Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity.
Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity.
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DOI：
10.1371/journal.ppat.1004858
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发表时间：
2015-05
期刊：
影响因子：
6.7
通讯作者：
Lamb TJ
中科院分区：
文献类型：
--
作者：
Matar CG;Anthony NR;O'Flaherty BM;Jacobs NT;Priyamvada L;Engwerda CR;Speck SH;Lamb TJ
据估计，在恶性疟原虫地方性传播地区，1-2例感染即可产生对非脑型严重疟疾的免疫力。然而，每年有近20%的受感染儿童死于严重疟疾。据推测，多种风险因素会加剧疟疾，其中之一是与其他病原体的合并感染。生活在撒哈拉以南非洲的儿童在6个月大时对爱泼斯坦巴尔病毒（EBV）呈血清阳性。这个时间与保护性母体抗体的减弱和对原发性疟原虫感染的易感性重叠。然而，急性EBV感染对抗疟疾免疫力的产生的影响是未知的。使用良好建立的小鼠感染模型，我们在这里表明，急性，但不是潜伏的小鼠γ疱疹病毒68（MHV 68）感染抑制抗疟疾体液反应继发疟疾感染。重要的是，这导致非致死性约氏疟原虫XNL感染转化为致死性感染;这一结果与脾脏中生殖中心B细胞和T滤泡辅助（Tfh）细胞的维持缺陷相关。此外，我们已经鉴定了MHV 68 M2蛋白作为重要的病毒编码蛋白，其可以：（i）在急性MHV 68感染期间抑制抗MHV 68体液应答;和（ii）在共感染的情况下在观察到的抗疟疾体液应答的抑制中起关键作用。值得注意的是，与M2无效突变体MHV 68的共感染消除了约氏疟原虫XNL的致死性。总的来说，我们的数据表明，急性γ疱疹病毒感染会对抗疟疾免疫反应的发展产生负面影响。这表明，急性感染EB病毒应调查的危险因素，为非脑严重疟疾的幼儿生活在地区流行的疟原虫传播。每年有近100万人死于与恶性疟原虫感染有关的并发症，5岁以下儿童是最易感染的年龄组。早期的研究表明，儿童合并感染恶性疟原虫和EB病毒（EBV）会损害控制EBV的免疫反应，这可能导致称为地方性伯基特淋巴瘤（eBL）的颌骨肿瘤的发展。目前尚不清楚急性EBV感染是否对抗疟疾免疫力的产生有任何影响。我们已经使用EBV [鼠γ疱疹病毒68（MHV 68）]和疟疾（约氏疟原虫XNL）的小鼠模型来证明急性γ疱疹病毒感染可以损害控制疟原虫寄生虫血症的抗体的产生，进而导致非致死性约氏疟原虫XNL感染变为致死性。我们确定了MHV 68 M2蛋白在介导急性MHV 68感染对继发性疟疾感染产生体液免疫的抑制作用中的关键作用。这项工作表明，γ-疱疹病毒感染可以抑制有效的抗疟疾免疫反应的产生，并建议应将急性EBV感染作为幼儿严重疟疾发展的风险因素进行研究。
Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68) infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i) suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii) plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2-null mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission. Nearly 1 million deaths occur annually as a result of complications associated with P. falciparum infection, with children younger than 5 being the most susceptible age group. Earlier studies have demonstrated that children co-infected with P. falciparum and Epstein-Barr virus (EBV) have impaired immune responses to control EBV, and this can result in the development of a jaw tumor called endemic Burkitt’s lymphoma (eBL). It is not known if there is any impact of acute EBV infection on the generation of anti-malarial immunity. We have used mouse models of EBV [murine gammaherpesvirus 68 (MHV68)] and malaria (P. yoelii XNL) to demonstrate that acute gammaherpesvirus infection can impair the generation of antibodies that control Plasmodium parasitemia, in turn causing a non-lethal P. yoelii XNL infection to become lethal. We identify a critical role for the MHV68 M2 protein in mediating the suppressive effect of acute MHV68 infection on the generation of humoral immunity to a secondary malaria infection. This work demonstrates that gammaherpesvirus infections can suppress the generation of an effective anti-malaria immune response and suggests that acute EBV infection should be investigated as a risk factor for the development of severe malaria in young children.
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DOI：
10.4049/jimmunol.1201407
发表时间：
2012-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Getahun A;Smith MJ;Kogut I;van Dyk LF;Cambier JC
通讯作者：
Cambier JC
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
6.4
作者：
Hasang, Wina;Dembo, Edson G.;Rogerson, Stephen
通讯作者：
Rogerson, Stephen
影响因子：
--
作者：
Cardiff, Robert D;Miller, Claramae H;Munn, Robert J
通讯作者：
Munn, Robert J
影响因子：
6.4
作者：
BIGGAR, RJ;HENLE, W;HENLE, G
通讯作者：
HENLE, G