PDF(Pubmed)
Abstract：
Streptococcus suis (S. suis) is widely acknowledged as a significant zoonotic pathogen in Southeast Asia and China, which has led to a substantial number of fatalities in both swine and humans. Despite the prevalent use of mice as the primary animal model to study S. suis pathogenesis, the substantial differences in the major histocompatibility complex (MHC) between humans and mice underscore the ongoing exploration for a more suitable and effective animal model. In this study, humanized transgenic HLA-A11/DR1 genotypes mice were used to evaluate the differences between humanized HLA and murine H2 in S. suis infection. Following intravenous administration of S. suis suspensions, we investigated bacterial load, cytokine profiles, pathological alterations, and immune cell recruitment in both Wild-type (WT) and humanized mice across different post-infection time points. Relative to WT mice, humanized mice exhibited heightened pro-inflammatory cytokines, exacerbated tissue damage, increased granulocyte recruitment with impaired resolution, notably more pronounced during the late infection stage. Additionally, our examination of bacterial clearance rates suggests that HLA-A11/DR1 primarily influences cell recruitment and mitochondrial reactive oxygen species (ROS) production, which affects the bacterial killing capacity of macrophages in the late stage of infection. The reduced IL-10 production and lower levels of regulatory T cells in humanized mice could underlie their compromised resolution ability. Intervention with IL-10 promotes bacterial clearance and inflammatory regression in the late stages of infection in transgenic mice. Our findings underscore the heightened sensitivity of HLA-A11/DR1 mice with impaired resolution to S. suis infection, effectively mirroring the immune response seen in humans during infection. The humanized HLA-A11/DR1 mice could serve as an optimal animal model for investigating the pathogenic and therapeutic mechanisms associated with sepsis and other infectious diseases.
摘要：
猪链球菌（S.Suis）在东南亚和中国被广泛认为是一种重要的人畜共患病原体，导致猪和人类大量死亡。尽管普遍使用小鼠作为研究猪链球菌发病机制的主要动物模型，人与小鼠之间在主要组织相容性复合体(MHC)方面的显著差异,凸显了对更合适和更有效的动物模型的持续探索.在这项研究中,人源化转基因HLA-A11/DR1基因型小鼠用于评估人源化HLA和鼠H2在猪链球菌感染中的差异。静脉注射猪链球菌悬浮液后，我们调查了细菌负荷，细胞因子谱，病理改变,以及在不同的感染后时间点的野生型(WT)和人源化小鼠中的免疫细胞募集。相对于WT小鼠，人源化小鼠表现出升高的促炎细胞因子，加剧了组织损伤，粒细胞募集增加，分辨率受损，在感染后期更为明显。此外,我们对细菌清除率的检查表明，HLA-A11/DR1主要影响细胞募集和线粒体活性氧（ROS）的产生，这会影响感染后期巨噬细胞的细菌杀伤能力。人源化小鼠中减少的IL-10产生和较低水平的调节性T细胞可能是其受损的分辨能力的基础。IL-10干预可促进转基因小鼠感染后期的细菌清除和炎症消退。我们的发现强调了HLA-A11/DR1小鼠对猪链球菌感染的敏感性增强，有效地反映了感染过程中人类的免疫反应。人源化HLA-A11/DR1小鼠可以作为研究与脓毒症和其他感染性疾病相关的致病和治疗机制的最佳动物模型。
