Immune recognition of Klebsiella pneumoniae O2v1 and O2v2 O-antigen subtypes
肺炎克雷伯菌 O2v1 和 O2v2 O 抗原亚型的免疫识别
基本信息
- 批准号:10739041
- 负责人:
- 金额:$ 23.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcuteAffectAntibiotic ResistanceAntibiotic-resistant organismAntibioticsAntibodiesAntibody ResponseAntigensBacteriaBacteriologyBiological AssayBody Weight decreasedCessation of lifeClinicalComplementConjugate VaccinesDevelopmentDiseaseEnzyme-Linked Immunosorbent AssayEuropeExhibitsFlow CytometryFutureGalactansGalactoseGlycosyltransferase GeneGoalsGram-Negative BacteriaHospitalizationHospitalsHumanHumoral ImmunitiesImmuneImmune responseImmunizationImmunoglobulin GImmunologic TechniquesIn VitroInfectionInfection preventionInnate Immune ResponseKlebsiella pneumoniaeKnowledgeLipopolysaccharidesLiteratureLungMeasuresMediatingMicrobial BiofilmsMonitorMusNatural ImmunityO AntigensOrganismOzonePathogenesisPathogenicityPatientsPhagocytosisPhase I Clinical TrialsPhenotypePneumoniaPolysaccharidesPredispositionProductionResearch Project GrantsResearch Project SummariesResistanceRespiratory SystemRespiratory Tract InfectionsSepsisSerumStructureSurfaceTestingUrinary tract infectionVaccinatedVaccinationVaccine DesignVaccinesVertebral columnVirulenceVirulence FactorsWestern Blottingadaptive immune responsebacterial fitnessbacterial resistancebactericidecapsulecarbapenem resistancecarbapenemasecombatcross immunitycross reactivitycytokineexperimental studyfitnesshealthcare-associated infectionsimmunogenicimmunogenicityin vivoinnate immune functioninterestmortalitymouse modelmutantneutrophilnovelpathogenpneumonia modelpreventresistant Klebsiella pneumoniaeresponsevaccine development
项目摘要
PROJECT SUMMARY
This research project will enhance our understanding of the immune responses elicited by the O-antigen of
Klebsiella pneumoniae (Kp), an important target in putative vaccine development. The long-term goal of this
proposal is to further our knowledge of the innate and adaptive immune responses elicited by two subtypes of
the common serogroup O2 of Kp, O2v1 and O2v2. We seek to understand how the addition of the single
branched galactose of O2v2 changes its bacterial fitness and host immune susceptibility relative to O2v1.
Further, we will determine cross-reactivity between these two subtypes and whether infection or vaccination with
one subtype confers cross-protection against the other, information critical to the design of vaccines that can
broadly target this increasingly antibiotic-resistant organism. Kp infections, including pneumonia, urinary tract
infection, and bloodstream infection, are sharply on the rise among hospitalized patients; CDC has declared that
infections with Kp and other carbapenem-resistant Enterobacteriales demand a threat level of urgent.
This project builds on the PI's background in bacteriology, murine models of infection, and pathogenesis studies
of Gram-negative bacteria, by focusing specifically on the Kp virulence factor O-antigen and the host
immunogenic response. We have previously demonstrated that use of bioconjugate vaccines targeting Kp are
beneficial in preventing disease and seek to increase our understanding and breadth of coverage of future
vaccines. Kp historically has eleven known serogroups of O-antigen. Recently, additional O-antigen subtypes
within these serogroups have been identified. Yet, differences in pathogenic fitness, immunogenicity, functional
antibody response, and cross-protection between related subtypes are not well understood.
We have constructed a mutant of a classical Kp strain expressing O-antigen subtype O2v2 to generate an
otherwise isogenic strain expressing O2v1. We will test if these bacteria exhibit similar phenotypic expression of
virulence factors by measuring capsule, hypermucoviscosity, fimbriae and biofilm. A well-established murine
model of pneumonia will be leveraged to determine pulmonary fitness and delineate host innate immune
response to each pathogen. Neutrophil and complement-mediated bacterial killing assays will be employed to
further explore bacterial resistance to innate immune attack, which the literature indicates may be enhanced in
O2v2 strains. Next, we will perform a range of experiments testing if O2v1 and O2v2 are cross-protective. Using
classically immunological techniques including ELISA and flow cytometry, we will determine the IgG subclasses
and effector cytokines elicited by respiratory tract infection with these pathogens. Lastly, using novel O2v1 or
O2v2 bioconjugate vaccines followed by challenge with O2v1 or O2v2 strains, we will assess cross-protection
against weight loss and mortality from pneumonia. We will further characterize antibody functionality using serum
bactericidal and opsonophagocytic killing assays. These studies will significantly advance our understanding of
immune response to Kp O-antigen and aid in vaccine design to combat this pathogen.
