Co-infection of mice with MHV68 and rodent Plasmodium species

描述(由申请人提供)：这是一种新的R21应用程序，用于表征小鼠与小鼠伽马疱疹病毒68(MHV68)雄鼠疟原虫物种的混合感染。在地方性Burkitt淋巴瘤(EBL)的发生中，已知EBV感染与幼儿恶性疟之间的密切联系--尽管这种情况只发生在一小部分合并感染的人中。在中部非洲的许多地区，恶性疟疾是5岁以下儿童死亡的主要原因[例如，在中非共和国，估计每1000名5岁儿童中有34人死亡]。导致儿童恶性疟原虫感染的不同结果的因素在很大程度上仍不确定。重要的是，目前尚不清楚EBV和恶性疟原虫混合感染是否还有其他病理表现(例如，某些儿童的EBV联合感染是否导致恶性疟原虫的发病率和死亡率)。虽然许多研究已经确定了疟疾儿童对EBV感染的宿主反应的变化，但由于在获得适当的预期患者样本方面的限制，以及无法控制感染参数，合并感染(特别是急性EBV和恶性疟原虫感染的时间)的实际贡献尚未得到严格解决。确实有 几种啮齿动物疟原虫，通常在小鼠身上用来模拟人类疟原虫感染的各个方面。我们已经启动了小鼠与小鼠伽玛疱疹病毒MHV68和约氏疟原虫混合感染的研究，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]已经证明了MHV68和约氏P.yoelii混合感染小鼠之间具有很强的协同作用-提供了一个实验模型，在该模型中可以观察到干扰疟疾和伽马疱疹病毒感染的正常宿主控制。为了扩展这些研究，我们提出了以下两个具体目标：目标1.描述啮齿动物疟原虫和MHV68混合感染小鼠的增强病理特征：目标1.1。确定MHV68和约氏肺孢子虫或沙包氏肺孢子虫混合感染的时间与疾病严重程度的关系；目标1.2。描述混合感染与单独感染动物的病理变化；目标1.3。监测单独感染和混合感染的小鼠中疟疾和病毒感染的进展情况；目标1.4。研究单独感染和混合感染小鼠的细胞因子、T细胞和B细胞反应。目的2.确定和表征导致MHV68感染小鼠疟原虫感染致死的特定因素：目的2.1。确定导致疾病严重程度的病毒基因；目标2.2。确定贫血相关低氧对病毒重新激活/持续复制的影响；目标2.3。审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。评估在有利于动物存活的条件下合并感染的长期后遗症。

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.