Mechanisms of Protection of Universal Therapeutic Antibodies to Influenza A
甲型流感通用治疗抗体的保护机制
基本信息
- 批准号:10078587
- 负责人:
- 金额:$ 77.37万
- 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:2019-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdamantaneAnimal ModelAnimalsAntibodiesAntibody Binding SitesAntibody TherapyAntiviral AgentsAvian Influenza A VirusB-LymphocytesBindingBinding SitesBiologicalCell LineCellsClinicalComplementComplement ActivationDataDevelopmentDiseaseDoseEffectivenessEpitopesEscape MutantExtracellular DomainFc ReceptorFerretsGoalsHealthHemagglutininHumanIgG1ImmuneImmune responseImmunoglobulin Class SwitchingImmunologic MemoryImmunologicsImmunologistIn VitroInbred BALB C MiceIndividualInfectionInfection preventionInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A virusInfluenza vaccinationIon ChannelMediatingModelingMonoclonal AntibodiesMorbidity - disease rateMusMutant Strains MiceMutationNeuraminidaseOrthomyxoviridaePathogenicityPathologyPeptidesPhagocytosisProteinsScientistSerotypingSpecific qualifier valueSpleenTestingTherapeuticTherapeutic AgentsTherapeutic InterventionTherapeutic Monoclonal AntibodiesTherapeutic antibodiesTimeTreatment ProtocolsVaccinatedVaccinationVaccinesViralVirionVirusVirus DiseasesVirus ReplicationVirus SheddingZoonosesadaptive immune responseantibody-dependent cell cytotoxicitybasedosageextracellularhuman modelin vivoinfluenza infectioninfluenzavirusinhibitor/antagonistlead candidatemortalitymouse modelmutantnanoGoldneutralizing monoclonal antibodiesoverexpressionpandemic influenzapreventprophylacticrespiratoryresponseviral resistance
项目摘要
Influenza virus infection causes contagious respiratory illness in humans and animals, and significant morbidity
and mortality worldwide. Humans fail to make a universally protective memory immune response to influenza
A, as Hemagglutinin and Neuraminidase, the two immune-dominant influenza A virus-encoded epitopes,
undergo antigenic shift and drift, resulting in influenza A strains to which even previously infected humans are
susceptible to. In the absence of a universal influenza A vaccine, prophylactic or therapeutic agent, influenza A
will remain a significant threat to human health. To generate such agents, we developed a panel of Matrix
Protein 2 extracellular (M2e)-specific monoclonal antibodies (MAbs). The extracellular domain of the M2-ion
channel is an ideal antigenic target for a universal therapeutic agent: It is 99% conserved across influenza A
serotypes, has a low mutation rate, and is essential for viral entry and replication. However, less than 20% of
infected individuals generate M2e-specific antibodies in response to influenza A infection, perhaps due to
M2e's small size and rarity. Thus, we seek to accomplish our long-term goal, to develop a universal
prophylactic or therapeutic agent to prevent or treat influenza A infection and associated pathologies, by
provision of M2e-specific MAbs, an essential component of a protective influenza A-specific immune response
currently lacking in most humans. To achieve this goal, we generated seven monoclonal antibodies specific to
M2e, two of which completely protect, and three of which partially protect highly influenza A virus susceptible
Balb/c mice from lethal challenge. Based on these considerations, it is our central hypothesis that a cocktail of
M2e-specific MAbs can prevent or ameliorate influenza A infection and associated pathology. As antibodies
can mediate a variety of complementary effector functions that contribute to host protection, we hypothesize
that a combination of M2e-specific MAbs capable of interference with M2-ion channel activity, elicitation of
ADCC, phagocytosis and complement activation will be most effective at reducing influenza A virus replication
and associated pathology, while preventing immune escape. We expect to test our central hypothesis and to
achieve the objective of this application by pursuing the following three specific aims: Aim 1: to identify
biological effects of MAb binding on M2e-function and viral replication in vitro; Aim 2: to develop protective and
therapeutic MAb treatment regimens in vivo; and Aim 3: to dissect the individual contributions of M2e-specific
MAb-dependent cytotoxicity, phagocytosis and complement activation to host protection from influenza A virus
infection. To achieve our aims, we have assembled and expert team of collaborating scientists: Dr. Beeton, an
expert in the ion channel function; Dr. Tompkins, an expert in animal models of human and zoonotic influenza
infection, vaccination, and therapeutics, with specified M2 expertise; Dr. Ross, an expert in the ferret model of
influenza vaccination and infection; and, myself, Dr. Paust, an expert immunologist with a detailed
understanding of the innate and adaptive immune response to Influenza A infection.
流感病毒感染可在人类和动物中引起传染性呼吸道疾病,并造成严重的发病率
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30.
甲型流感病毒血凝素和其他病原体糖蛋白与 NK 细胞天然细胞毒性受体 NKp46、NKp44 和 NKp30 的相互作用。
- DOI:10.3390/v13020156
- 发表时间:2021-01-21
- 期刊:
- 影响因子:0
- 作者:Luczo JM;Ronzulli SL;Tompkins SM
- 通讯作者:Tompkins SM
Divergent Mast Cell Responses Modulate Antiviral Immunity During Influenza Virus Infection.
不同的肥大细胞反应调节流感病毒感染期间的抗病毒免疫力
- DOI:10.3389/fcimb.2021.580679
- 发表时间:2021
- 期刊:
- 影响因子:5.7
- 作者:Murphy-Schafer AR;Paust S
- 通讯作者:Paust S
{{
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 }}
Silke Paust其他文献
Silke Paust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('Silke Paust', 18)}}的其他基金
Novel mechanisms regulating immunity to respiratory virus infection
调节呼吸道病毒感染免疫力的新机制
- 批准号:
10753849 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Novel mechanisms regulating immunity to respiratory virus infection
调节呼吸道病毒感染免疫力的新机制
- 批准号:
10931141 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10924725 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes
细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制
- 批准号:
10559918 - 财政年份:2022
- 资助金额:
$ 77.37万 - 项目类别:
Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes
细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制
- 批准号:
10674910 - 财政年份:2022
- 资助金额:
$ 77.37万 - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10561720 - 财政年份:2021
- 资助金额:
$ 77.37万 - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10374918 - 财政年份:2021
- 资助金额:
$ 77.37万 - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
8996549 - 财政年份:2015
- 资助金额:
$ 77.37万 - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
9204387 - 财政年份:2015
- 资助金额:
$ 77.37万 - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
9430685 - 财政年份:2015
- 资助金额:
$ 77.37万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




