal sites. Failure of these systems to establish critical spatial configurations could ironically facilitate HBV invasion and entrenchment. Investigating the impacts of spatial and structural variations on the HBV infection dynamic is experimentally challenging at best. Alternatively, mathematical modeling methods provide exquisite control over said variations, permitting teasing out the subtle and competing dynamics at play within the liver terrain. Coordinating with experimental observations, multi-scale modeling methods hold promise to illuminate HBV reliance on features of the liver terrain, and potentially how it may be defeated.
不幸的是，对于全球约2.5亿慢性乙型肝炎病毒（HBV）感染者来说，肝脏的地形特征通常被忽视。肝脏是一个对病原体具有吸引力的免疫耐受环境，其基本的代谢作用和结构特征与沿着流经称为肝血窦的基本肝脏处理单元的血流所建立的独特氧气和营养梯度相一致。肝血窦是被肝细胞群包围的毛细血管，它不仅表达代谢作用的空间配置和浓度，还表达免疫细胞定位、血液过滤和转运蛋白特化的空间配置和浓度：即肝脏的地形特征。HBV靶向调节糖异生的蛋白质，糖异生是肝脏管理血糖的一项关键功能，在血液进入点——肝血窦的门静脉周围部位高度活跃。与此同时，在这些相同的部位，专门的肝脏巨噬细胞，即库普弗细胞（KC）聚集并执行关键的病原体捕获、检测和信号传递，以调节免疫反应。与KC协同作用的是，肝血窦内皮细胞（LSEC）补充KC的血液过滤和病原体捕获，并决定KC在门静脉周围部位的聚集。具有讽刺意味的是，这些系统未能建立关键的空间配置可能会促进HBV的入侵和盘踞。研究空间和结构变化对HBV感染动态的影响，充其量在实验上具有挑战性。或者，数学建模方法可以对上述变化进行精确控制，可以梳理出肝脏地形特征中微妙且相互竞争的动态变化。与实验观察结果相协调，多尺度建模方法有望阐明HBV对肝脏地形特征的依赖性，以及潜在的攻克方法。
