Co-infection of mice with MHV68 and rodent Plasmodium species

小鼠同时感染 MHV68 和啮齿类疟原虫

基本信息

批准号：
8285405
负责人：
SAMUEL H SPECK
金额：
$ 19.38万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-02 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8285405
关键词：
5 year old Accounting Acute Address Africa African Burkitt&apos s lymphoma Age Anemia Animal Model Animals Antimalarials Area B-Lymphocytes Burkitt Lymphoma Cause of Death Central Africa Central African Republic Cerebral Malaria Cessation of life Child Childhood Chronic Data Development Disease Dose Epstein-Barr Virus Infections Experimental Models Exposure to Falciparum Malaria Goals Human Hypoxia Immune response Immunity Individual Infection Infection Control Lead Light Malaria Malignant Neoplasms Minority Modeling Monitor Morbidity - disease rate Mus Outcome Parasitemia Pathogenesis Pathologic Pathology Patients Plasmodium Plasmodium berghei Plasmodium falciparum Primates Sampling Severities Severity of illness Staging T-Lymphocyte Time Viral Viral Genes Virus Virus Diseases Work cytokine gammaherpesvirus infected B cell insight mortality mouse model prospective response vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): This is a new R21 application to characterize co-infection of mice with murine gammaherpesvirus 68 (MHV68)androdent Plasmodiumspecies. Atightassociation between EBV infection and Plasmodiumfalciparum malaria in young children is known in the genesis of endemic Burkitt's lymphoma (eBL) - although this only occurs in a small minority of co-infected individuals. In many regions of central Africa, Plasmodium falciparum malaria is the leading cause of death of children under 5 years old [e.g., in the Central African Republic it is estimated to account for 34 deaths per 1,000 children < 5 yrs of age]. Factors contributing to the variable outcome of P. falciparum infection in young children remain largely undefined. Importantly, it is not known whether there are other pathologic manifestations of EBV and P. falciparum co-infections (e.g., does EBV co-infection in some children contribute to morbidity and mortality from P. falciparum). While a number of studies have identified alterations in the host response to EBV infection in children with malaria, the actual contribution of co-infection (particularly, the timing of acute EBV and P. falciparum infections) has not been rigorously addressed due to limitations in obtaining appropriate prospective patient samples, as well as the inability to control parameters of infection. There are several rodent Plasmodium species that have been routinely used in mice to model aspects of Plasmodium infections in humans. We have initiated studies on co-infection of mice with a murine gammaherpesvirus, MHV68, and P. yoelii to assess how co-infection may alter the outcome of chronic MHV68 infection - as well as its impact on P. yoelii infection. Our preliminary data [as well as the studies of Haque et al.] have demonstrated a strong synergy between co-infection of mice with MHV68 and P. yoelii - providing an experimental model in which interference in normal host control of both Plasmodium and gammaherpesvirus infections is observed. To extend these studies we propose the following 2 specific aims: Aim 1. Characterize enhanced pathology in mice co-infected with rodent Plasmodium species and MHV68: Aim 1.1. Determine timing of MHV68 and P. yoelii or P. chabaudi co-infection vs. severity of disease; Aim 1.2. Characterize pathological changes in co-infected vs. singly infected animals; Aim 1.3. Monitor progression of malaria and virus infections in singly and co-infected mice; and Aim 1.4. Characterize cytokine, T cell and B cell responses in singly and co-infected mice. Aim 2. Identification and characterization of specific factors contributing to lethality of Plasmodium infections in MHV68 infected mice: Aim 2.1. Identify viral genes contributing to disease severity; Aim 2.2. Determine impact of anemia-associated hypoxia on virus reactivation/persistent replication; Aim 2.3. Examine impact of anti-malarial and anti-viral treatment on disease severity; and Aim 2.4. Assess long-term sequelae from co-infection under conditions that favor animal survival. PUBLIC HEALTH RELEVANCE: There is a clear association between EBV infection and Plasmodium falciparum malaria in the genesis of Burkitt's lymphoma in young children. However, little is known about whether EBV co-infection also impacts the severity of acute P. falciparum malaria - which is the leading cause of death in children under 5 years of age in Africa. Murine gammaherpesvirus 68 (MHV68) and rodent Plasmodium species infection of mice provide tractable small animal models for characterizing the impact of Plasmodium species on chronic gammaherpesvirus infections - which may lead to new insights that impact how children with acute P. falciparum malaria are treated.

描述（由申请人提供）：这是一种新的R21应用程序，可以表征与鼠γHERPESVIRUS68（MHV68）雄性疟原虫相关的小鼠共感染。幼儿中EBV感染与疟原虫疟疾之间的抗刺激性在流行伯基特的淋巴瘤（EBL）的起源中是众所周知的 - 尽管这仅发生在少数共同感染的个体中。在中非的许多地区，恶性疟疾疟疾是5岁以下儿童死亡的主要原因[导致幼儿恶性疟原虫感染结果可变结果的因素仍然在很大程度上不确定。重要的是，尚不清楚EBV和恶性疟原虫共同感染是否还有其他病理表现（例如，某些儿童的EBV共同感染是否有助于恶性疟原虫的发病率和死亡率）。虽然许多研究已经确定疟疾儿童对宿主对EBV感染的反应改变，但由于获得适当的前瞻性患者样本，以及无法控制感染参数的急性EBV和恶性疟原虫感染的实际贡献（尤其是，急性EBV和恶性疟原虫感染的时间）尚未受到严格解决。有几种啮齿动物质质植物通常在小鼠中用于模拟人类疟原虫感染的各个方面。我们已经开始对小鼠与鼠伽马疱疹病毒，MHV68和P. yoelii共同感染的研究，以评估共同感染如何改变慢性MHV68感染的结果，以及对P. yoelii感染的影响。我们的初步数据[以及Haque等人的研究]已经证明了小鼠与MHV68和P. yoelii的共同感染 - 提供了一个实验模型，在该模型中，观察到疟原虫的正常宿主控制和γ-瘤病毒感染的干扰。为了扩展这些研究，我们提出了以下2个特定目的：目标1。表征与啮齿动物疟原虫物种和MHV68共同感染的小鼠的增强病理学：AIM 1.1。确定MHV68和P. Yoelii或P. chabaudi共同感染与疾病严重程度的时间；目标1.2。表征共同感染与单一感染动物的病理变化；目标1.3。监测单一和共感染小鼠中疟疾和病毒感染的进展；和目标1.4。表征单一和共同感染的小鼠中细胞因子，T细胞和B细胞反应。目标2。鉴定和表征有助于MHV68感染小鼠疟原虫感染致死性的特定因素：AIM 2.1。确定导致疾病严重程度的病毒基因；目标2.2。确定贫血相关缺氧对病毒重新激活/持续复制的影响；目标2.3。检查抗疟疾和抗病毒治疗对疾病严重程度的影响；和目标2.4。在有利于动物存活的条件下，从共同感染中评估后遗症。公共卫生相关性：EBV感染与恶性疟原虫疟疾之间存在明显的关联。但是，对于EBV共感染是否也影响急性恶性疟原虫疟疾的严重程度，这是非洲5岁以下儿童死亡的主要原因。小鼠的鼠γγγ病毒68（MHV68）和啮齿动物质质子感染提供了可拖动的小动物模型，以表征疟原虫对慢性伽马病毒感染的影响，这可能会导致急性疟原虫疟原虫疟疾的新见解。