Persistent Post-Viral State of Bacterial Pneumonia Susceptibility and Severity in Down Syndrome
唐氏综合症细菌性肺炎易感性和严重程度的持续病毒感染后状态
基本信息
- 批准号:10177857
- 负责人:
- 金额:$ 38.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultAreaAttenuatedBacterial InfectionsBacterial PneumoniaBiological MarkersBloodBone Marrow AblationCellsCessation of lifeChildChromosome 21Chromosome abnormalityChronicChronic lung diseaseCognitive deficitsCommunicable DiseasesCongenital AbnormalityDataDevelopmentDiseaseDown SyndromeEtiologyEyeFrequenciesFunctional disorderGene Expression ProfileGenesHealthHospital MortalityHospitalizationHumanHuman ChromosomesImmuneImmune systemImmunosuppressionIncidenceIndividualInfectionInfectious Lung DisorderInfluenza A Virus, H1N1 SubtypeInfluenza A virusIntellectual functioning disabilityInterferon ActivationInterferon ReceptorInterferonsInterleukin-10LearningLeukocytesLinkLive BirthLongevityLungLung diseasesLung infectionsMedicalMorbidity - disease rateMusNasopharynxPathway interactionsPatientsPersonsPharmacologyPhenocopyPhenotypePneumoniaPopulationPredispositionPublishingQuality of lifeReceptor GeneRecurrenceRespiratory Tract InfectionsSeveritiesSeverity of illnessSignal TransductionStreptococcus pneumoniaeTestingTrisomyVirus Diseasesbasecell typeclinically significantcytokinedosagehigh riskimprovedinfluenza infectioninterleukin-10 receptormortalitymouse modelneglectnovelnovel therapeuticspandemic diseasepandemic influenzaperipheral bloodreconstitutionrespiratoryresponsetargeted agenttherapeutic target
项目摘要
PROJECT SUMMARY
With an incidence of one in 700-1000 live births worldwide, Down Syndrome (DS), or trisomy of human
chromosome 21 (Hsa21), is the most common chromosomal abnormality. While DS is most often recognized for
intellectual disability, congenital malformations, and dysmorphic features, it is also associated with seriously
increased rates and severity of respiratory infection. Indeed, infectious respiratory disease in those with DS
accounts for 54% of hospital admissions and more deaths than any other medical condition. Children with DS
have a 62-fold higher rate of pneumonia than children without DS(1). During the influenza A (H1N1) pandemic
in 2009, 23% of hospitalized patients with DS died vs. only 0.1% of those without DS. Collectively, these data
point to an urgent need to understand how the condition of trisomy 21 contributes to respiratory infectious disease
and to identify potential therapeutic targets. Currently, infectious respiratory disease in DS is commonly attributed
to congenital abnormalities of the nasopharynx and upper and lower airways. However, our preliminary data
support the novel hypothesis that immune cell dysfunction is a primary driver of increased incidence and severity
of infectious respiratory disease in DS. Our data show that the trisomic Dp16 mouse lung has higher levels of
interferons and the immunosuppressive cytokine Interleukin (IL)-10. These changes closely mimic the
dysregulated cytokine response in the human lung that has long been observed following influenza infection,
and is a state linked to increased susceptibility to lethal bacterial pneumonia. Importantly, Dp16 mice are trisomic
for the Hsa21-encoded interferon receptors and interferon-responsive genes. Based on these data, we
hypothesize that the constitutive activation state of interferon signaling and IL-10 signaling in the DS lung drives
immune suppression and predisposes individuals with DS to S. pneumoniae pneumonia. This state phenocopies
the increased susceptibility and severity of S. pneumoniae pneumonia that is observed in non-DS individuals
after a course of viral infection. The high morbidity and mortality associated with infectious respiratory disease
is a seriously neglected area of medical need for people with DS. In addition, chronic lung disease is increasingly
associated with cognitive deficit. Conceptualizing DS as a post-viral state of susceptibility to bacterial infection
challenges the existing paradigm of congenital abnormality. Proposing to understand the mechanisms involved
in immune suppression and to identify therapeutic targets and agents to ameliorate frequency and severity of
disease, while high risk, would, if successful, provide a high payoff in the increased health and longevity of people
with and without DS.
项目总结
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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MICHAEL E. YEAGER其他文献
MICHAEL E. YEAGER的其他文献
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{{ truncateString('MICHAEL E. YEAGER', 18)}}的其他基金
RAT21: Generation and Characterization of Rat Models of Down Syndrome
RAT21:唐氏综合症大鼠模型的生成和表征
- 批准号:
10089663 - 财政年份:2020
- 资助金额:
$ 38.88万 - 项目类别:
Bronchus-Associated Lymphoid Tissue & Lung Infection in Down Syndrome
支气管相关淋巴组织
- 批准号:
10168185 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
Persistent Post-Viral State of Bacterial Pneumonia Susceptibility and Severity in Down Syndrome
唐氏综合症细菌性肺炎易感性和严重程度的持续病毒感染后状态
- 批准号:
9817272 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
Bronchus-Associated Lymphoid Tissue & Lung Infection in Down Syndrome
支气管相关淋巴组织
- 批准号:
9894473 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
Persistent Post-Viral State of Bacterial Pneumonia Susceptibility and Severity in Down Syndrome
唐氏综合症细菌性肺炎易感性和严重程度的持续病毒感染后状态
- 批准号:
10624885 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
Persistent Post-Viral State of Bacterial Pneumonia Susceptibility and Severity in Down Syndrome
唐氏综合症细菌性肺炎易感性和严重程度的持续病毒感染后状态
- 批准号:
10415117 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
Bronchus-Associated Lymphoid Tissue & Lung Infection in Down Syndrome
支气管相关淋巴组织
- 批准号:
10018101 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
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