Comparison of circumsporozoite proteins from avian and mammalian malarias: biological and phylogenetic implications.

The circumsporozoite (CS) protein of malaria parasites (Plasmodium) covers the surface of sporozoites that invade hepatocytes in mammalian hosts and macrophages in avian hosts. CS genes have been characterized from many Plasmodium that infect mammals; two domains of the corresponding proteins, identified initially by their conservation (region I and region II), have been implicated in binding to hepatocytes. The CS gene from the avian parasite Plasmodium gallinaceum was characterized to compare these functional domains to those of mammalian Plasmodium and for the study of Plasmodium evolution. The P. gallinaceum protein has the characteristics of CS proteins, including a secretory signal sequence, central repeat region, regions of charged amino acids, and an anchor sequence. Comparison with CS signal sequences reveals four distinct groupings, with P. gallinaceum most closely related to the human malaria Plasmodium falciparum. The 5-amino acid sequence designated region I, which is identical in all mammalian CS and implicated in hepatocyte invasion, is different in the avian protein. The P. gallinaceum repeat region consists of 9-amino acid repeats with the consensus sequence QP(A/V)GGNGG(A/V). The conserved motif designated region II-plus, which is associated with targeting the invasion of liver cells, is also conserved in the avian protein. Phylogenetic analysis of the aligned Plasmodium CS sequences yields a tree with a topology similar to the one obtained using sequence data from the small subunit rRNA gene. The phylogeny using the CS gene supports the proposal that the human malaria P. falciparum is significantly more related to avian parasites than to other parasites infecting mammals, although the biology of sporozoite invasion is different between the avian and mammalian species.     

Plasmodium falciparum appears to have arisen as a result of lateral transfer between avian and human hosts.

It has been proposed that the acquisition of Plasmodium falciparum by man is a relatively recent event and that the sustained presence of this disease in man is unlikely to have been possible prior to the establishment of agriculture. To establish phylogenetic relationships among the Plasmodium species and to unravel the mystery of the origin of P. falciparum, we have analyzed and compared phylogenetically the small-subunit ribosomal RNA gene sequences of the species of malaria that infect humans as well as a number of those sequences from species that infect animals. Although this comparison confirmed the three established major subgroups, broadly classed as avian, simian, and rodent, we find that the human pathogen P. falciparum is monophyletic with the avian subgroup, indicating that P. falciparum and avian parasites share a relatively recent avian progenitor. The other important human pathogen, P. vivax, is very similar to a representative of the simian group of Plasmodium. The relationship between P. falciparum and the avian parasites, and the overall phylogeny of the genus, provides evidence of an exception to Farenholz's rule, which propounds synchronous speciation between host and parasite.     

Homeotic effects,somitogenesis and the evolution of vertebral numbers in recent and fossil amniotes

The development of distinct regions in the amniote vertebral column results from somite formation and Hox gene expression, with the adult morphology displaying remarkable variation among lineages. Mammalian regionalization is reportedly very conservative or even constrained, but there has been no study investigating vertebral count variation across Amniota as a whole, undermining attempts to understand the phylogenetic, ecological, and developmental factors affecting vertebral column variation. Here, we show that the mammalian (synapsid) and reptilian lineages show early in their evolutionary histories clear divergences in axial developmental plasticity, in terms of both regionalization and meristic change, with basal synapsids sharing the conserved axial configuration of crown mammals, and basal reptiles demonstrating the plasticity of extant taxa. We conducted a comprehensive survey of presacral vertebral counts across 436 recent and extinct amniote taxa. Vertebral counts were mapped onto a generalized amniote phylogeny as well as individual ingroup trees, and ancestral states were reconstructed by using squared-change parsimony. We also calculated the relationship between presacral and cervical numbers to infer the relative influence of homeotic effects and meristic changes and found no correlation between somitogenesis and Hox-mediated regionalization. Although conservatism in presacral numbers characterized early synapsid lineages, in some cases reptiles and synapsids exhibit the same developmental innovations in response to similar selective pressures. Conversely, increases in body mass are not coupled with meristic or homeotic changes, but mostly occur in concert with postembryonic somatic growth. Our study highlights the importance of fossils in large-scale investigations of evolutionary developmental processes.     

