Department of Otolaryngology, Head and Neck Surgery, Stanford University, Stanford, CA, USA.
Department of Medicine, Section of Computational Biomedicine and Biomedical Data Science, University of Chicago, Chicago, IL, USA.
NPJ Biofilms Microbiomes. 2021 Apr 6;7(1):31. doi: 10.1038/s41522-021-00200-z.
Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.
慢性化脓性中耳炎（CSOM）是一种广泛存在且使人虚弱的疾病，其免疫学机制尚不清楚。在这里，我们在 CSOM 小鼠模型和患有该疾病的人类受试者中，评估了中耳感染后一个月内宿主对感染的反应。我们使用多参数流式细胞术和二项式广义线性机器学习模型，确定 Ly6G（成熟中性粒细胞的表面标志物）为驱动 CSOM 小鼠模型疾病的宿主反应的最具信息量的因素。与这一结果一致的是，中性粒细胞是感染小鼠中最丰富的细胞类型，并且 Ly6G 表达与感染过程相关。此外，在该模型中，使用中性粒细胞弹性蛋白酶抑制剂 GW 311616A 进行的中性粒细胞特异性免疫调节治疗与仅用氧氟沙星治疗的动物相比，显著降低了细菌负荷。CSOM 患者和小鼠的中耳积液样本中的双链 DNA（dsDNA）水平升高，在治疗过程中降低，表明 dsDNA 可能是治疗反应的分子生物标志物。这些数据强烈表明中性粒细胞参与了 CSOM 中对铜绿假单胞菌感染的无效免疫反应，并表明免疫调节策略可能有益于对慢性生物膜介导疾病具有耐药性的感染。
