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Natural Killer Cell Responses of Aged Mice to Primary Influenza Infection

老年小鼠对原发性流感感染的自然杀伤细胞反应

基本信息

批准号：
8284334
负责人：
Elizabeth M. Gardner
金额：
$ 33.7万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8284334
关键词：
Ablation Acute Address Adoptive Transfer Affect Age Age-Years Animal Model Antibodies Apoptosis Body Weight decreased C57BL/6 Mouse Cause of Death Cell Count Cell Proliferation Cell physiology Cells Cessation of life Cytokine Receptors Cytolysis Cytotoxic T-Lymphocytes Data Defect Dendritic Cells Dendritic cell activation Dependence Dose Elderly Environment Exhibits Family suidae Future Goals Histology Homing Hospitalization Human Immune Immune response Immunoglobulin G Individual Infection Infiltration Influenza Influenza A Virus, H1N1 Subtype Influenza vaccination Leucocytic infiltrate Lung Lytic Measures Mus Natural Killer Cells Pathology Persons Pneumonia Population Predisposition Prevalence Production Recovery Reporting Research Resistance Role Signal Transduction Therapeutic Transgenic Mice United States Vaccines Virus Virus Diseases Vulnerable Populations Weight Gain age related aged base cytokine cytotoxicity human old age (65+)in vivo influenzavirus mouse model novel prophylactic public health relevance receptor function response seasonal influenza statistics

项目摘要

DESCRIPTION (provided by applicant): Despite vaccination, influenza and secondary pneumonias are the fourth leading cause of death in individuals 65 years and older. The recent emergence of the novel 2009-H1N1 influenza, to which vaccines are limited or unavailable, has the potential to cause 30,000-90,000 deaths in people under 65 years of age. These staggering statistics mandate the need to better understand age-related changes in primary immune responses to acute influenza infection. We have recently identified a critical role for natural killer (NK) cells in controlling early influenza infection ex vivo and in vivo. Aged C57BL/6 mice exhibited increased lung virus titers, weight loss, decreased NK cytotoxicity, and a reduced number of NK cells during early influenza infection. Importantly, in vivo NK cell depletion by anti-NK1.1 IgG antibody (PK136) treatment induced marked weight loss and increased lung virus titers after influenza infection of both young and aged mice. These data suggest that NK cells are essential in early control of influenza infection. Thus, our overarching hypothesis is that the induction of an effective NK cell response is vital for controlling early influenza infection in vulnerable populations, including the elderly. Our studies will characterize age-related changes in NK cell function, elucidate potential intrinsic and extrinsic mechanisms for impaired NK cell function, and establish the critical role of NK cells in controlling early infection to influenza virus in vivo. In Aim 1, age-related differences in susceptibility and the role of NK cell function during the first critical four days of infection will be assessed. We will perform influenza dose responses and measure age-related differences lung virus titers, pathology, histology and cellular infiltrates in lung, weight loss, and recovery from infection. Age-related changes in NK subsets, cytolytic function of NK cells, dendritic cell (DCs) function, and local and systemic cytokine production will be measured during infection. In Aim 2, we will elucidate age-related changes in intrinsic and extrinsic mechanism(s) for impaired NK cell function during influenza infection. Age-related differences in lytic efficiency, activation receptor function/signaling, and cytokine receptor/function will be measured in purified NK cells to identify intrinsic NK cell defects. Adoptive transfer studies will delineate between intrinsic and extrinsic effects on NK cell proliferation, apoptosis, and homing as related to susceptibility to influenza. We hypothesize that DCs are critical extrinsic effectors on NK cell function in early infection. Thus, we will measure DC activation of NK cells, DC cytokine production, and the effects of DC ablation on NK cell function. In Aim 3, we will validate the essential role of NK cells in controlling the in vivo response to influenza. In vivo NK cytolysis in young and aged mice will be assessed along with survival, weight loss, and lung virus titers. The specific role of NK cells in controlling susceptibility to influenza will be addressed in mice after NK depletion in vivo with PK136 or in RAG-1-/- or NKD transgenic mice. These three mouse models will afford a clear delineation of the specific contribution of NK cells in controlling the early response to influenza. PUBLIC HEALTH RELEVANCE: The prevalence of seasonal influenza and the recent emergence of swine 2009-H1N1 mandate the need to study age-related changes in the primary response to influenza infection. Aged mice show decreased NK cell function and elevated lung virus titers during the first four days of infection, and more importantly, die prior the initiation of an adaptive primary response. If applicable to humans, this suggests that the ability of young and aged individuals to mount an early and effective NK cell response to influenza infection is vital, especially when vaccine is limited or unavailable.