Role of secreted NS1 and anti-NS1 antibodies in dengue pathogenesis

分泌型 NS1 和抗 NS1 抗体在登革热发病机制中的作用

• 批准号: 7480758
• 负责人: Scott J. Balsitis
• 金额: $ 4.45万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-12 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480758
• 关键词: Antibodies; Antibody Formation; Binding; Blood Coagulation Disorders; Blood Platelets; Cells; Clinical; Clinical Trials; Coagulation Process; Complement; Complement Activation; Complex; Dengue; Dengue Hemorrhagic Fever; Dengue Shock Syndrome; Dengue Virus; Development; Disease; Dose; Extravasation; Health; Health Priorities; Life; Measures; Mus; PTPN11 gene; Pathogenesis; Patients; Peripheral; Phenotype; Plasma; Play; Proteins; Public Health; Research; Role; Route; Serotyping; Serum; Severity of illness; Thrombocytopenia; Vaccines; Vascular Permeabilities; Vascular System; Viral; Virus; Virus Diseases; Virus Replication; cross reactivity; mouse model; tissue tropism; virus pathogenesis

DESCRIPTION (provided by applicant): Dengue virus (DENV) infections result in an estimated 50 million cases of self-limited Dengue Fever (DF) every year and 250,000 to 500,000 cases of life-threatening Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS), which is characterized by thrombocytopenia, coagulopathy, complement depletion, and increased vascular permeability with leakage of plasma from the vascular system. The pathogenesis of DF and DHF/DSS is complex and poorly understood, but DENV NS1 protein, which is secreted by infected cells and found in infected patient sera, is likely to play an important role. NS1 can directly activate complement, and levels of soluble NS1 (sNS1) in patient sera correlate with disease severity. Furthermore, multiple studies indicate that antibodies to NS1 can be immunopathogenic. We hypothesize that DENV sNS1 and anti-NS1 antibodies contribute to DHF/DSS by modulating viral replication, activating complement, triggering thrombocytopenia and coagulopathy, and increasing vascular permeability. The role of sNS1 in viral infection and the mechanisms by which sNSI and anti-NS1 antibody contribute to clinical features of dengue disease have been difficult to study due to the lack of an appropriate mouse model. We have developed new mouse models that include the use of non-neuroadapted virus administered via relevant routes and at reasonable doses to produce peripheral tissue tropism and, at higher doses, fatal plasma leakage. These mouse models will be used to achieve the following specific aims: Specific Aim 1: Characterize hematologic disturbances induced by sNSI and anti-NS1 antibodies. Aim 1A: Characterize serotype cross-reactivity and platelet-binding activities of anti-NS1 antibodies. Aim 1B: Measure the effects of sNS1 and anti-NS1 antibodies on platelets, coagulation, and vascular permeability in mice. Aim 1C: Determine the role of complement activation in sNS1- and anti-NS1 antibody-induced phenotypes. Specific Aim 2: Evaluate the effects of sNS1 and anti-NS1 antibodies on DENV pathogenesis in mice. Aim 2A: Assess effects of sNS1 and anti-NS1 antibody on DENV replication and thrombocytopenia. Aim 2B: Assess the effects of sNS1 and anti-NS1 antibody on DENV-induced vascular permeability. This research will produce information critical to the development of a safe and effective dengue vaccine, a global public health priority. NS1 is a proposed target of dengue vaccines, and most vaccine candidates currently in clinical trials include NS1. It is critical to determine if the induced antibody responses will be protective, or alternatively, deleterious to patient health.

描述（申请人提供）：登革病毒（DENV）感染每年导致估计5000万例自限性登革热（DF）和250，000至500，000例危及生命的登革出血热/登革休克综合征（DHF/DSS），其特征在于血小板减少症、凝血病、补体耗竭，以及随着血浆从血管系统渗漏而增加的血管渗透性。DF和DHF/DSS的发病机制复杂且知之甚少，但由感染细胞分泌并在感染患者血清中发现的DENV NS 1蛋白可能发挥重要作用。NS 1可以直接激活补体，患者血清中可溶性NS 1（sNS 1）的水平与疾病的严重程度相关。此外，多项研究表明，NS 1的抗体可能是免疫致病性的。我们假设DENV sNS 1和抗NS 1抗体通过调节病毒复制、激活补体、触发血小板减少症和凝血病以及增加血管通透性而促成DHF/DSS。由于缺乏合适的小鼠模型，sNS 1在病毒感染中的作用以及sNS 1和抗NS 1抗体对登革热临床特征的作用机制一直难以研究。我们已经开发了新的小鼠模型，包括使用非神经适应性病毒通过相关途径和合理剂量给药，以产生外周组织嗜性，并在较高剂量下，致命的血浆泄漏。这些小鼠模型将用于实现以下特定目标：特定目标1：表征sNSI和抗NS 1抗体诱导的血液学紊乱。 目的1A：表征抗NS 1抗体的血清型交叉反应性和血小板结合活性。目的1B：测定sNS 1和抗NS 1抗体对小鼠血小板、凝血和血管通透性的影响。 目的1C：确定补体激活在sNS 1和抗NS 1抗体诱导的表型中的作用。具体目的2：评价sNS 1和抗NS 1抗体对小鼠中DENV发病的影响。 目的2A：评估sNS 1和抗NS 1抗体对DENV复制和血小板减少症的影响。 目的2B：评估sNS 1和抗NS 1抗体对DENV诱导的血管通透性的影响。这项研究将产生对开发安全有效的登革热疫苗至关重要的信息，这是全球公共卫生的优先事项。NS 1是登革热疫苗的一个拟议靶点，目前临床试验中的大多数候选疫苗都包括NS 1。确定诱导的抗体应答是否对患者健康具有保护性或有害性是至关重要的。