项目概要
该研究项目将增强我们对 O 抗原引发的免疫反应的理解
肺炎克雷伯菌 (Kp),假定疫苗开发的重要目标。本次活动的长远目标
该提案是为了进一步了解由两种亚型引起的先天性和适应性免疫反应
常见血清群O2为Kp、O2v1和O2v2。我们试图了解如何添加单个
相对于 O2v1,O2v2 的支链半乳糖改变了其细菌适应性和宿主免疫敏感性。
此外,我们将确定这两种亚型之间的交叉反应性以及是否感染或接种疫苗
一种亚型具有针对另一种亚型的交叉保护作用,这些信息对于疫苗的设计至关重要
广泛针对这种日益耐药的生物体。 Kp 感染,包括肺炎、尿路感染
住院患者中感染和血流感染急剧上升;美国疾病控制与预防中心 (CDC) 已宣布
Kp 和其他碳青霉烯类耐药肠杆菌感染需要紧急威胁级别。
该项目以 PI 在细菌学、感染小鼠模型和发病机制研究方面的背景为基础
革兰氏阴性菌,特别关注 Kp 毒力因子 O 抗原和宿主
免疫原性反应。我们之前已经证明,使用针对 Kp 的生物结合疫苗是
有益于预防疾病,并寻求增加我们对未来的理解和覆盖范围
疫苗。 Kp 历史上有十一个已知的 O 抗原血清群。最近,额外的 O 抗原亚型
这些血清群中的病毒已被鉴定。然而,致病适应性、免疫原性、功能性方面的差异
抗体反应和相关亚型之间的交叉保护尚不清楚。
我们构建了表达 O 抗原亚型 O2v2 的经典 Kp 菌株的突变体,以产生
表达 O2v1 的其他等基因菌株。我们将测试这些细菌是否表现出相似的表型表达
通过测量荚膜、高粘膜粘度、菌毛和生物膜来确定毒力因子。一个完善的小鼠
将利用肺炎模型来确定肺部健康状况并描绘宿主先天免疫
对每种病原体的反应。中性粒细胞和补体介导的细菌杀灭测定将用于
进一步探索细菌对先天免疫攻击的抵抗力,文献表明这种抵抗力可能会增强
O2v2 菌株。接下来,我们将进行一系列实验来测试O2v1和O2v2是否具有交叉保护作用。使用
经典免疫学技术,包括 ELISA 和流式细胞术,我们将确定 IgG 亚类
以及由这些病原体呼吸道感染引起的效应细胞因子。最后,使用新颖的 O2v1 或
O2v2 生物结合疫苗,然后用 O2v1 或 O2v2 菌株进行攻击,我们将评估交叉保护
对抗肺炎引起的体重减轻和死亡。我们将使用血清进一步表征抗体功能
杀菌和调理吞噬杀灭试验。这些研究将极大地增进我们对
对 Kp O 抗原的免疫反应,有助于设计对抗这种病原体的疫苗。
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)
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David A. Rosen其他文献
<em>Klebsiella pneumoniae</em> bioconjugate vaccine functional durability in mice
- DOI:
10.1016/j.vaccine.2024.126536 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:
- 作者:
Paeton L. Wantuch;Cory J. Knoot;Emily C. Marino;Christian M. Harding;David A. Rosen - 通讯作者:
David A. Rosen
Longitudinal results after first-stage palliation for hypoplastic left heart syndrome.
左心发育不全综合征第一阶段姑息治疗后的纵向结果。
- DOI:
- 发表时间:
1990 - 期刊:
- 影响因子:37.8
- 作者:
Jon N. Meliones;A. Snider;E. L. Bove;Amnon Rosenthal;David A. Rosen - 通讯作者:
David A. Rosen
Outpatient sedation: An essential addition to gynecologic care for persons with mental retardation
- DOI:
10.1016/0002-9378(91)90524-u - 发表时间:
1991-03-01 - 期刊:
- 影响因子:
- 作者:
David A. Rosen;Kathleen R. Rosen;Thomas E. Elkins;H. Frank Andersen;S. Gene McNeeley;Cheryl Sorg - 通讯作者:
Cheryl Sorg
Anaesthesia in Ophthalmology
- DOI:
10.1007/bf03019196 - 发表时间:
1962-11-01 - 期刊:
- 影响因子:3.300
- 作者:
David A. Rosen - 通讯作者:
David A. Rosen
Fentanyl uptake by the scimed membrane oxygenator.
连续膜氧合器吸收芬太尼。
- DOI:
- 发表时间:
1988 - 期刊:
- 影响因子:0
- 作者:
David A. Rosen;K. Rosen;Bruce A. Davidson;L. Broadman - 通讯作者:
L. Broadman
David A. Rosen的其他文献
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{{ truncateString('David A. Rosen', 18)}}的其他基金
Protective immunity elicited by distinct polysaccharide antigens of classical and hypervirulent Klebsiella
经典和高毒力克雷伯氏菌的不同多糖抗原引发的保护性免疫
- 批准号:
10795212 - 财政年份:2023
- 资助金额:
$ 23.33万 - 项目类别:
VIRULENCE REGULATION AND PROTECTIVE IMMUNITY IN KLEBSIELLA PNEUMONIA
肺炎克雷伯菌的毒力调节和保护性免疫
- 批准号:
9385544 - 财政年份:2017
- 资助金额:
$ 23.33万 - 项目类别:
VIRULENCE REGULATION AND PROTECTIVE IMMUNITY IN KLEBSIELLA PNEUMONIA
肺炎克雷伯菌的毒力调节和保护性免疫
- 批准号:
9980694 - 财政年份:2017
- 资助金额:
$ 23.33万 - 项目类别:
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