Sex in Myocarditis

心肌炎中的性行为

• 批准号: 6911795
• 负责人: Sally A Huber
• 金额: $ 30.3万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-20 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911795
• 关键词: Coxsackievirus; MHC class I antigen; decay accelerating factor; gender difference; genetic strain; hormone regulation /control mechanism; laboratory mouse; myocarditis; pathologic process; sex cycle; tumor necrosis factor alpha; virus receptors

DESCRIPTION (provided by applicant): Myocarditis is an inflammation of the heart which usually follows microbial infections. Men are more likely to develop myocarditis than women. The reasons for the gender bias in this disease are not completely clear, however, we have shown that young cycling women show natural fluctuations in expression of decay accelerating factor (DAF; CD55) which is a known receptor for coxsackieviruses. Furthermore, B lymphocytes are more susceptible to coxsackievirus infection when DAF expression is highest in the luteal phase of the ovarian cycle. We have established a murine model of coxsackievirus B3 (CVB3) induced myocarditis. Male mice are highly susceptible to inflammatory heart disease. Female mice in estrus and metestrus phases of the ovarian cycle are highly resistant, but females in diestrus and proestrus phases are suscceptible to the disease. Virus titers in the pancreas 24 hours after infection correlate to myocarditis susceptibility. Published studies have shown that only CVB3 variants which rapidly infect and replicate to high titers in the pancreas are able to induce myocarditis. We hypothesize that this early pancreatic infection elevates circulating TNFa levels which up-regulate DAF in the heart and promote cardiac infection. Estrogen suppresses systemic tumor necrosis factor-alpha (TNFa) responses which may explain the reduced pathogenicity of CVB3 in this sex. We have also shown that TNFa up-regulates expression of CD1d, a major histocompatibility complex class l-like molecule involved in innate immunity. CD1d is required for activation of T cells expressing the Vy4+ T cell receptor. vy4+ cells infiltrate the hearts of CVB3 infected male but not female mice and are required for pathogenicity. Increased circulating TNFa or cytokine produced in the heart after augmented virus infection (due to enhanced DAF expression) may be responsible for the increased CD1d levels. The Specific Aims of this proposal are to: 1) determine the ability of heart-specific TNFa to promote myocarditis in infected female mice; and the relationship to CD1d expression in the heart; and 2) evaluate the role of DAF in myocarditis and hormonal influence on DAF expression and infection. By understanding the factors controlling virus infection and induction of innate immunity, better mechanism for controlling viral disease should be possible.

描述（由申请人提供）：心肌炎是心脏的炎症，通常遵循微生物感染。男性比女性更可能患上心肌炎。但是，这种疾病中性别偏见的原因尚不完全清楚，但是，我们已经表明，年轻的骑自行车妇女在衰减加速因子表达（DAF; CD55）表达的自然波动，这是Coxsackieviviruses的已知受体。此外，当DAF表达在卵巢周期的黄体期最高时，B淋巴细胞更容易受到Coxsackievivirus感染的影响。我们已经建立了Coxsackievivirus B3（CVB3）诱导心肌炎的鼠模型。雄性小鼠非常容易患炎症性心脏病。卵巢周期的雌性小鼠在雌性阶段和杀虫阶段具有高度抗性，但胸腔和前弹性阶段的女性对该疾病有可能。感染后24小时，胰腺中的病毒滴度与心肌炎的敏感性相关。已发表的研究表明，只有迅速感染并复制到胰腺高滴度的CVB3变体能够诱导心肌炎。我们假设这种早期的胰腺感染升高了循环的TNFA水平，这些水平将DAF上调并促进心脏感染。雌激素抑制了全身性肿瘤坏死因子-Alpha（TNFA）反应，这可能解释了这种性别中CVB3的致病性降低。我们还表明，TNFA上调CD1D的表达是CD1D的表达，这是一种参与先天免疫的主要组织相容性复合物类Like分子。 CD1D是激活表达VY4+ T细胞受体的T细胞所必需的。 Vy4+细胞渗入CVB3感染的雄性而不是雌性小鼠的心脏，是致病性所必需的。增加病毒感染后，心脏中产生的循环TNFA或细胞因子增加（由于DAF表达增强）可能导致CD1D水平升高。该建议的具体目的是：1）确定心脏特异性TNFA促进感染雌性小鼠心肌炎的能力；以及与心脏中CD1D表达的关系； 2）评估DAF在心肌炎和激素对DAF表达和感染的影响。通过了解控制病毒感染的因素和先天免疫的诱导，应该可以更好地控制病毒疾病。