Phylogeny of the malarial genus Plasmodium, derived from rRNA gene sequences.

Malaria is among mankind's worst scourges, affecting many millions of people, particularly in the tropics. Human malaria is caused by several species of Plasmodium, a parasitic protozoan. We analyze the small subunit rRNA gene sequences of 11 Plasmodium species, including three parasitic to humans, to infer their evolutionary relationships. Plasmodium falciparum, the most virulent of the human species, is closely related to Plasmodium reichenowi, which is parasitic to chimpanzee. The estimated time of divergence of these two Plasmodium species is consistent with the time of divergence (6-10 million years ago) between the human and chimpanzee lineages. The falciparum-reichenowi clade is only remotely related to two other human parasites, Plasmodium malariae and Plasmodium vivax, which are also only remotely related to each other. Thus, the parasitic associations of the Plasmodium species with their human hosts are phylogenetically independent. The remote phylogenetic relationship between the two bird parasites, Plasmodium gallinaceum and Plasmodium lophurae, and any of the human parasites provides no support for the hypothesis that infection by Plasmodium falciparum is a recent acquisition of humans, possibly coincident with the onset of agriculture.     

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Antigenic variation enables pathogens to avoid the host immune response by continual switching of surface proteins. The protozoan blood parasite Trypanosoma brucei causes human African trypanosomiasis ("sleeping sickness") across sub-Saharan Africa and is a model system for antigenic variation, surviving by periodically replacing a monolayer of variant surface glycoproteins (VSG) that covers its cell surface. We compared the genome of Trypanosoma brucei with two closely related parasites Trypanosoma congolense and Trypanosoma vivax, to reveal how the variant antigen repertoire has evolved and how it might affect contemporary antigenic diversity. We reconstruct VSG diversification showing that Trypanosoma congolense uses variant antigens derived from multiple ancestral VSG lineages, whereas in Trypanosoma brucei VSG have recent origins, and ancestral gene lineages have been repeatedly co-opted to novel functions. These historical differences are reflected in fundamental differences between species in the scale and mechanism of recombination. Using phylogenetic incompatibility as a metric for genetic exchange, we show that the frequency of recombination is comparable between Trypanosoma congolense and Trypanosoma brucei but is much lower in Trypanosoma vivax. Furthermore, in showing that the C-terminal domain of Trypanosoma brucei VSG plays a crucial role in facilitating exchange, we reveal substantial species differences in the mechanism of VSG diversification. Our results demonstrate how past VSG evolution indirectly determines the ability of contemporary parasites to generate novel variant antigens through recombination and suggest that the current model for antigenic variation in Trypanosoma brucei is only one means by which these parasites maintain chronic infections.     

Virulence and competitive ability in genetically diverse malaria infections

Explaining parasite virulence is a great challenge for evolutionary biology. Intuitively, parasites that depend on their hosts for their survival should be benign to their hosts, yet many parasites cause harm. One explanation for this is that within-host competition favors virulence, with more virulent strains having a competitive advantage in genetically diverse infections. This idea, which is well supported in theory, remains untested empirically. Here we provide evidence that within-host competition does indeed select for high parasite virulence. We examine the rodent malaria Plasmodium chabaudi in laboratory mice, a parasite-host system in which virulence can be easily monitored and competing strains quantified by using strain-specific real-time PCR. As predicted, we found a strong relationship between parasite virulence and competitive ability, so that more virulent strains have a competitive advantage in mixed-strain infections. In transmission experiments, we found that the strain composition of the parasite populations in mosquitoes was directly correlated with the composition of the blood-stage parasite population. Thus, the outcome of within-host competition determined relative transmission success. Our results imply that within-host competition is a major factor driving the evolution of virulence and can explain why many parasites harm their hosts.     

