Immunotherapy of KPC Infection
KPC感染的免疫治疗
基本信息
- 批准号:10443796
- 负责人:
- 金额:$ 48.64万
- 依托单位:
- 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:
- 关键词:AffectAntibiotic TherapyAntibodiesAntimicrobial ResistanceApplications GrantsAreaAsiaB-LymphocytesBacteriaBacterial Antibiotic ResistanceBacterial InfectionsC57BL/6 MouseCalcineurinCellsCenters for Disease Control and Prevention (U.S.)ClinicalClinical PharmacologyClinical TrialsCytokine ReceptorsDataDendritic CellsDependenceDiabetic Foot UlcerFK506FecesGeneticGoalsHealthHematologic NeoplasmsHospitalsHost DefenseHumanImmune responseImmunizationImmunosuppressionImmunosuppressive AgentsImmunotherapyInfectionInfection ControlIntegration Host FactorsInterferonsInterleukin-12Interleukin-17Kidney DiseasesKlebsiellaKlebsiella pneumoniaeKnockout MiceLethal Dose 50LungLung infectionsLymphoid CellMechanical ventilationMediatingMemoryMethodsModelingMucosal ImmunityMucous MembraneMulti-Drug ResistanceMusNK Cell ActivationNatural Killer CellsOpportunistic InfectionsOrganOrgan TransplantationOrganismPatientsPerformance StatusPharmacologyPopulationPredispositionPublic HealthReportingResistanceRiskRoleSiteSolidSourceSpleenStem cell transplantStructure of parenchyma of lungT-LymphocyteTestingTissuesTransplant RecipientsTransplantationUniversitiesVirulentWorkWorld Health Organizationantagonistantimicrobialbasecapsulecarbapenemaseclinically relevantcomorbiditycytokinegraft vs host diseaseinterleukin-22mortalitymucoidnovelrecruitresponsesingle-cell RNA sequencingtranscriptome 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.
对人类健康的持续和新出现的威胁是多重耐药细菌感染。在这些
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JAY K KOLLS其他文献
JAY K KOLLS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JAY K KOLLS', 18)}}的其他基金
Generation of Novel Human Monoclonals for Lung Disease
用于肺部疾病的新型人单克隆抗体的产生
- 批准号:
9250044 - 财政年份:2016
- 资助金额:
$ 48.64万 - 项目类别:
Generation of Novel Human Monoclonals for Lung Disease
用于肺部疾病的新型人单克隆抗体的产生
- 批准号:
9128312 - 财政年份:2016
- 资助金额:
$ 48.64万 - 项目类别:
相似海外基金
SBIR Phase II: Development of a urine dipstick test that can guide immediate and appropriate antibiotic therapy for treatment of complicated urinary tract infections
SBIR II 期:开发尿液试纸测试,可以指导复杂尿路感染的立即和适当的抗生素治疗
- 批准号:
2213034 - 财政年份:2023
- 资助金额:
$ 48.64万 - 项目类别:
Cooperative Agreement
Personalized Antibiotic Therapy in the Emergency Department: PANTHER Trial
急诊科的个性化抗生素治疗:PANTHER 试验
- 批准号:
10645528 - 财政年份:2023
- 资助金额:
$ 48.64万 - 项目类别:
Strategies for improving the efficacy of combinatorial antibiotic therapy in chronic infections
提高慢性感染联合抗生素治疗疗效的策略
- 批准号:
10736285 - 财政年份:2023
- 资助金额:
$ 48.64万 - 项目类别:
A Novel Bone Targeted Antibiotic Therapy for the Treatment of Infected Fractures
一种治疗感染性骨折的新型骨靶向抗生素疗法
- 批准号:
10603486 - 财政年份:2023
- 资助金额:
$ 48.64万 - 项目类别:
Severe Cutaneous Adverse Reactions Following Outpatient Antibiotic Therapy: A Population-based Study
门诊抗生素治疗后的严重皮肤不良反应:一项基于人群的研究
- 批准号:
449379 - 财政年份:2020
- 资助金额:
$ 48.64万 - 项目类别:
Studentship Programs
Sex-Specific Differences in End-of-Life Burdensome Interventions and Antibiotic Therapy in Nursing Home Residents With Advanced Dementia
患有晚期痴呆症的疗养院居民的临终干预和抗生素治疗的性别差异
- 批准号:
422034 - 财政年份:2020
- 资助金额:
$ 48.64万 - 项目类别:
Optimizing outpatient parenteral antibiotic therapy to support hospital-in-the-home program across the unique environmental conditions of Australia
优化门诊肠外抗生素治疗,以支持澳大利亚独特环境条件下的家庭医院计划
- 批准号:
nhmrc : 1197866 - 财政年份:2020
- 资助金额:
$ 48.64万 - 项目类别:
Investigator Grants
Resistance evolution in the presence of combination antibiotic therapy
联合抗生素治疗下耐药性的演变
- 批准号:
2241853 - 财政年份:2019
- 资助金额:
$ 48.64万 - 项目类别:
Studentship
Host-pathogen interactions in antibiotic therapy for listeriosis
李斯特菌病抗生素治疗中宿主与病原体的相互作用
- 批准号:
18K07106 - 财政年份:2018
- 资助金额:
$ 48.64万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Multipurpose targeted nano-antibiotic therapy to fight tough infection in bones
多用途靶向纳米抗生素疗法可对抗骨骼中的严重感染
- 批准号:
9788269 - 财政年份:2018
- 资助金额:
$ 48.64万 - 项目类别: