Vitamin A-Mediated Protection in Measles

描述（由申请人提供）：麻疹仍然是全世界儿童发病和死亡的最重要原因之一，最年幼的儿童负担最重。大多数麻疹死亡是由于继发感染造成的，继发感染是由于对麻疹引起的对其他病原体的免疫反应的抑制知之甚少。虽然在皮疹消退后传染性病毒不能再恢复，但麻疹病毒（MV） RNA可在呼吸道分泌物、尿液和血液中检测到数月，这种持续存在可能与麻疹引起的免疫抑制有因果关系。除了急性感染的风险外，2岁以下儿童和免疫功能低下（例如艾滋病毒感染）的儿童和成人由于无法清除病毒和神经系统感染，很容易发展为致命的进行性神经系统疾病。尽管通过实施大规模疫苗接种运动在控制麻疹方面取得了进展，但这些运动难以维持。因此，麻疹再次广泛传播，预计未来死亡人数将继续增加，而不是减少。麻疹唯一可用的“治疗”是维生素A。在疾病急性期给予维生素A可降低死亡率，但这种保护作用的机制尚不清楚，许多儿童没有得到这种补充。了解维生素A如何改善麻疹的康复，可以更广泛地使用这种简单而廉价的干预措施，更有效地预防MV感染的严重并发症，并可能确定发展中国家麻疹或其他高死亡率儿童感染的相关治疗方法。没有令人满意的麻疹小动物模型，但恒河猴易受野生型MV感染，并产生皮疹疾病，完全模仿人类的麻疹，包括淋巴细胞增殖的长期抑制。与人类一样，在感染后的几个月里可以检测到中程RNA。在皮疹期间出现抗体和T细胞反应。对补充维生素A对麻疹的影响的了解只能来自对猕猴的研究，因为出于伦理考虑，不可能对人类进行对照研究。我们假设维生素A提高了免疫介导的MV清除，缩短了免疫抑制期。由于所有反式维甲酸的实验效果都是增强Th2， Treg和CD8+ T细胞反应，抑制Th1和Th17反应，我们预测补充维生素a的猴子将具有改善的抗体，CD8+ T细胞和CD4+ Th2对麻疹的反应，这将与改善的病毒清除和减少免疫抑制相关。我们计划以下具体目标：(1)确定补充维生素A对感染性病毒和病毒RNA清除的影响；(2)鉴定补充维生素A对感染后mv特异性抗体和T细胞反应的影响；(3)确定补充维生素A是否会降低mv诱导的淋巴细胞增殖抑制的程度或持续时间。

DESCRIPTION (provided by applicant): Measles remains one of the most important causes of child morbidity and mortality worldwide with the greatest burden in the youngest children. Most measles deaths are due to secondary infections that result from a poorly understood measles-induced suppression of immune responses to other pathogens. Although infectious virus can no longer be recovered after the rash fades, measles virus (MV) RNA can be detected in respiratory secretions, urine and blood for several months and this persistence may be causally related to measles-induced immunosuppression. In addition to the risks of acute infection, children under the age of 2 yrs and immune-compromised (e.g. HIV-infected) children and adults are vulnerable to development of fatal progressive neurologic disease due to failure to clear virus and infection of the nervous system. Although gains have been made in measles control by implementing mass vaccination campaigns, these campaigns have been difficult to sustain. As a result, measles has again become widespread and deaths are predicted to continue to increase, rather than decrease, in the future. The only available "treatment" for measles is vitamin A. Vitamin A given during the acute phase of disease decreases mortality, but the mechanism for this protective effect is not known and many children do not receive this supplementation. An understanding of how vitamin A improves recovery from measles could result in more widespread use of this simple inexpensive intervention, more effective prevention of the severe complications of MV infection and perhaps identification of related treatments for measles or other childhood infections with high mortality in developing countries. There are no satisfactory small animal models for measles, but rhesus macaques are susceptible to wild type MV infection and develop a rash disease that faithfully mimics measles in humans, including prolonged suppression of lymphocyte proliferation. As in humans, MV RNA can be detected for several months after infection. Antibody and T cell responses appear during the rash. An understanding of the effect of vitamin A supplementation on measles will only come from studies of macaques because controlled studies in humans are not possible due to ethical considerations. We hypothesize that vitamin A improves the immune-mediated clearance of MV and shortens the period of immune suppression. Because the experimental effects of all trans-retinoic acid are to boost Th2, Treg and CD8+ T cell responses and to suppress Th1 and Th17 responses, we predict that vitamin A-supplemented monkeys will have improved antibody, CD8+ T cell and CD4+ Th2 responses to measles that will correlate with improved virus clearance and reduced immune suppression. We plan the following specific aims: (1) Determine the effect of supplemental vitamin A on clearance of infectious virus and viral RNA; (2) Identify the effect of supplemental vitamin A on MV-specific antibody and T cell responses after infection; (3) Determine whether supplemental vitamin A decreases the magnitude or duration of MV-induced suppression of lymphocyte proliferation.