Holistic Characterization of a Salmonella Typhimurium Infection Model Using Integrated Molecular Imaging

A more complete and holistic view on host–microbe interactions is needed to understand the physiological and cellular barriers that affect the efficacy of drug treatments and allow the discovery and development of new therapeutics. Here, we developed a multimodal imaging approach combining histopathology with mass spectrometry imaging (MSI) and same section imaging mass cytometry (IMC) to study the effects of Salmonella Typhimurium infection in the liver of a mouse model using the S. Typhimurium strains SL3261 and SL1344. This approach enables correlation of tissue morphology and specific cell phenotypes with molecular images of tissue metabolism. IMC revealed a marked increase in immune cell markers and localization in immune aggregates in infected tissues. A correlative computational method (network analysis) was deployed to find metabolic features associated with infection and revealed metabolic clusters of acetyl carnitines, as well as phosphatidylcholine and phosphatidylethanolamine plasmalogen species, which could be associated with pro-inflammatory immune cell types. By developing an IMC marker for the detection of Salmonella LPS, we were further able to identify and characterize those cell types which contained S. Typhimurium.

要理解影响药物治疗效果的生理与细胞屏障，并推动新型治疗手段的发现与开发，我们需要对宿主-微生物互作（host–microbe interactions）形成更全面、完整的认知。为此，本研究开发了一种结合组织病理学、质谱成像（mass spectrometry imaging, MSI）与同切片成像质谱流式（imaging mass cytometry, IMC）的多模态成像方法，利用鼠伤寒沙门氏菌（Salmonella Typhimurium）菌株SL3261与SL1344，在小鼠模型肝脏中探究该菌感染的效应。该方法可实现组织形态学、特定细胞表型与组织代谢分子图像的关联分析。成像质谱流式（IMC）结果显示，感染组织中免疫细胞标志物的表达显著上调，免疫细胞在免疫聚集体内的定位亦出现明显改变。我们采用关联计算方法（网络分析，network analysis）筛选与感染相关的代谢特征，鉴定出乙酰肉碱类、磷脂酰胆碱及磷脂酰乙醇胺缩醛磷脂类的代谢簇，这类代谢产物可能与促炎性免疫细胞类型存在关联。通过开发用于检测鼠伤寒沙门氏菌脂多糖的IMC标志物，我们进一步得以鉴定并表征携带鼠伤寒沙门氏菌的细胞类型。