Complement Resistance Acquired During Acute to Persistent Rubulavirus Infection
急性至持续性风疹病毒感染期间获得的补体耐药性
基本信息
- 批准号:10645486
- 负责人:
- 金额:$ 24.12万
- 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:2023-01-23 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAirBindingBiochemicalBiological AssayCell Culture TechniquesCell LineCell SurvivalCellsClinicalClinical TrialsComplementComplement Factor HComplement InactivatorsCytolysisDataDrug ModulationEngineeringEnvironmentEpithelial CellsFibrinogenFutureGenetic PolymorphismGenomeGoalsHumanIn VitroInfectionInflammationInnate Immune SystemLiquid substanceLungLung infectionsMediatingMumps virusParamyxovirusPathway interactionsPopulationProductionProteomicsRNA Virus InfectionsResistanceRespiratory SystemRespiratory Tract InfectionsRoleRubulavirusRubulavirus InfectionsSeveritiesSurfaceTestingTherapeuticTimeTracheaVariantViralViral Respiratory Tract InfectionVirionVirusVirus DiseasesVirus ReplicationVitronectinWorkacute infectionchronic infectionconditioninggene complementationinhibitorinnate immune mechanismsinnate immune pathwaysinterestparainfluenza viruspathogenprototyperecruitrespiratoryrespiratory infection virusresponsesulfated glycoprotein 2transcriptomics
项目摘要
For many RNA virus infections, an initial acute infection can transition to a prolonged or persistent
infection, in which infected cells survive and continue to produce progeny virus. Complement (C’) is a
powerful innate immune system which can directly lyse virus-infected cells or neutralize virus (1-4), but
the role of C’ in controlling persistent respiratory RNA virus infections is not well understood. Given that
viruses have mechanisms to block C’-mediated cell lysis, persistent infections can set up a prolonged
inflammation cycle – where activated C’ continues to provide damaging inflammation, but viral inhibitory
mechanisms block elimination of pathogen and infected cells.
This project emerged from our striking findings that during an initial acute infection of human lung
cells with the Rubulavirus Parainfluenza virus 5 (PIV5), infected cells are very sensitive to C’-mediated
lysis. Importantly however, after transitioning to a persistent infection, PIV5-infected cells are nearly
completely resistant to C’ lysis. Our transcriptomics data show that PIV5 acutely infected cells have low
level expression of C’ inhibitors, but this shifts to high level expression of cellular C’ inhibitors Factor H,
Factor I, Vitronectin and Clusterin in persistently infected cells.
Our central hypothesis is that PIV5 persistently infected cells acquire resistance to C’-mediated
lysis due to their acquired ability to express high levels of C’ inhibitors Factor H and Vitronectin. Our
goals are to identify: 1) the mechanisms for acquiring C’ resistance during the PIV5 acute-to-persistent
transition (Aim 1), and 2) consequences of this shift for production of C’-resistant virus (Aim 2).
Aim 1 will define the mechanism for differential sensitivity of airway cells to C’-mediated lysis
during transition from acute to persistent infection. Engineered respiratory tract cell lines and primary
tracheal or bronchial air-liquid interface (ALI) cell cultures will be used to test the hypothesis that
synthesis of C’ inhibitors Factor H and Vitronectin by persistently infected cells results in conditioning of
the cells to be resistant to C’-mediated lysis. Aim 2 will identify C’ factors associated with virus particles
derived from acute versus persistently infected cells and define the sensitivity of persistent virus to C’-
mediated neutralization. Proteomics and biochemical assays will test the hypothesis that virus derived
from persistently infected cells will be C’-resistant due to recruitment of Factor H or Vitronectin.
Results from our work on C’ interactions with persistent RNA virus infections will have strong
potential to inform therapeutics, given: 1) the clinical impact of prolonged viral respiratory infections, 2)
polymorphisms in C’ genes can correlate with severity of viral infections, and 3) clinical trials for
respiratory tract infections are underway with drugs that modulate C’ responses.
对于许多RNA病毒感染,最初的急性感染可以转变为长期或持续性感染
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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Griffith D. Parks其他文献
Complement evasion by vesicular stomatitis virus involves recruitment of host complement regulatory proteins
- DOI:
10.1016/j.molimm.2010.05.129 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:
- 作者:
John B. Johnson;Douglas S. Lyles;Griffith D. Parks - 通讯作者:
Griffith D. Parks
Griffith D. Parks的其他文献
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{{ truncateString('Griffith D. Parks', 18)}}的其他基金
Assembly of Live Nipah Virus with Complement Factors
活尼帕病毒与补体因子的组装
- 批准号:
8470128 - 财政年份:2012
- 资助金额:
$ 24.12万 - 项目类别:
Assembly of Live Nipah Virus with Complement Factors
活尼帕病毒与补体因子的组装
- 批准号:
8896985 - 财政年份:2012
- 资助金额:
$ 24.12万 - 项目类别:
Assembly of Live Nipah Virus with Complement Factors
活尼帕病毒与补体因子的组装
- 批准号:
8358727 - 财政年份:2012
- 资助金额:
$ 24.12万 - 项目类别:
Paramyxovirus Activation and Inhibition of Complement Pathways
副粘病毒激活和补体途径的抑制
- 批准号:
8286153 - 财政年份:2011
- 资助金额:
$ 24.12万 - 项目类别:
Paramyxovirus Activation and Inhibition of Complement Pathways
副粘病毒激活和补体途径的抑制
- 批准号:
8897063 - 财政年份:2011
- 资助金额:
$ 24.12万 - 项目类别:
Paramyxovirus Activation and Inhibition of Complement Pathways
副粘病毒激活和补体途径的抑制
- 批准号:
8469683 - 财政年份:2011
- 资助金额:
$ 24.12万 - 项目类别:
Paramyxovirus Activation and Inhibition of Complement Pathways
副粘病毒激活和补体途径的抑制
- 批准号:
8848749 - 财政年份:2011
- 资助金额:
$ 24.12万 - 项目类别:
Paramyxovirus Activation and Inhibition of Complement Pathways
副粘病毒激活和补体途径的抑制
- 批准号:
8660023 - 财政年份:2011
- 资助金额:
$ 24.12万 - 项目类别:
Paramyxovirus Activation and Inhibition of Complement Pathways
副粘病毒激活和补体途径的抑制
- 批准号:
8039506 - 财政年份:2011
- 资助金额:
$ 24.12万 - 项目类别:
Complement-mediated Neutralization of Mumps Virus and SV5
补体介导的腮腺炎病毒和 SV5 的中和
- 批准号:
8069009 - 财政年份:2010
- 资助金额:
$ 24.12万 - 项目类别:
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