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：
8416962
负责人：
SAMUEL H SPECK
金额：
$ 23.25万
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/8416962
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 Human Herpesvirus 4 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.

描述（由申请人提供）：这是一项新的 R21 申请，用于表征小鼠与鼠伽马疱疹病毒 68 (MHV68) 和啮齿类疟原虫物种的共同感染。已知幼儿中的 EBV 感染与恶性疟原虫疟疾之间存在密切关联，这与地方性伯基特淋巴瘤 (eBL) 的发生有关，尽管这种情况只发生在极少数共同感染的个体中。在中部非洲的许多地区，恶性疟原虫疟疾是 5 岁以下儿童死亡的主要原因 [例如，在中非共和国，估计每 1,000 名 5 岁以下儿童中有 34 人死亡]。导致幼儿恶性疟原虫感染的不同结果的因素在很大程度上仍不清楚。重要的是，目前尚不清楚 EBV 和恶性疟原虫合并感染是否存在其他病理表现（例如，某些儿童的 EBV 合并感染是否会导致恶性疟原虫的发病和死亡）。虽然许多研究已经发现疟疾儿童宿主对 EBV 感染的反应发生了变化，但由于研究的局限性，合并感染的实际影响（特别是急性 EBV 和恶性疟原虫感染的时间）尚未得到严格解决。获得适当的前瞻性患者样本，以及无法控制感染参数。有几种啮齿动物疟原虫物种已常规用于小鼠以模拟人类疟原虫感染的各个方面。我们已经启动了小鼠伽马疱疹病毒、MHV68 和约氏疟原虫联合感染的研究，以评估联合感染如何改变慢性 MHV68 感染的结果，以及它对约氏疟原虫感染的影响。我们的初步数据[以及 Haque 等人的研究]已经证明，小鼠同时感染 MHV68 和约氏疟原虫之间存在很强的协同作用——提供了一个实验模型，在该模型中干扰疟原虫和伽马疱疹病毒感染的正常宿主控制被观察到。为了扩展这些研究，我们提出以下 2 个具体目标：目标 1. 表征啮齿类疟原虫和 MHV68 共同感染的小鼠的增强病理学特征：目标 1.1。确定 MHV68 和 P. yoelii 或 P. chabaudi 共同感染的时间与疾病严重程度的关系；目标 1.2。表征共同感染与单独感染动物的病理变化；目标 1.3。监测单一和共同感染小鼠的疟疾和病毒感染进展情况；和目标 1.4。表征单一和共同感染小鼠的细胞因子、T 细胞和 B 细胞反应。目标 2. 鉴定和表征导致 MHV68 感染小鼠中疟原虫感染致死的特定因素：目标 2.1。识别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。在有利于动物生存的条件下评估共同感染的长期后遗症。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity.

伽玛疱疹病毒与疟疾合并感染抑制抗寄生虫体液免疫。

DOI：
发表时间：
2015-05
期刊：
影响因子：
6.7
作者：
Matar, Caline G;Anthony, Neil R;O'Flaherty, Brigid M;Jacobs, Nathan T;Priyamvada, Lalita;Engwerda, Christian R;Speck, Samuel H;Lamb, Tracey J
通讯作者：
Lamb, Tracey J