巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

巨噬细胞迁移抑制因子与疟原虫感染的相关研究进展

疟疾是世界上主要的致死性感染性疾病之一,但是目前药物抗性虫株的出现、有效疫苗的缺乏,特别是对疟原虫生物学、疟疾病理机制以及宿主在疟原虫感染后的免疫应答等方面了解不足是控制疟疾的主要困难.大量研究发现,机体内的巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)在包括疟疾在内的多种感染性疾病中发挥着重要作用,凶此受到研究者口益广泛的关注.近年来研究者们从疟原虫等寄生虫巾也先后鉴定出MIF分子,它们不仅在结构上具有高等牛物MIF分子的典型特征,而且还具有与之相似的功能.尽管其在感染过程巾的作用尚不清楚,但迄今为止多项研究表明,这些宿主MIF的同源分子具有调节宿主免疫系统的能力.该文综述了宿主MIF和寄生虫MIF在疟疾感染和病理机制中的作用的研究现状.     

The effects of cortisone on immunity during chronic rodent malaria

The temporal effects were studied of a single dose of hydrocortisone acetate on the development and expression of immune responses to Plasmodium berghei in mice with chronic infections. Cortisone administration prior to primary infection reduced malaria-specific secondary humoral and cellular responses, as well as the ability to survive parasite challenge. Once protective humoral immunity was established after chemotherapy of primary infection, cortisone treatment did not disrupt its expression. Administration of cortisone during subpatent chronic infection resulted in a transient recrudescence of parasitemia not apparent in untreated mice. Clearance of recrudescence or parasite challenge was associated with a rapid cortisone-resistant antibody response. During subpatent chronic infection, malaria-specific antibody levels were reduced, whereas delayed-type hypersensitivity (DTH) to malaria antigens and heterologous antigens was well developed. At least two systems of immunity to malaria appear to be present during chronic infection. Recrudescence of parasitemia may be prevented by antibody-independent, cortisone-sensitive cellular immunity. Once parasitemia becomes overt after cortisone treatment, or parasites are reintroduced with challenge, cortisone-resistant humoral immunity appears to mediate parasite clearance. Regulation of these systems may be a dose-dependent phenomenon which results in the persistence of parasites, albeit at subpatent levels.     

Reduction of parasite levels in patients with uncomplicated malaria by treatment with HE2000

16alpha-Bromoepiandrosterone (HE2000) is a synthetic androstane steroid that has immune effects in pre-clinical models of malaria, tuberculosis, and infection with human immunodeficiency virus. In pilot studies, 42 patients with confirmed uncomplicated Plasmodium falciparum malaria were treated with a seven-day course of HE2000 by either buccal administration or intramuscular injection. Of the 42 patients, 41 showed a 50% reduction in blood levels of parasites, the primary endpoint of the study. Of these, 32 (76%) cleared malaria parasites below detectable levels. All febrile patients became afebrile by the end of treatment. There was no reduction in gametocyte forms. Adverse events were transient and mild to moderate in intensity. The anti-malarial response was generally similar with either the intramuscular or buccal routes of administration. HE2000 shows a safety profile and pharmacologic activity worthy of further investigation to understand its role in the treatment of malaria, perhaps in combination with anti-malarial agents.     

The pathology of Plasmodium chabaudi infection is not ameliorated by the secreted filarial nematode immunomodulatory molecule, ES-62

ES-62 is a phosphorylcholine-containing glycoprotein secreted by filarial nematodes. This molecule has been shown to reduce the severity of inflammation in collagen-induced arthritis (CIA) in mice, a model of rheumatoid arthritis, via down-regulation of anti-collagen type 1 immune responses. Malaria parasites induce a pro-inflammatory host immune response and many of the symptoms of malaria are immune system-mediated. Therefore we have asked whether the immunomodulatory properties of ES-62 can down-regulate the severity of malaria infection in BALB/c mice infected with Plasmodium chabaudi. We have found that ES-62 has no significant effect on the course of P. chabaudi parasitaemia, and does not significantly affect any of the measures of malaria-induced pathology taken throughout infection.     

Polymorphisms of innate immunity receptors in infection by parasites

The innate immune system is the first line of defence against infection by pathogenic bacteria, virus and parasites and is also responsible for initiating an adaptive immune response. In contrast to the receptors of adaptive immunity (TCRs and antibodies) which are generated by gene recombination, receptors of the innate immune system are encoded in the germline and are thus inherited from generation to generation. Although evolutionarily selected, the genes encoding the innate recognition receptors show variations among individuals, and these polymorphisms may have an impact on the ability of an individual to deal with an infection. In recent years, several polymorphisms have been identified in innate recognition receptors, and efforts are being made to determine whether these polymorphisms are associated with a higher or lower susceptibility to infectious diseases. These studies will allow a better understanding of the role of innate receptors in specific diseases and are valuable in the design of preventive or therapeutic interventions to fight the disease. In this review, we summarize studies aimed at determining the influence of polymorphisms in innate recognition receptors on the susceptibility to diseases caused by parasites.     

