Host immunology and rational immunotherapy for carbapenem-resistant Klebsiella pneumoniae infection
Host immunology and rational immunotherapy for carbapenem-resistant Klebsiella pneumoniae infection
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DOI：
10.1172/jci.insight.135591
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发表时间：
2020-04-23
期刊：
影响因子：
8
通讯作者：
Kolls, Jay K.
中科院分区：
文献类型：
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作者：
Iwanaga, Naoki;Sandquist, Ivy;Kolls, Jay K.
由于碳青霉烯类耐药肺炎克雷伯氏菌的广泛耐药性，其感染已成为全球性威胁。移植受者和恶性血液病患者死亡率高，提示宿主因素在易感性中起重要作用。本研究利用优势克雷伯菌ST 258株C4、KPC-2克隆建立了肺部感染模型。结果表明，Rag 2（-/-）Il 2 rg（-/-）小鼠-而不是WT C57 BL/6或Rag 2（-/-）小鼠-对这种机会性感染易感。在感染的Rag 2（-/-）小鼠中使用单细胞RNA测序，我们鉴定了lfng（+）NK细胞和IL 170 a（+）、IL 22（+）和诱导型T细胞共刺激分子阳性（ICOS+）第3组先天淋巴细胞（ILC）的不同簇，这些细胞对宿主抗性至关重要。由于实体器官移植是一个风险因素，我们在WT C57 BL/6小鼠中使用FK 506生成了一个更具临床相关性的模型。我们进一步证明，重组IL-22治疗的免疫治疗通过肝脏IL-22 ra 1信号传导改善了FK 506治疗的WT小鼠和Rag 2（-/-）Il 2 rg（-/-）小鼠中的ST 258肺部感染。这些数据支持宿主导向免疫疗法作为新抗生素的辅助治疗的发展。
Infections due to carbapenem-resistant Klebsietta pneumoniae have emerged as a global threat due to its widespread antimicrobial resistance. Transplant recipients and patients with hematologic malignancies have high mortality rate, suggesting host factors in susceptibility. We developed a model of pulmonary infection using ST258 strain C4, KPC-2 clone, which are predominant K. pneumoniae carbapenemase-producing (KPC-producing) bacteria, and demonstrated that Rag2(-/-) Il2rg(-/-) mice - but not WT C57BL/6 or Rag2(-/-) mice -were susceptible to this opportunistic infection. Using single cell RNA sequencing in infected Rag2(-/-) mice, we identified distinct clusters of lfng(+) NK cells and Il170a(+), il22(+), and inducible T cell costimulatory molecule-positive (ICOS+) group 3 innate lymphoid cells (ILCs) that were critical for host resistance. As solid organ transplantation is a risk factor, we generated a more clinically relevant model using FK506 in WT C57BL/6 mice. We further demonstrated that immunotherapy with recombinant IL-22 treatment ameliorated the ST258 pulmonary infection in both FK506-treated WT mice and Rag2(-/-) Il2rg(-/-) mice via hepatic IL-22ra1 signaling. These data support the development of host-directed immunotherapy as an adjunct treatment to new antibiotics.