Neuroendocrine Modulation of Neonatal Antiviral Immunity

新生儿是一种免疫缺陷的宿主，其对可能在出生时或出生后不久遇到的病原体产生免疫反应的能力严重受损。因此，新生儿严重依赖母源性免疫，产前通过胎盘途径获得，产后通过初乳和母乳获得，以保护他们在出生后的头几周免受各种感染。这项应用的广泛目标是确定母亲心理应激及其相关神经内分泌衍生多肽和激素的产生对新生儿免疫和感染疾病易感性的影响。提出这项研究的理由是基于这样一个事实，即在成年人中，有大量证据表明，心理应激通过各种神经内分泌相关机制显著影响免疫功能。然而，尽管在成人中明显存在神经内分泌-免疫相互作用，但对于这种相互作用在新生儿和幼儿中所起的作用，特别是这种相互作用如何影响免疫介导的抵御病原体的作用，还缺乏了解。这项建议中描述的研究将使用已建立的单纯疱疹病毒(HSV)感染的小鼠模型来检验这一假设，即母亲出生前和出生后的应激(包括急性和慢性)，以及与应激相关的母亲下丘脑-垂体肾上腺(HPA)轴的激活，都会改变母亲对新生儿的抗体转移，以及新生儿和婴儿暴露在其中的母亲皮质酮水平。预计这两个因素将反过来影响新生儿母源免疫的可获得性和利用率，以及婴儿HSV特异性免疫的产生。这些参数中的每一个对新生儿HSV感染发病机制的影响也将被确定。总体而言，这些研究将确定母亲应激对新生儿不仅对单纯疱疹病毒的易感性的影响，还将确定其对免疫耐受并对新生儿健康构成威胁的其他病原体的易感性的潜在影响。这类研究可推动就压力管理等问题提供产妇咨询，并建立社会支持网络，作为提高新生儿免疫力的一种手段。

The neonate is an immunodeficient host that is severely compromised in its ability to generate an immune response to pathogens which may be encountered at, or shortly after birth. Thus, neonates rely heavily on maternally-derived immunity, obtained both prenatally via transplacental means postnatally via the colostrums and breast milk, to protect them from a variety of infections during the first few weeks of like. The broad objective of this application is to determine the impact of maternal psychological stress and its associated production of neuroendocrine-derived peptides and hormones on neonatal immunity and susceptibility to infectious disease. The rationale for the proposed research is based on the fact that, in the adult, there is substantial evidence that psychological stress significantly affects immune function via a variety of neuroendocrine-associated mechanisms. However, despite the clear existence of neuroendocrine- immune interactions in adults, there is a dearth of knowledge as to the role that such interactions play in the neonate and young infant and, in particular, how such interactions affect immune-mediated defense against pathogens. The studies described in this proposal will use a well-established murine model of herpes simplex virus (HSV) infection to test the hypothesis that pre- and postnatal maternal stress (both acute and chronic), and stress-associated activation of the maternal hypothalamic- pituitary adrenal (HPA) axis alters both the transfer of maternally-derived antibody to the neonate and the levels of maternal corticosterone to which the neonate and young infant are exposed. It is expected that both of these factors will, in turn, affect both the availability and utilization of maternal-derived immunity in the neonate and the generation of HSV-specific immunity in the young infant. The effects of each of these parameters on the pathogenesis of neonate HSV infection will also be determined. Overall, these studies will determine the impact of maternal stress on neonatal susceptibility to not only HSV but also its potential impact on susceptibility to other pathogens that are immunologically resisted and pose a threat to neonatal health. Such studies may serve as the impetus for efforts to provide maternal counseling on issues such as stress management and the establishment of social support networks as a means to enhance neonatal immunity.