Goswami Dinesh G, Garcia Luiz F, Dodoo Christopher, Dwivedi Alok K, Zhou Yun, Pappas Dimitri, Walker Wendy E
Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas.
Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas.
Shock. 2021 Apr 1;55(4):507-518. doi: 10.1097/SHK.0000000000001650.
Sepsis occurs when an infection induces a dysregulated immune response, and is most commonly bacterial in origin. This condition requires rapid treatment for successful patient outcomes. However, the current method to confirm infection (blood culture) requires up to 48 h for a positive result and many true cases remain culture-negative. Therefore, new diagnostic tests are urgently needed. Recent clinical studies suggest that CD69, CD64, and CD25 may serve as useful biomarkers of sepsis. In this study, we evaluated the cecal ligation and puncture and cecal slurry mouse models as tools to study these biomarkers in young and aged mice, and elucidate the timeliness and specificity of sepsis diagnosis. Fluorescence-activated cell sorting analysis revealed that all three biomarkers were elevated on blood leukocytes during sepsis. CD69 was specifically upregulated during sepsis, while CD64 and CD25 were also transiently upregulated in response to sham surgery. The optimal biomarker, or combination of biomarkers, depended on the timing of detection, mouse age, and presence of surgery. CD69 demonstrated an excellent capacity to distinguish sepsis, and in some scenarios the diagnostic performance was enhanced by combining CD69 with CD64. We also analyzed biomarker expression levels on specific cell populations (lymphocytes, monocytes, and neutrophils) and determined the cell types that upregulate each biomarker. Elevations in blood biomarkers were also detected via microfluidic analyses; in this case CD64 distinguished septic mice from naive controls. Our results suggest that CD69 and CD64 are valuable biomarkers to rapidly detect sepsis, and that mouse models are useful to study and validate sepsis biomarkers.
当感染引发免疫反应失调时，就会发生脓毒症，其最常见的病因是细菌感染。这种情况需要迅速治疗才能使患者获得成功的治疗结果。然而，目前用于确诊感染的方法（血培养）需要长达48小时才能得到阳性结果，而且许多实际病例血培养仍为阴性。因此，迫切需要新的诊断测试。最近的临床研究表明，CD69、CD64和CD25可能是脓毒症有用的生物标志物。在本研究中，我们评估了盲肠结扎穿刺和盲肠匀浆小鼠模型，作为在年轻和老年小鼠中研究这些生物标志物以及阐明脓毒症诊断的及时性和特异性的工具。荧光激活细胞分选分析显示，在脓毒症期间，所有这三种生物标志物在血液白细胞上均升高。CD69在脓毒症期间特异性上调，而CD64和CD25在假手术时也会短暂上调。最佳生物标志物或生物标志物组合取决于检测时间、小鼠年龄和是否进行手术。CD69具有出色的区分脓毒症的能力，在某些情况下，将CD69与CD64结合可提高诊断性能。我们还分析了特定细胞群体（淋巴细胞、单核细胞和中性粒细胞）上生物标志物的表达水平，并确定了上调每种生物标志物的细胞类型。通过微流控分析也检测到了血液生物标志物的升高；在这种情况下，CD64可区分脓毒症小鼠和未感染的对照小鼠。我们的结果表明，CD69和CD64是快速检测脓毒症的有价值的生物标志物，并且小鼠模型对于研究和验证脓毒症生物标志物很有用。
