An Infection-Tolerant Mammalian Reservoir for Several Zoonotic Agents Broadly Counters the Inflammatory Effects of Endotoxin.
An Infection-Tolerant Mammalian Reservoir for Several Zoonotic Agents Broadly Counters the Inflammatory Effects of Endotoxin.
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DOI：
10.1128/mbio.00588-21
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发表时间：
2021-04-13
期刊：
影响因子：
6.4
通讯作者：
Barbour AG
中科院分区：
文献类型：
--
作者：
Balderrama-Gutierrez G;Milovic A;Cook VJ;Islam MN;Zhang Y;Kiaris H;Belisle JT;Mortazavi A;Barbour AG
动物是引起人类疾病的病原体的天然携带者，通常在感染后很少或根本不会生病。这些例子包括鹿鼠、白过omyscus leucopus，它是莱姆病和北美其他几种疾病病原体的储存库，以及某些类型的蝙蝠，它们是对人类具有致病性的病毒的携带者。作为人畜共患病原体的宿主的动物通常很少因感染而发病。为了研究这种感染耐受的机制，我们使用单剂量脂多糖（LPS）作为炎症的实验模型，并比较了两种啮齿动物的反应：白足鹿鼠和家鼠小家鼠。白足鹿鼠是莱姆病和其他人畜共患病病原体的储存库。注射LPS或生理盐水4小时后，采集血液、脾脏和肝脏样本，进行转录组测序（RNA-seq）、代谢组学和特异性逆转录酶定量PCR （RT-qPCR）。在基因、通路和网络水平上进行差异表达分析。脂多糖处理过的鹿鼠表现出与接触过脂多糖的鼠相似的疾病迹象，皮质酮水平和白细胞介素6 （IL-6）、肿瘤坏死因子、IL-1β和c反应蛋白的表达也有类似的增加。通过网络分析，m.s musus对LPS的反应特征为细胞因子相关，而p.a leucopus的反应以中性粒细胞活性项为主。此外，精氨酸酶1和一氧化氮合酶2以及IL-10和IL-12表达水平的二分类与小鼠的M1型巨噬细胞反应和鹿鼠的M2型巨噬细胞反应一致。血浆代谢产物和器官RNA的分析揭示了色氨酸代谢的物种差异。其中两个基因（Slpi和Ibsp）特别代表了鹿鼠和小鼠的不同表型。在老年动物、全身性细菌感染和培养成纤维细胞中复制了白色假单胞菌的关键RNA-seq结果。研究结果表明，在平衡感染抗性和耐受性的过程中，白蜡蒿具有一些适应炎症的特征。
Animals that are natural carriers of pathogens that cause human diseases commonly manifest little or no sickness as a consequence of infection. Examples include the deer mouse, Peromyscus leucopus, which is a reservoir for Lyme disease and several other disease agents in North America, and some types of bats, which are carriers of viruses with pathogenicity for humans. Animals that are competent reservoirs of zoonotic pathogens commonly suffer little morbidity from the infections. To investigate mechanisms of this tolerance of infection, we used single-dose lipopolysaccharide (LPS) as an experimental model of inflammation and compared the responses of two rodents: Peromyscus leucopus, the white-footed deermouse and reservoir for the agents of Lyme disease and other zoonoses, and the house mouse Mus musculus. Four hours after injection with LPS or saline, blood, spleen, and liver samples were collected and subjected to transcriptome sequencing (RNA-seq), metabolomics, and specific reverse transcriptase quantitative PCR (RT-qPCR). Differential expression analysis was at the gene, pathway, and network levels. LPS-treated deermice showed signs of sickness similar to those of exposed mice and had similar increases in corticosterone levels and expression of interleukin 6 (IL-6), tumor necrosis factor, IL-1β, and C-reactive protein. By network analysis, the M. musculus response to LPS was characterized as cytokine associated, while the P. leucopus response was dominated by neutrophil activity terms. In addition, dichotomies in the expression levels of arginase 1 and nitric oxide synthase 2 and of IL-10 and IL-12 were consistent with type M1 macrophage responses in mice and type M2 responses in deermice. Analysis of metabolites in plasma and RNA in organs revealed species differences in tryptophan metabolism. Two genes in particular signified the different phenotypes of deermice and mice: the Slpi and Ibsp genes. Key RNA-seq findings for P. leucopus were replicated in older animals, in a systemic bacterial infection, and with cultivated fibroblasts. The findings indicate that P. leucopus possesses several adaptive traits to moderate inflammation in its balancing of infection resistance and tolerance.