Mali International Center for Excellence in Research: Filariasis

马里国际卓越研究中心：丝虫病

• 批准号: 8555975
• 负责人: Thomas Nutman
• 金额: $ 22.84万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8555975
• 关键词: Acute; Address; Africa South of the Sahara; Anemia; Antigens; Area; Blood; CD4 Positive T Lymphocytes; CXCL10 gene; CXCL11 gene; CXCL9 gene; Cells; Chronic; Clinical; Communicable Diseases; Country; Data; Dentistry; Developing Countries; Development; Emerging Communicable Diseases; Endemic Diseases; Faculty; Falciparum Malaria; Fever; Filariasis; Flow Cytometry; Fostering; Frequencies; Future; Genetic Transcription; Goals; HIV; Helminths; Immune response; Immunity; In Vitro; India; Individual; Infection; Inflammatory; Interferon Regulatory Factor 1; Interferon Regulatory Factor 2; Interferon Type II; Interferons; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-4; Life; Malaria; Mali; Measures; Mediating; Medicine; Microfilaria; Parasites; Pharmacy facility; Physicians; Play; Production; Repression; Research; Role; Scientist; Seasons; Serum; Severities; Small Interfering RNA; Symptoms; T cell response; T-Lymphocyte; Th1 Cells; Time; Tissues; Training; Tuberculosis; Tumor Necrosis Factor-alpha; Uganda; Universities; base; burden of illness; chemokine; cytokine; data modeling; filaria; human IRF3 protein; human TNF protein; interferon regulatory factor-3; interleukin-12 receptor; interleukin-12 subunit p35; interleukin-12 subunit p40; international center; laboratory facility; programs; response; transmission process

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.

在多寄生现象非常普遍的地区，多种寄生虫对宿主反应的影响被低估了。特别是，与疟疾同时发生的蠕虫感染的存在深刻地改变了疟疾特异性IFN-γ、IL-12 p70、CXCL 9、CXCL 10和CXCL 11的产生，这些细胞因子/趋化因子已知在介导疟疾特异性免疫中至关重要。为了阐明抑制疟疾特异性细胞因子/趋化因子的潜在机制，我们评估了在马里丝虫-疟疾共流行区的18名丝虫感染（Fil（+））和17名丝虫未感染（Fil（-））个体的血液中疟疾特异性IL-12 R1、IL-12 R 2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应答中IRF-1的RNA表达显著降低，但IL-12 R 1或IL-12 R 2的RNA表达不显著降低。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IL-12（+）mDC的频率低于Fil（-）受试者。在体外模拟这些数据，我们发现，与未暴露于微丝蚴的mDC相比，预先暴露于活微丝蚴的mDC在用疟疾抗原刺激后不仅产生显著较低水平的CXCL-9、CXCL-10、IL-12 p35、IL-12 p40、IL-12 p19和CXCL-11，而且还显著下调IRF-1、IRF-2和IRF-3的表达。mDC中irf-1的siRNA抑制通过抑制IL-12 p35下调IL-12 p70的产生。我们的数据表明，在丝虫（以及可能的其他组织侵入性蠕虫）感染中观察到的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/趋化因子在对疟疾的免疫中起着至关重要的作用。 在伴随蠕虫感染的情况下，调节疟疾特异性免疫反应和临床疟疾病程的机制尚不清楚。我们使用多参数流式细胞术来表征马里丝虫感染和未感染个体伴随无症状恶性疟原虫疟疾的疟疾特异性T细胞应答的质量和幅度。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-17 A的CD 4（+）细胞的体外频率较高相关（分别为p = 0.01、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IFN-γ、TNF-α和IL-17 A的较低频率的CD 4（+）T细胞（分别为p < 0.001、p = 0.04和p = 0.04）和较高频率的CD 4（+）IL 10（+）T细胞（p = 0.0005）相关。重要的是，丝虫感染与疟疾抗原特异性Th 1（p < 0.0001）、Th 17（p = 0.012）和TNF-α（p = 0.0008）细胞频率显著降低以及疟疾特异性多功能Th 1细胞完全缺失相关。丝虫感染也与疟疾特异性适应性调节性T/Tr 1细胞的频率显著增加相关（p = 0.024），并且添加中和性抗IL-10抗体增加了每个细胞产生的Th 1相关细胞因子的量。因此，在疟疾感染的个体中，伴随的丝虫感染显著降低了疟疾特异性Th 1和Th 17 T细胞的频率，并改变了疟疾特异性T细胞应答的质量和幅度。 在世界上许多地区，包括撒哈拉以南非洲，同时感染多种寄生虫是常见的。为了研究丝虫病（一种慢性蠕虫感染）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名丝虫未感染者（FIL-）进行了临床疟疾发展的跟踪调查（在可检测到血液寄生虫的情况下的发热或疟疾的其他症状）。在急性临床疟疾时，FIL+受试者中先前与严重疟疾相关的炎性细胞因子的血清水平降低。尽管FIL+和FIL-受试者在首次疟疾发作时间或疟疾发作次数或严重程度方面没有差异，但丝虫感染似乎可以在疟疾传播季节防止贫血的发展。这些发现表明，慢性丝虫感染调节对急性疟疾的免疫反应。对贫血的明显影响是有趣的，值得进一步研究。