Immunotherapy of KPC Infection

KPC感染的免疫治疗

基本信息

批准号：
9981924
负责人：
JAY K KOLLS
金额：
$ 48.64万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981924
关键词：
Affect Antibiotic Therapy Antibodies Antimicrobial Resistance Applications Grants Area Asia B-Lymphocytes Bacteria Bacterial Antibiotic Resistance Bacterial Infections C57BL/6 Mouse Calcineurin Cells Centers for Disease Control and Prevention (U.S.)Clinical Clinical Pharmacology Clinical Trials Cytokine Receptors Data Dendritic Cells Dependence Diabetic Foot Ulcer FK506 Feces Genetic Goals Health Hematologic Neoplasms Hospitals Host Defense Human Immune response Immunization Immunosuppression Immunotherapy Infection Infection Control Integration Host Factors Interferons Interleukin-12 Interleukin-17 Kidney Diseases Klebsiella Klebsiella pneumoniae Knockout Mice Lethal Dose 50 Lung Lung infections Lymphoid Cell Mechanical ventilation Mediating Memory Methods Modeling Mucosal Immunity Mucous Membrane Multi-Drug Resistance Mus NK Cell Activation Natural Killer Cells Opportunistic Infections Organ Organ Transplantation Organism Patients Performance Status Pharmaceutical Preparations Pharmacology Population Predisposition Public Health Reporting Resistance Risk Role Site Solid Source Spleen Stem cell transplant Structure of parenchyma of lung T-Lymphocyte Testing Tissues Transplant Recipients Transplantation Universities Virulent Work World Health Organization antimicrobial base capsule carbapenemase clinically relevant comorbidity cytokine graft vs host disease interleukin-22 mortality mucoid novel recruit response single-cell RNA sequencing transcriptome sequencing

项目摘要

A continued and emerging threat to human health are multi-drug resistant bacterial infections. Among these threats, carbapenemase producing strains of Klebsiella spp has been recognized by the World Health Organization and the Centers for Disease Control has a global threat to human health particularly in the hospital setting. Clinically these infections often appear to be opportunistic infections affecting patients with co-morbidities such as immunosuppressive drugs, poor performance status, mechanical ventilation, and kidney disease. In addition, hematologic malignancies and solid organ and stem cell transplant recipients are at risk. Recently hyervirulent strains with mucoid capsule have been reported but carriage rates in areas of Asia can approach 5% in stool, which far exceeds the rate of clinical infection, suggesting host factors are important. Pulmonary inoculation of the non-mucoid ST258C4 strain was avirulent in WT mice as well as Rag-/- mice which lack T and B cells. In contrast Rag2, Il2rg -/- which additionally lack NK cells and innate lymphoid cells, were susceptible to infection and had mortality, which was associated bacterial dissemination. Single cell RNAseq of lung tissue demonstrated that NK cells and group 3 innate lymphoid cells were associated with bacterial clearance. In preliminary studies, only dual antagonism of both NK cells and group 3 ILCs resulted in ST258 infection suggesting these two cell populations are key to host defense against this organism. As IL-22:Fc is clinical trial for gut graft versus host disease and diabetic foot ulcers, we investigated if systemic IL-22:Fc administration could be used as immunotherapy. Preliminary studies show that IL-22:Fc can substantially reduce bacterial burdens in mice susceptible Rag2-/-, Il2rg -/- mice. To examine if these cellular responses were perturbed by clinically relevant immunosuppression, we administered FK506, which is used in solid organ transplant, to mice. FK506 treatment increased susceptibility to infection and reduced IFNg, Il17a, and Il22 in the lung. Thus, we have developed genetic and pharmacological models that allow us to propose the following testable hypothesis: ST258 C4 infection requires NK cells and group 3 ILC cells for clearance and these populations are inhibited by calcineurin inhibition. Moreover we hypothesize that cytokine based immunotherapy can be developed to augment endogenous host responses to clear this infection. We will test these hypotheses with the following specific Aims using both non-mucoid (C4) as well as hypermucoid strains of KPC: Specific Aim 1. Test the prediction that both NK cells and group 3 innate lymphoid cells are required for lung mucosal immunity against Kpc infection. Specific Aim 2. Develop a clinically and pharmacologically relevant model of Kpc infection. Specific Aim 3. Test the prediction that systemic or local immunotherapy is effective in controlling Kpc infection.

对人类健康持续存在的新威胁是多重耐药细菌感染。其中威胁，产生碳青霉烯酶的克雷伯氏菌菌株已得到世界卫生组织的认可组织和疾病控制中心对人类健康构成全球威胁，特别是在医院环境。临床上这些感染通常表现为影响患者的机会性感染合并症，如免疫抑制药物、体能状态不佳、机械通气和肾脏疾病。此外，血液系统恶性肿瘤以及实体器官和干细胞移植受者有危险。最近报道了带有粘液囊的高毒力菌株，但在以下地区的携带率亚洲粪便中的感染率可接近 5%，远远超过临床感染率，表明宿主因素重要的。非粘液 ST258C4 菌株的肺部接种对 WT 小鼠和缺乏 T 和 B 细胞的 Rag-/- 小鼠。相比之下，Rag2、Il2rg -/- 还缺乏 NK 细胞和先天性淋巴细胞易受感染并导致死亡，这与细菌传播有关。肺组织的单细胞 RNAseq 表明 NK 细胞和第 3 组先天淋巴细胞与细菌清除有关。在初步研究中，只有 NK 细胞和第 3 组细胞具有双重拮抗作用 ILC 导致 ST258 感染，表明这两个细胞群是宿主防御这种感染的关键生物。由于 IL-22:Fc 是针对肠道移植物抗宿主病和糖尿病足溃疡的临床试验，我们研究了全身性 IL-22:Fc 给药是否可以用作免疫疗法。初步研究表明 IL-22:Fc 可大幅减少易感 Rag2-/-、Il2rg -/- 小鼠的细菌负荷。要检查这些是否细胞反应受到临床相关免疫抑制的干扰，我们施用了 FK506，它是用于小鼠实体器官移植。 FK506治疗增加了感染的易感性并减少了肺中的 IFNg、Il17a 和 Il22。因此，我们开发了遗传和药理学模型，使我们能够提出以下可检验的假设：ST258 C4 感染需要 NK 细胞和第 3 组 ILC 细胞清除率并且这些群体受到钙调神经磷酸酶抑制作用的抑制。此外，我们假设细胞因子可以开发基于免疫疗法来增强内源性宿主反应以清除这种感染。我们将使用非粘液 (C4) 和超粘液测试这些假设，并达到以下具体目标 KPC 菌株：具体目标 1. 测试 NK 细胞和第 3 组先天淋巴细胞均是的预测肺粘膜免疫抵抗 Kpc 感染所需的。具体目标 2. 开发临床和 Kpc感染的药理学相关模型。具体目标 3. 测试系统或局部的预测免疫疗法可有效控制 Kpc 感染。