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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结