Co-infection of mice with MHV68 and rodent Plasmodium species

小鼠同时感染 MHV68 和啮齿类疟原虫

• 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
• 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' 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

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（由申请方提供）：这是一项新的R21应用，用于表征小鼠与鼠γ疱疹病毒68（MHV 68）雄齿疟原虫种属的共感染。在地方性伯基特淋巴瘤（eBL）的发生中，已知幼儿EB病毒感染和恶性疟原虫疟疾之间存在密切联系，尽管这仅发生在少数合并感染的个体中。在中非的许多地区，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可变结果的因素在很大程度上仍不明确。重要的是，还不知道是否存在EBV和恶性疟原虫共感染的其他病理学表现（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率和死亡率）。虽然一些研究已经确定了疟疾儿童对EBV感染的宿主反应的改变，但由于获得适当的前瞻性患者样本的限制以及无法控制感染参数，尚未严格解决合并感染（特别是急性EBV和恶性疟原虫感染的时间）的实际贡献。有 几种啮齿类疟原虫物种已常规用于小鼠中以模拟人类疟原虫感染的各个方面。我们已经启动了小鼠与鼠γ疱疹病毒MHV 68和约氏疟原虫共感染的研究，以评估共感染如何改变慢性MHV 68感染的结果-以及其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]已经证明了MHV 68和约氏疟原虫共感染小鼠之间的强协同作用-提供了一种实验模型，其中观察到疟原虫和γ疱疹病毒感染的正常宿主控制的干扰。为了扩展这些研究，我们提出了以下2个具体目标：目标1。表征啮齿类疟原虫种属和MHV 68共感染小鼠的病理学增强：目的1.1。确定MHV 68和约氏疟原虫或夏氏疟原虫共感染的时间与疾病的严重程度;目的1.2。描述合并感染与单独感染动物的病理变化;目标1.3。监测疟疾和病毒感染在单一和合并感染小鼠中的进展;和目标1.4.表征单感染和共感染小鼠中的细胞因子、T细胞和B细胞应答。目标二。在MHV 68感染小鼠中鉴定和表征导致疟原虫感染致死的特异性因素：目的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再激活/持续复制的影响;目的2.3。检查抗疟疾和抗病毒治疗对疾病严重程度的影响;目标2.4。在有利于动物生存的条件下评估合并感染的长期后遗症。 公共卫生关系：在幼儿伯基特淋巴瘤的发生中，EB病毒感染和恶性疟原虫疟疾之间存在明显的相关性。然而，关于EB病毒合并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-却知之甚少。小鼠γ疱疹病毒68（MHV 68）和啮齿动物疟原虫属感染小鼠提供了易于处理的小动物模型，用于表征疟原虫属对慢性γ疱疹病毒感染的影响-这可能会导致影响急性恶性疟原虫疟疾儿童治疗的新见解。