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人类感染疟原虫后细胞免疫反应的持久性和组成。

Longevity and composition of cellular immune responses following experimental Plasmodium falciparum malaria infection in humans.

机构信息

Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

出版信息

PLoS Pathog. 2011 Dec;7(12):e1002389. doi: 10.1371/journal.ppat.1002389. Epub 2011 Dec 1.


DOI:10.1371/journal.ppat.1002389
PMID:22144890
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3228790/
Abstract

Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only 'adaptive' but also 'innate' lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO(+) CD62L(-) effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ(+)IL-2(+)) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field.

摘要

疟原虫寄生虫对细胞的反应,特别是干扰素-γ(IFNγ)的产生,在抗疟免疫中起着重要作用。然而,在自然暴露人群中,对疟疾的临床免疫力发展缓慢,与暴露相关的细胞反应的动态难以研究,并且关于此类反应持续存在的数据存在争议。在这里,我们评估了人类志愿者感染实验性疟疾后细胞免疫反应的持久性和组成。我们对在高度受控条件下接受单次(n = 5)或多次(n = 10)实验性疟原虫感染的幼稚人类志愿者对孢子(PfSpz)和无性血期(PfRBC)疟原虫寄生虫的细胞免疫反应进行了纵向研究。在感染前、感染期间和感染后一年以上,通过流式细胞术测量体外再刺激后的 IFNγ 和白细胞介素-2(IL-2)反应。我们表明,即使是单次疟疾发作后,对 PfSpz 和 PfRBC 的细胞反应也被诱导并几乎保持不变,长达 14 个月。值得注意的是,不仅“适应性”,而且“先天”淋巴细胞亚群也有助于增加 IFNγ 反应,包括αβT 细胞、γδT 细胞和 NK 细胞。此外,淋巴细胞亚群的耗竭和自体重组实验的结果表明,PfRBC 的免疫记忆存在于αβT 细胞和γδT 细胞中。事实上,感染后早期和晚期,大多数产生细胞因子的 T 淋巴细胞表达 CD45RO(+) CD62L(-) 效应记忆(EM)表型。最后,我们证明疟原虫感染诱导并维持针对 PfRBC 和 PfSpz 的多效性(IFNγ(+)IL-2(+))EM 反应,先前发现这些反应与保护相关。这些数据表明,在感染疟原虫后,细胞反应可以很容易地被诱导并持续存在,不仅适应性而且(半)先天淋巴细胞亚群也持续发挥作用。这对疟疾疫苗的开发具有积极意义,但需要关注那些可能在现场抑制此类反应的因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/11d15b25cadf/ppat.1002389.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/8bc9d316296b/ppat.1002389.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/28c22815a2ab/ppat.1002389.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/01238b0dfd95/ppat.1002389.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/6d9097632cb8/ppat.1002389.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/345467db006b/ppat.1002389.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/11d15b25cadf/ppat.1002389.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/8bc9d316296b/ppat.1002389.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/28c22815a2ab/ppat.1002389.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/01238b0dfd95/ppat.1002389.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/6d9097632cb8/ppat.1002389.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/345467db006b/ppat.1002389.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3110/3228790/11d15b25cadf/ppat.1002389.g006.jpg

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本文引用的文献

[1]
Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study.

Lancet. 2011-4-22

[2]
Short-lived IFN-γ effector responses, but long-lived IL-10 memory responses, to malaria in an area of low malaria endemicity.

PLoS Pathog. 2011-2-10

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Experimental human challenge infections can accelerate clinical malaria vaccine development.

Nat Rev Immunol. 2011-1

[4]
Memory-like IFN-γ response by NK cells following malaria infection reveals the crucial role of T cells in NK cell activation by P. falciparum.

Eur J Immunol. 2010-12

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Curr Opin Immunol. 2010-4-29

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J Immunol. 2010-4-28

[8]
Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum.

Eur J Immunol. 2010-2

[9]
Early interferon-gamma response against Plasmodium falciparum correlates with interethnic differences in susceptibility to parasitemia between sympatric Fulani and Dogon in Mali.

J Infect Dis. 2010-1-1

[10]
Stability of interferon-gamma and interleukin-10 responses to Plasmodium falciparum liver stage antigen 1 and thrombospondin-related adhesive protein immunodominant epitopes in a highland population from Western Kenya.

Am J Trop Med Hyg. 2009-9

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