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.

在高度普遍存在的多种寄生虫的地区，多个寄生虫对宿主反应的影响被低估了。尤其是，与疟疾同时发生的蠕虫感染的存在深刻改变了疟疾特异性IFN-γ，IL-12P70，CXCL9，CXCL9，CXCL10和CXCL11的产生，细胞因子/趋化因子，已知在介导疟疾特异性免疫力方面至关重要。 In order to elucidate the mechanisms underlying the suppression of malaria-specific cytokines/chemokines, we assessed the expression of malaria-specific IL-12Rβ1, IL-12Rβ2 and interferon regulatory factor (IRF)-1 in blood obtained from 18 filaria-infected (Fil(+)) and 17 filaria-uninfected (Fil(-)) individuals in a filaria-malaria马里的协会地区。我们发现，响应于疟疾抗原刺激的FIL（+）个体的IRF-1的RNA表达明显降低，而IL-12Rβ1或IL-12Rβ2的RNA表达显着降低。我们还测量了这些受试者的IL-12产生DC的频率，发现疟疾抗原刺激后的FIL（+）受试者的IL-12（+）MDC的频率低于FIL（ - ）受试者。 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。 IRF-1在MDC中抑制siRNA通过抑制IL-12p35下调IL-12P70的产生。我们的数据表明，在丝状（和大概其他组织侵入性的蠕虫）感染中看到的IRF的调节是抑制疟疾特异性细胞因子/趋化因子的抑制，这些因子/趋化因子在对疟疾的免疫中起着至关重要的作用。 在伴随蠕虫感染的背景下，对疟疾特异性免疫反应的调节和临床疟疾进程的调节的基础机制尚不清楚。我们使用多参数流式细胞术来表征丝虫感染的疟疾特异性T细胞反应的质量和幅度，并未感染的患者具有伴有无症状的恶性疟原虫恶性疟疾的疟疾。与丝状未感染的受试者相比，丝状感染与产生IL-4，IL-10和IL-17A的CD4（+）细胞的较高体内频率有关（分别为p = 0.01，p = 0.001和p = 0.03）。然而，针对疟疾Ag刺激，丝状感染与CD4（+）T细胞的频率较低有关，产生IFN-GAMMA； TNF-ALPHA; TNF-ALPHA;和IL-17A（P <0.001，P = 0.04，P = 0.04和P = 0.04），以及较高的CD4（+）IL10（+）IL10（+）TILLE（P = 0.04）（p = 0.04）。重要的是，丝状感染与明显较低的疟疾Ag特异性Th1（P <0.0001），Th17（P = 0.012）和TNF-Alpha（P = 0.0008）细胞以及完全没有疟疾特异性多核电TH1细胞有关。丝状感染还与疟疾特异性适应性调节T/TR1细胞的频率显着增加有关（P = 0.024），并且添加中和中和抗IL-10 AB增加了每个细胞产生的Th1相关细胞因子的量。因此，在感染疟疾的个体中，伴随丝状感染会大大降低疟疾特异性Th1和Th17 T细胞的频率，并改变了疟疾特异性T细胞反应的质量和幅度。 在包括撒哈拉以南非洲在内的世界许多地区，与多种寄生虫同时感染是常见的。为了检查丝虫病的影响，慢性蠕虫感染，对急性疟疾感染的免疫反应和临床表现，作者遵循31个感染了炎症（FIL+）和31个未感染的（FIL）和31个未感染的（FILARIA）（FIL）（FIL-），生活在整个疟疾型疟疾型疟疾或疟疾中的疟疾型疟疾症状（疟疾）中的疟疾症状（疟疾）中的疟疾症状（疟疾）的开发型（可检测的血寄生虫）。急性临床疟疾时，FIL+受试者的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-受试者在疟疾的第一集或疟疾发作的数量或严重程度方面没有差异，但在疟疾传播季节期间，丝状感染似乎可以预防贫血的发展。这些发现表明，慢性丝状感染调节对急性疟疾的免疫反应。对贫血的明显影响令人着迷，值得进一步研究。