Memory T cell protection of reproductive health following influenza infection

流感感染后记忆 T 细胞对生殖健康的保护

• 批准号: 9590193
• 负责人: Tara Marlene Strutt
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9590193
• 关键词: Activities of Daily Living; Animals; Antiviral Agents; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Cause of Death; Cell Survival; Cell physiology; Cells; Cellular Immunity; Cessation of life; Child; Conceptions; Coupled; Cytoprotection; Data; Defense Mechanisms; Development; Epidemic; Estrogen Receptors; Estrogens; Exposure to; Female; Fetal Development; Fetal health; Generations; Genes; Gravid; High Risk Woman; Histopathology; Hormone Receptor; Hormones; Human; Immune response; Immunity; Immunologic Memory; Immunosuppressive Agents; Impairment; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; Lead; Lung; Lymphoid Cell; Maintenance; Mediating; Memory; Morbidity - disease rate; Morphology; Mus; Outcome; Physiological; Placentation; Pregnancy; Pregnancy Trimesters; Pregnant Women; Progesterone; Progesterone Receptors; Public Health; Regulation; Reproductive Health; Research; Resolution; Respiratory Tract Infections; Role; Seasons; Second Pregnancy Trimester; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Third Pregnancy Trimester; Time; Tissues; Vaccination; Vaccines; Viral; Viral Proteins; Virus; Virus Diseases; Work; adverse outcome; anti-influenza; cell mediated immune response; cytokine release syndrome; cytotoxic; fetal; high risk; improved; insight; memory CD4 T lymphocyte; mortality; mouse model; neutralizing antibody; novel; novel strategies; pandemic disease; pandemic influenza; pathogen; prevent; repaired; respiratory infection virus; respiratory virus; response; tissue repair; translational impact; universal vaccine; uptake; vaccine efficacy; vaccine-induced immunity

Project Summary Respiratory tract infections are a leading cause of death worldwide. Compromised cell-mediated immune responses, low vaccine efficacy, and poor vaccine uptake all increase the likelihood that serious infection will ensue in pregnant women following exposure to respiratory viruses such as Influenza A virus (IAV); approximately 80% of pregnant women are at high risk for influenza-associated complications. Our best defense is vaccination. Vaccine-induced protection is mediated by immunological memory. The majority of immunological memory studies to date have focused on the differentiation, survival, and delineation of the antipathogen defense mechanisms employed by pathogen-specific T cells under normal physiological circumstances. The impact of pregnancy on the persistence and functional recall potential of memory T cells is surprisingly unknown. The overarching hypothesis of this proposal is that IAV-specific T cell memory generated prior to conception will mediate potent universal, heterosubtypic protection throughout pregnancy. This hypothesis arose from our observations that memory effector CD4 T cells isolated from influenza infected lungs express low levels of estrogen and progesterone hormone receptors in comparison to primary effector CD4 T cells. Pregnancy hormones are well known to have detrimental impacts on the generation and function of primary anti-viral immune responses. Preliminary findings herein show that heterosubtypic recall responses are indeed protective in gravid animals primed prior to conception. In the first aim, the persistence of IAV-specific CD4 and CD8 memory T cells during pregnancy, as well as their ability to differentiate into the many protective subsets that mediate diverse and potent anti-viral effector functions will be determined. Our prior work has shown that memory CD4 T cells regulate both local and systemic anti-viral inflammatory responses, and, additionally, mobilize innate lymphoid cells during pathogen infection. Innate lymphoid cells, which function in tissue repair, have recently been shown to be present in placental tissue. In the second aim, we will thus elucidate the role of IAV-specific memory T cells in preserving both healthy placental and fetal development through the regulation of systemic innate inflammatory and cellular responses following IAV infection. The insight gained from the proposed, `reverse-mechanism', studies will advance our ability to develop improved vaccines that elicit memory T cells capable of orchestrating protective anti-viral defenses during pregnancy. This research may also lead to the development of novel strategies to treat expectant mothers suffering from serious influenza for which current therapeutic options are lacking. Respiratory tract infection with Influenza A virus remains a serious public health concern, particularly for pregnant women, who have suffered disproportionally high morbidity and mortality in past epidemic and pandemic seasons. The proposed study has the potential to make a broad and significant translational impact on human reproductive health.

项目摘要 呼吸道感染是全世界死亡的主要原因。受损的细胞介导免疫 反应，疫苗效力低，疫苗吸收差，都增加了严重感染的可能性， 孕妇在接触呼吸道病毒如甲型流感病毒（IAV）后发生; 大约80%的孕妇面临流感相关并发症的高风险。我们最好的防守 就是接种疫苗疫苗诱导的保护是由免疫记忆介导的。大多数免疫学 迄今为止的记忆研究主要集中在抗病原体防御的分化、存活和描绘上 病原体特异性T细胞在正常生理环境下使用的机制。的影响 怀孕对记忆T细胞的持久性和功能回忆潜力的影响令人惊讶地未知。 该提议的首要假设是，IAV特异性T细胞记忆在免疫前产生。 在整个怀孕期间，受孕将介导有效的普遍的异亚型保护。这一假设产生于 根据我们的观察，从流感感染的肺中分离的记忆效应CD 4 T细胞表达低水平的 雌激素和孕激素受体与初级效应CD 4 T细胞的比较。妊娠 众所周知激素对初级抗病毒药物的产生和功能具有不利影响 免疫反应。本文的初步研究结果表明，异亚型回忆反应确实是保护性的， 在怀孕前准备好的妊娠动物中。在第一个目标中，IAV特异性的CD 4和CD 8的持续存在， 怀孕期间的记忆T细胞，以及它们分化成许多保护性亚群的能力， 将确定介导的多种和有效的抗病毒效应子功能。我们之前的研究表明记忆 CD 4 T细胞调节局部和全身抗病毒炎症反应，并且另外动员先天性免疫应答。 淋巴细胞在病原体感染。在组织修复中起作用的先天性淋巴样细胞， 已经被证明存在于胎盘组织中在第二个目标中，我们将阐明IAV特异性 记忆性T细胞通过调节全身性免疫调节来保护健康胎盘和胎儿发育 IAV感染后的先天性炎症和细胞反应。 从拟议的“反向机制”研究中获得的见解将提高我们的发展能力， 改进的疫苗，诱导记忆T细胞，能够协调保护性抗病毒防御， 怀孕这项研究也可能导致开发新的策略来治疗孕妇 患有目前缺乏治疗选择的严重流感。呼吸道感染 甲型流感病毒仍然是一个严重的公共卫生问题，特别是对孕妇来说， 在过去的流行病和大流行季节，发病率和死亡率都非常高。拟议的研究已 对人类生殖健康产生广泛和重大转化影响的潜力。