Congenital CMV and CNS Infection Mechanisms of Protective Immunity

先天性巨细胞病毒和中枢神经系统感染的保护性免疫机制

• 批准号: 10398817
• 负责人: William Jarvis Britt
• 金额: $ 58.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-13 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398817
• 关键词: Animal Model; Antibodies; Antibody Response; Antiviral Agents; Attenuated; Attenuated Vaccines; Auditory system; Biological; Biological Products; Birth; Brain; Brain Diseases; Brain Injuries; CD8-Positive T-Lymphocytes; Central Nervous System Diseases; Central Nervous System Infections; Child Health; Clinical; Cochlea; Complex; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease; Engineering; Fetal Development; Fetus; Glycoproteins; Goals; HIV Infections; Human; Human Characteristics; Immune response; Immunity; Immunologics; In Vitro; Infant; Infection; Investigation; Kinetics; Literature; Live Birth; Mediating; Modeling; Morbidity - disease rate; Mus; Natural History; Nature; Nervous System Trauma; Neuraxis; Neurodevelopmental Impairment; Outcome; Pathogenesis; Pregnancy; Pregnant Women; Prevention; Preventive vaccine; Reporting; Research; Role; Sample Size; Secondary to; Symptoms; System; T-Lymphocyte; Testing; Translating; Transplant Recipients; Vaccines; Viral; Viral Antibodies; Viral Vaccines; Virion; Virus; Virus Diseases; Woman; adaptive immune response; adaptive immunity; chronic infection; congenital cytomegalovirus; design; disorder prevention; env Gene Products; experimental study; hearing impairment; human disease; in utero; in vitro Assay; in vivo; infant infection; infant outcome; intrauterine infection; long-term sequelae; maternal outcome; mouse model; neurodevelopment; neutralizing antibody; offspring; prevent; primary endpoint; response; transmission process; vaccine development; vaccine efficacy; vaccine response; vaccine trial

Project Summary/Abstract Congenital human cytomegalovirus (HCMV) represents the most common viral infection acquired by the developing fetus. Although most infants infected in-utero do not suffer long term symptoms, approximately 10% can have long term sequelae. Central nervous system (CNS) damage is the singular cause of these long term sequelae. Prevention of CNS infection and disease is the target of current antiviral treatment and has been proposed as a goal of prophylactic vaccines. The pathogenesis of CNS disease in congenitally infected human infants remains undefined and to date studies in animal models of CNS infection by HCMV have provided little information secondary to significant limitations inherent in these models. We have recently developed a murine model of infection of the developing CNS with the related murine CMV that recapitulates many key characteristics of the human disease, including hearing loss that is common in infants with congenital CMV infections. Using this model we propose to define mechanisms of protective antibodies that limit CNS infection and disease. In addition, we will explore the use of engineered viruses that are attenuated in their capacity to cause CNS disease and establish persistent infection to induce protective antibody responses. We anticipate that these studies will identify strategies for development of targeted biologics such as antibodies and attenuated viruses that can provide immunologically mediated protection from CNS infection and damage that can follow congenital HCMV infection. Because of the relatedness between MCMV and HCMV, these strategies could be rapidly transitioned into development of similar biologics for human use.

项目摘要/摘要 先天性人类巨细胞病毒（HCMV）代表最常见的病毒感染 由发育中的胎儿获得。虽然大多数感染了Utero中的婴儿不会受苦 长期症状，大约10％可以具有长期后遗症。中央紧张 系统（CNS）损害是这些长期后遗症的奇异原因。预防 中枢神经系统感染和疾病是当前抗病毒药物治疗的目标，已经是 提议作为预防性疫苗的目标。中枢神经系统疾病的发病机理 先天感染的人类婴儿仍然不确定，迄今为止在动物中进行研究 HCMV感染中枢神经系统感染的模型几乎没有提供任何次要的信息 这些模型固有的重大局限性。我们最近开发了一个小鼠 与相关的鼠CMV概括的开发中枢神经系统感染模型 人类疾病的许多关键特征，包括听力损失 先天性CMV感染的婴儿。使用此模型，我们建议定义 限制CNS感染和疾病的保护性抗体的机制。另外，我们 将探索以造成能力减弱的工程病毒的使用 中枢神经系统疾病并建立持续感染以诱导保护性抗体反应。 我们预计这些研究将确定针对目标的制定策略 可以在免疫学上提供的生物制剂，例如抗体和减毒病毒 可介导的防御中枢神经系统感染和可能遵循先天性HCMV的损害的保护 感染。由于MCMV和HCMV之间的相关性，这些策略可以 迅速过渡到用于人类使用的类似生物制剂的发展。

项目成果

Congenital cytomegalovirus infection as a cause of sensorineural hearing loss in a highly immune population.

• DOI: 10.1097/inf.0b013e31822d9640
• 发表时间: 2011-12
• 期刊: The Pediatric infectious disease journal
• 作者: Yamamoto AY;Mussi-Pinhata MM;Isaac Mde L;Amaral FR;Carvalheiro CG;Aragon DC;Manfredi AK;Boppana SB;Britt WJ
• 通讯作者: Britt WJ

Cytomegalovirus Infection: Mouse Model.

• DOI: 10.1002/cpim.51
• 发表时间: 2018-08
• 期刊: Current protocols in immunology
• 作者: Brizić I;Lisnić B;Brune W;Hengel H;Jonjić S
• 通讯作者: Jonjić S

Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development.

对感染 MCMV 的新生小鼠进行糖皮质激素治疗可减轻中枢神经系统炎症并限制小脑发育缺陷。

• DOI: 10.1371/journal.ppat.1003200
• 发表时间: 2013-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Kosmac K;Bantug GR;Pugel EP;Cekinovic D;Jonjic S;Britt WJ
• 通讯作者: Britt WJ

SARS-CoV-2 Spike Protein Is Capable of Inducing Cell-Cell Fusions Independent from Its Receptor ACE2 and This Activity Can Be Impaired by Furin Inhibitors or a Subset of Monoclonal Antibodies.

• DOI: 10.3390/v15071500
• 发表时间: 2023-07-04
• 期刊: Viruses
• 作者: Reuter N;Chen X;Kropff B;Peter AS;Britt WJ;Mach M;Überla K;Thomas M
• 通讯作者: Thomas M

Birth prevalence and natural history of congenital cytomegalovirus infection in a highly seroimmune population.

• DOI: 10.1086/600882
• 发表时间: 2009-08-15
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Mussi-Pinhata MM;Yamamoto AY;Moura Brito RM;de Lima Isaac M;de Carvalho e Oliveira PF;Boppana S;Britt WJ
• 通讯作者: Britt WJ