Suppression of anti-malarial humoral immune responses by gamaherpesviruses
伽马疱疹病毒抑制抗疟疾体液免疫反应
基本信息
- 批准号:9444089
- 负责人:
- 金额:$ 39.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-01 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAffinityAfrica South of the SaharaAgeAlpha CellAnemiaAntibodiesAntibody FormationAntibody ResponseAntibody SpecificityAntigensAntimalarialsB-LymphocytesBloodCapsidCellsCerebral MalariaCessation of lifeChildChildhoodCoinCountryDataDevelopmentDiseaseEpitopesEpstein-Barr Virus InfectionsEventFalciparum MalariaFeverGenetic TranscriptionGoalsHelper-Inducer T-LymphocyteHospitalizationHuman Herpesvirus 4Humoral ImmunitiesImmuneImmune responseImmunityImmunoglobulin MImmunosuppressionImmunosuppressive AgentsImpairmentIncomeInfantInfectionInterleukin-10KnowledgeLaboratoriesLifeLongevityMalariaMemoryMissionMonitorMoralsOutcomeParasitemiaParasitesPlasmodiumPlasmodium falciparumPopulationPrimary InfectionProteinsPublic HealthPublishingResearchRisk FactorsRodent ModelSecondary toTestingUnited States National Institutes of HealthViralVirus DiseasesVirus LatencyWorkantigen challengeclinical developmentco-infectiondisabilityexperiencegammaherpesvirushuman diseaseinfected B cellinnovationinsightlatency-associated proteinmalaria infectionmouse modelnegative affectnovelnovel therapeutic interventionpreventresponseseropositivestem
项目摘要
The humoral response to malaria is critical in the control of blood stage parasitemia and the breadth of
the antibody response is protective against the development of clinical malaria. It is not understood why
some children fail to develop adequate humoral immune responses to Plasmodium infection early in
life. Both Plasmodium falciparum malaria and Epstein Barr virus (EBV) are childhood infections in sub-
Saharan Africa. The majority of children become seropositive for EBV within the first years of life, an
event that is normally asymptomatic but accompanied by potent immunosuppression. The long term
goal of this proposal is to provide mechanistic evidence that overlapping acute gammaherpesvirus coin-
fections are responsible for suppressing the development of humoral immunity during Plasmodium in-
fection in children. Using well established mouse models of EBV (MHV68) and malaria the objective of
this proposal is to identify how the humoral immune response to malaria is altered by an MHV68 la-
tency associated protein (M2), and to identify which features of the humoral response are affected
(magnitude, breadth, affinity and longevity). The central hypothesis of this proposal is that the induction
of IL-10 by M2 in MHV68-infected B cells impairs the ability of T follicular helper cells to provide B cell
help for effective, broad spectrum antibody production to incoming Plasmodium infection. This hypothe-
sis has been formulated from our published and preliminary data showing that M2 induces substantial
amount of IL-10 in B cells and that pre-existing suppression of humoral immunity to Plasmodium by
MHV68 in a primary infection also resulted in an ineffective memory responses upon challenge infec-
tion. The rationale for the proposed work is that the development of new therapeutic strategies to en-
sure protective humoral immunity develops in children depends on an understanding of the contributing
factors that prevent the development of the humoral response in the first place. Guided by strong pre-
liminary data, the central hypothesis will be tested by pursuing 3 specific aims: 1) To determine how the
response of Tfh cells to an incoming Plasmodium infection is altered by M2-induced IL-10 secretion
from MHV68-infected B cells 2) To determine how the breadth, affinity and longevity of the anti-malarial
humoral response is altered by pre-existing gammaherpesvirus infection (3) To demonstrate that hu-
moral immunity to P. falciparum in children is reduced by acute immunosuppressive EBV infection. The
approach is innovative because our proposed research uses novel rodent models of EBV and Plasmo-
dium co-infection and incorporates transcriptional profiling of B cell populations to enable the breadth of
humoral immune responses to malaria to be determined. The proposed research is significant because
it is expected to advance understanding of how the development of immunity to malaria can be ad-
versely impacted by viral co-infections.
疟疾的体液反应对于控制血期寄生虫病和疟疾的广度至关重要
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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Tracey Jane Lamb其他文献
Tracey Jane Lamb的其他文献
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{{ truncateString('Tracey Jane Lamb', 18)}}的其他基金
Genetic and Immunological Control for Development of Asymptomatic Malaria
无症状疟疾发展的遗传和免疫控制
- 批准号:
10260246 - 财政年份:2021
- 资助金额:
$ 39.51万 - 项目类别:
Genetic and Immunological Control for Development of Asymptomatic Malaria
无症状疟疾发展的遗传和免疫控制
- 批准号:
10415195 - 财政年份:2021
- 资助金额:
$ 39.51万 - 项目类别:
Ephrin ligands as novel targets for an adjunct therapy in cerebral malaria
Ephrin配体作为脑型疟疾辅助治疗的新靶点
- 批准号:
8771568 - 财政年份:2014
- 资助金额:
$ 39.51万 - 项目类别:
The development of probiotic yeast as an inexpensive vaccine delivery platform
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8572767 - 财政年份:2013
- 资助金额:
$ 39.51万 - 项目类别:
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