Mali International Center for Excellence in Research: Filariasis

在多寄生症高度流行的地区，多种寄生虫对宿主反应的影响被低估。特别是，与疟疾同时存在的蠕虫感染深刻改变了疟疾特异性干扰素、IL-12p70、CXCL9、CXCL10和CXCL11的产生，已知这些细胞因子/趋化因子在调节疟疾特异性免疫中起关键作用。为了阐明疟疾特异性细胞因子/趋化因子抑制的机制，我们研究了马里丝虫病共同流行地区18名丝虫感染者(FIL(+))和17名非丝虫感染者(FIL(-))的血液中疟疾特异性IL-12R、IL-12R和干扰素调节因子(IRF)-1的表达。我们发现，FIL(+)个体对疟疾抗原刺激的反应中，IRF-1的RNA表达显著降低，而IL-12R；1或IL-12R；2的RNA表达不明显。我们还测量了这些受试者产生IL-12的DC的频率，发现FIL(+)受试者在疟疾抗原刺激后产生IL-12(+)MDCs的频率低于FIL受试者(-)。在体外模拟这些数据，我们发现预先暴露于活的微丝虫的MDCs不仅在疟疾抗原刺激下产生的CXCL-9、CXCL-10、IL-12p35、IL-12p40、IL-12p19和CXCL-11的水平显著低于未暴露的MDCs，而且还显著下调了IRF-1、IRF-2和IRF-3的表达。抑制MDCS中IRF-1的siRNA通过抑制IL-12p35而下调IL-12p70的产生。我们的数据表明，丝虫(可能还有其他组织侵袭性蠕虫)感染中看到的IRF的调制是抑制疟疾特异性细胞因子/趋化因子的基础，这些细胞因子/趋化因子在疟疾免疫中发挥关键作用。 在伴随蠕虫感染的背景下，疟疾特异性免疫反应和临床疟疾病程的调节机制知之甚少。我们使用多参数流式细胞术来表征马里合并无症状恶性疟的丝虫感染者和未感染者的疟疾特异性T细胞反应的质量和大小。与未感染丝虫的受试者相比，丝虫感染与产生IL-4、IL-10和IL-17A的CD_4(+)细胞的体外频率有关(分别为p=0.001、p=0.001和p=0.03)。然而，在对疟疾抗原刺激的反应中，丝虫感染与产生干扰素-γ、肿瘤坏死因子-α和IL-17A的CD_4(+)T细胞的频率较低(p&lt；0.001，p=0.04和p=0.04)以及CD_4(+)IL_(10)(+)T细胞的频率较高(p=0.0005)有关。重要的是，丝虫感染与疟疾抗原特异性Th1(p&lt；0.0001)、Th17(p=0.012)和肿瘤坏死因子-α(p=0.0008)细胞的频率显著降低有关，并且完全缺乏疟疾特异性多功能Th1细胞。丝虫感染还与疟疾特异性适应性调节T/Tr1细胞的频率显著增加有关(p=0.024)，中和抗IL-10抗体的加入增加了每个细胞产生的Th1相关细胞因子的数量。因此，在疟疾感染者中，伴随的丝虫感染显著降低了疟疾特异性Th1和Th17 T细胞的频率，并改变了疟疾特异性T细胞反应的质量和大小。 在包括撒哈拉以南非洲在内的世界许多地区，同时感染多种寄生虫是很常见的。为了研究丝虫病这一慢性蠕虫感染对急性疟疾感染的免疫反应和临床表现的影响，作者在整个疟疾传播季节对生活在马里疟疾流行区的31名丝虫感染者(FIL+)和31名非丝虫感染者(FIL-)进行了临床疟疾(可检测到的血液寄生虫背景下的发热或其他疟疾症状)的跟踪调查。在急性临床疟疾发生时，FIL+受试者的血清中以前与严重疟疾相关的炎性细胞因子水平降低。尽管FIL+和FIL受试者之间在疟疾首次发作的时间或疟疾发作的数量或严重程度方面没有差异，但丝虫感染似乎可以防止疟疾传播季节期间贫血的发展。这些发现表明，慢性丝虫感染调节了对急性疟疾的免疫反应。对贫血的明显影响是耐人寻味的，值得进一步研究。

In areas where polyparasitism is highly prevalent, the impact of multiple parasites on the host response is underestimated. In particular, the presence of helminth infection coincident with malaria profoundly alters the production of malaria-specific IFN-&#947;, IL-12p70, CXCL9, CXCL10 and CXCL11, cytokines/chemokines known to be critical in mediating malaria-specific immunity. In order to elucidate the mechanisms underlying the suppression of malaria-specific cytokines/chemokines, we assessed the expression of malaria-specific IL-12R&#946;1, IL-12R&#946;2 and interferon regulatory factor (IRF)-1 in blood obtained from 18 filaria-infected (Fil(+)) and 17 filaria-uninfected (Fil(-)) individuals in a filaria-malaria co-endemic region of Mali. We found that Fil(+) individuals had significantly lower RNA expression of IRF-1 but not IL-12R&#946;1 or IL-12R&#946;2 in response to malaria antigen stimulation. We also measured the frequency of IL-12-producing DCs from these subjects and found that Fil(+) subjects had lower frequencies of IL-12(+) mDCs after malaria antigen stimulation than did the Fil(-) subjects. Modeling these data in vitro, we found that mDCs pre-exposed to live microfilariae not only produced significantly lower levels of CXCL-9, CXCL-10, IL-12p35, IL-12p40, IL-12p19 and CXCL-11 following stimulation with malaria antigen but also markedly downregulated the expression of IRF-1, IRF-2 and IRF-3 compared with microfilaria-unexposed mDCs. siRNA-inhibition of irf-1 in mDCs downregulated the production of IL-12p70 