CMV-encoded TNF receptor and viral dissemination

描述（由申请人提供）：巨细胞病毒（CMV）感染广泛，通常无症状。该病毒在宿主中建立终身潜伏期，并在妊娠期间从母亲传播给胎儿和免疫功能低下的宿主时成为主要病原体。CMV疾病的风险是由多种宿主和病毒因素决定的，但目前尚不清楚特定的CMV毒株是否比其他毒株更容易重新激活和传播。目前可用的抗病毒疗法降低了CMV疾病的发病率和死亡率，但受到毒性和对已确定疾病的可变疗效的限制。CMV疫苗目前不能用于预防免疫功能低下宿主的先天性感染或疾病。我们一直在研究位于病毒UL/B'区（UL 131-UL 150）的人CMV基因。这些基因在实验室适应菌株中缺失，但存在于所有临床分离株中;因此，被认为在宿主中起致病作用。这些基因中的一些编码细胞因子和趋化因子，其可干扰宿主免疫应答。我们从多个人类样本中测序了UL 144（TNF 1受体基因）、UL 146和UL 147（1趋化因子基因），并确定了它们的多态性。我们还在两项队列研究中发现，UL 144的多态性与先天性CMV感染的结局相关。最近的研究表明，UL 144的胞外域与B和T细胞淋巴细胞衰减剂相互作用，并在体外抑制T细胞增殖。UL 144还激活NF-：B，导致趋化因子CCL 22（Th 2淋巴细胞的化学引诱物）的表达增强。这些研究表明，UL 144可能通过影响Th 1/Th 2应答干扰宿主免疫监视，这可能有助于CMV传播。我们的假设是UL 144在允许CMV在宿主中传播中起作用。某些UL 144基因型可能引发比其他基因型更低效的宿主细胞介导的免疫，因为Th 1应答的信号传导和活化的差异，将免疫应答转向Th 2应答。我们提出了以下具体目标：1）确定UL 144激活NF-：B的分子机制的某些方面。我们将确定UL 144的哪个结构域在信号传导中是重要的，并鉴定与UL 144相互作用的蛋白质。2)研究UL 144对体外Th 1/Th 2应答的影响。利用共培养系统，将确定UL 144基因型对Th 1/Th 2淋巴细胞应答和细胞因子产生的影响。公共卫生相关性：我们希望提供新的视角，更好地理解UL 144激活NF-：B的机制。我们还将深入了解UL 144基因型在其信号传导和影响Th 1/Th 2反应的能力方面的差异。了解UL 144在允许病毒传播和免疫逃避中的作用，可能会为药物和疫苗开发开辟新的策略。

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) infection is widespread and is usually asymptomatic. The virus establishes lifelong latency in the host and becomes a major pathogen when transmitted during pregnancy from mother to fetus, and in immunocompromised hosts. The risk of CMV disease is determined by multiple host and viral factors, but it is unknown whether specific CMV strains are more likely to reactivate and disseminate than others. Currently available antiviral therapies have decreased morbidity and mortality of CMV disease but are limited by toxicities and by variable efficacy in established disease. CMV vaccine is currently not available to prevent congenital infection or disease in immunocompromised hosts. We have been studying human CMV genes located in the UL/b' region of the virus (UL131-UL150). These genes are deleted in laboratory adapted strains but exist in all clinical isolates; therefore, thought to play a pathogenesis role in the host. Some of these genes encode for cytokines and chemokines that may interfere with host immune responses. We sequenced UL144 (TNF1 receptor gene), UL146 and UL147 (1 chemokine genes) from multiple human samples, and defined their polymorphisms. We also showed in two cohort studies that polymorphisms in UL144 correlate with outcome of congenital CMV infection. Recent studies show that the ectodomain of UL144 interacts with the B and T cell lymphocyte attenuator and inhibits T cell proliferation in vitro. UL144 also activates NF-:B, resulting in enhanced expression of the chemokine CCL22, a chemoattractant for Th2 lymphocytes. These studies suggest that UL144 plays a role in interference with host immune surveillance possibly via effects on Th1/Th2 responses, which may help CMV to disseminate. Our hypothesis is that UL144 has a role in allowing CMV to disseminate in the host. Certain UL144 genotypes may elicit less effective host cell mediated immunity than others because of differences in signaling and in activation of Th1 responses, diverting the immune response towards a Th2 response. We propose the following specific aims: 1) to determine some aspects of the molecular mechanisms by which UL144 activates NF-:B. We will determine which domain of UL144 is important in signaling, and identify proteins that interact with UL144. 2) To determine the effects of UL144 on Th1/Th2 responses in vitro. Using co-culture system the effects of UL144 genotypes on Th1/Th2 lymphocyte responses and cytokine production will be determined. PUBLIC HEALTH RELEVANCE: We hope to provide new perspectives and better understanding of the mechanisms by which UL144 activates NF- :B. We will also provide insight into the differences between UL144 genotypes in their signaling and their ability to affect Th1/Th2 responses. Understanding the role of UL144 in allowing viral dissemination and immune evasion, may open a new strategy for drug and vaccine development.