The Toll pathway is important for an antiviral response in Drosophila

The innate immune response of Drosophila melanogaster is governed by a complex set of signaling pathways that trigger antimicrobial peptide (AMP) production, phagocytosis, melanization, and encapsulation. Although immune responses against both bacteria and fungi have been demonstrated in Drosophila, identification of an antiviral response has yet to be found. To investigate what responses Drosophila mounts against a viral infection, we have developed an in vivo Drosophila X virus (DXV)-based screening system that identifies altered sensitivity to viral infection by using DXV's anoxia-induced death pathology. Using this system to screen flies with mutations in genes with known or suggested immune activity, we identified the Toll pathway as a vital part of the Drosophila antiviral response. Inactivation of this pathway instigated a rapid onset of anoxia induced death in infected flies and increases in viral titers compared to those in WT flies. Although constitutive activation of the pathway resulted in similar rapid onset of anoxia sensitivity, it also resulted in decreased viral titer. Additionally, AMP genes were induced in response to viral infection similar to levels observed during Escherichia coli infection. However, enhanced expression of single AMPs did not alter resistance to viral infection or viral titer levels, suggesting that the main antiviral response is cellular rather than humoral. Our results show that the Toll pathway is required for efficient inhibition of DXV replication in Drosophila. Additionally, our results demonstrate the validity of using a genetic approach to identify genes and pathways used in viral innate immune responses in Drosophila.     

Liver-stage malaria parasites vulnerable to diverse chemical scaffolds

Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. All high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. To address these unmet needs, a high-throughput phenotypic liver-stage Plasmodium parasite screen was developed to systematically identify molecules with liver-stage efficacy. The screen recapitulates liver-stage infection by isolating luciferase-expressing Plasmodium berghei parasites directly from the salivary glands of infected mosquitoes, adding them to confluent human liver cells in 384-well plates, and measuring luciferase activity after a suitable incubation period. Screening 5,375 known bioactive compounds identified 37 liver-stage malaria inhibitors with diverse modes of action, as shown by inhibition time course experiments. Further analysis of the hits in the Food and Drug Administration-approved drug subset revealed compounds that seem to act specifically on the liver stage of infection, suggesting that this phase of the parasite's life cycle presents a promising area for new drug discovery. Notably, many active compounds in this screen have molecular structures and putative targets distinctly different from those of known antimalarial agents.     

Development of immunity to malaria may not be an entirely active process

It has never been explained why it takes so long for humans to develop immunity to malaria, although factors such as antigenic variation, antigenic polymorphism, and poor immunological responses to critical antigens are thought to be important. Models of malaria, particularly in rodents, have not been helpful. The course of malaria infection differs considerably between humans and rodents. Mice rapidly develop immunity whereas for most humans it takes several years of exposure for this to occur. Mice typically exhibit high parasitaemias whereas humans typically do not. A significant difference in the immune response of humans and mice to malaria parasites might, in part, explain these differences. Most humans have a preexisting population of activated malaria parasite-specific T cells (cross-reactive T cells) which we have referred to as 'natural' T cells, but such cells have not been observed in mice. These cells, many of which secrete interferon-γ), might control parasitaemia early in the infection, but a by-product of their further activation by malaria parasites might be disease symptoms. Development of immunity has been thought of as an active process–acquisition of specific antibody and effector T cell responses. However, it might in part reflect induction of tolerance of this preexisting population of disease-inducing Tcells as a result of chronic parasitaemia. The initial presence of these Th1-like cells may also impede the development of a Th2-like response necessary for the production of protective antibodies. Persistent cross-reactive stimulation may significantly impede this process.     

Gamma delta T cells contribute to immunity against the liver stages of malaria in alpha beta T-cell-deficient mice.

The functional role of gamma delta T cells (expressing the gamma delta heterodimeric T-cell receptor for antigen) in infectious diseases remains largely unknown. We have therefore attempted to define the possible role of these T cells in the immune response against the various developmental stages of malaria parasites. For this purpose, we monitored the immune response and the development of liver and blood stages of Plasmodium yoelii, a rodent malaria parasite, in immunized and nonimmunized alpha beta T-cell-deficient and gamma delta T-cell-deficient mice. Immunization of alpha beta T-cell-deficient mice with irradiated sporozoites induced an immune response that significantly inhibited the development of the parasite's liver stages. This inhibitory immune response was abolished by an antibody-mediated transient in vivo depletion of gamma delta T cells. Two gamma delta T-cell clones were derived from malaria-immunized alpha beta T-cell-deficient mice. The adoptive transfer of one of these gamma delta T-cell clones to normal mice inhibited the development of liver stages, following sporozoite inoculation. These results provide evidence for gamma delta T-cell-mediated protective immunity against parasites, in the absence of alpha beta T cells. As for the blood phase of the infection, both normal mice and gamma delta T-cell-deficient mice cleared the blood stages of the nonlethal strain of P. yoelii, while alpha beta T-cell-deficient mice failed to control the parasitemia.