through repression of IL-12p35. Our data demonstrate that the modulation of IRFs seen in filarial (and presumably other tissue-invasive helminths) infection underlies the suppression of malaria-specific cytokines/chemokines that play a crucial role in immunity to malaria. The mechanisms underlying the modulation of both the malaria-specific immune response and the course of clinical malaria in the context of concomitant helminth infection are poorly understood. We used multiparameter flow cytometry to characterize the quality and the magnitude of malaria-specific T cell responses in filaria-infected and -uninfected individuals with concomitant asymptomatic Plasmodium falciparum malaria in Mali. In comparison with filarial-uninfected subjects, filarial infection was associated with higher ex vivo frequencies of CD4(+) cells producing IL-4, IL-10, and IL-17A (p = 0.01, p = 0.001, and p = 0.03, respectively). In response to malaria Ag stimulation, however, filarial infection was associated with lower frequencies of CD4(+) T cells producing IFN-gamma;, TNF-alpha;, and IL-17A (p < 0.001, p = 0.04, and p = 0.04, respectively) and with higher frequencies of CD4(+)IL10(+)T cells (p = 0.0005). Importantly, filarial infection was associated with markedly lower frequencies of malaria Ag-specific Th1 (p < 0.0001), Th17 (p = 0.012), and TNF-alpha (p = 0.0008) cells, and a complete absence of malaria-specific multifunctional Th1 cells. Filarial infection was also associated with a marked increase in the frequency of malaria-specific adaptive regulatory T/Tr1 cells (p = 0.024), and the addition of neutralizing anti-IL-10 Ab augmented the amount of Th1-associated cytokine produced per cell. Thus, among malaria-infected individuals, concomitant filarial infection diminishes dramatically the frequencies of malaria-specific Th1 and Th17 T cells, and alters the quality and magnitude of malaria-specific T cell responses. In many regions of the world, including sub-Saharan Africa, concomitant infection with multiple parasites is common. In order to examine the effects of filariasis, a chronic helminth infection, on immune responses and clinical manifestations of acute malaria infection, the authors followed 31 filaria-infected (FIL+) and 31 filaria-uninfected (FIL-) individuals living in a malaria-endemic area of Mali through an entire malaria transmission season for the development of clinical malaria (fever or other symptoms of malaria in the setting of detectable blood parasites). Serum levels of inflammatory cytokines previously associated with severe malaria were decreased in FIL+ subjects at the time of acute clinical malaria. Although there were no differences between FIL+ and FIL- subjects with respect to the time to first episode of malaria or the number or severity of malaria episodes, filarial infection appeared to protect against the development of anemia during the malaria transmission season. These findings demonstrate that chronic filarial infection modulates the immune response to acute malaria. The apparent effect on anemia is intriguing and deserves further study.