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.     

Rodent blood-stage Plasmodium survive in dendritic cells that infect naive mice

Plasmodium spp. parasites cause malaria in 300 to 500 million individuals each year. Disease occurs during the blood-stage of the parasite's life cycle, where the parasite is thought to replicate exclusively within erythrocytes. Infected individuals can also suffer relapses after several years, from Plasmodium vivax and Plasmodium ovale surviving in hepatocytes. Plasmodium falciparum and Plasmodium malariae can also persist after the original bout of infection has apparently cleared in the blood, suggesting that host cells other than erythrocytes (but not hepatocytes) may harbor these blood-stage parasites, thereby assisting their escape from host immunity. Using blood stage transgenic Plasmodium berghei-expressing GFP (PbGFP) to track parasites in host cells, we found that the parasite had a tropism for CD317(+) dendritic cells. Other studies using confocal microscopy, in vitro cultures, and cell transfer studies showed that blood-stage parasites could infect, survive, and replicate within CD317(+) dendritic cells, and that small numbers of these cells released parasites infectious for erythrocytes in vivo. These data have identified a unique survival strategy for blood-stage Plasmodium, which has significant implications for understanding the escape of Plasmodium spp. from immune-surveillance and for vaccine development.     

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.     

An anti-Chitinase malaria transmission-blocking single-chain antibody as an effector molecule for creating a Plasmodium falciparum-refractory mosquito

Indirect evidence has suggested the existence of a second chitinase gene, PgCHT2, in the avian malaria parasite Plasmodium gallinaceum. We have now identified PgCHT2 as the orthologue of the P. falciparum chitinase gene PfCHT1, a malaria transmission-blocking target. Computational phylogenetic evidence and biochemical and cell biological functional data support the hypothesis that an avian-related Plasmodium species was the ancestor of both P. falciparum and P. reichenowi, and this single lineage gave rise to another lineage of malaria parasites, including P. vivax, P. knowlesi, P. berghei, P. yoelii, and P. chabaudi. A recombinant PfCHT1/PgCHT2-neutralizing single-chain antibody significantly reduced P. falciparum and P. gallinaceum parasite transmission to mosquitoes. This single-chain antibody is the first anti-P. falciparum effector molecule to be validated for making a malaria transmission-refractory transgenic Anopheles species mosquito. P. gallinaceum is a relevant animal model that facilitates a mechanistic understanding of P. falciparum invasion of the mosquito midgut.     

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.     

Anti-mosquito midgut antibodies block development of Plasmodium falciparum and Plasmodium vivax in multiple species of Anopheles mosquitoes and reduce vector fecundity and survivorship

The mosquito midgut plays a central role in the sporogonic development of malaria parasites. We have found that polyclonal sera, produced against mosquito midguts, blocked the passage of Plasmodium falciparum ookinetes across the midgut, leading to a significant reduction of infections in mosquitoes. Anti-midgut mAbs were produced that display broad-spectrum activity, blocking parasite development of both P. falciparum and Plasmodium vivax parasites in five different species of mosquitoes. In addition to their parasite transmission-blocking activity, these mAbs also reduced mosquito survivorship and fecundity. These results reveal that mosquito midgut-based antibodies have the potential to reduce malaria transmission in a synergistic manner by lowering both vector competence, through transmission-blocking effects on parasite development, and vector abundance, by decreasing mosquito survivorship and egg laying capacity. Because the intervention can block transmission of different malaria parasite species in various species of mosquitoes, vaccines against such midgut receptors may block malaria transmission worldwide.     

Application of genomics to field investigations of malaria by the international centers of excellence for malaria research

Success of the global research agenda toward eradication of malaria will depend on development of new tools, including drugs, vaccines, insecticides and diagnostics. Genomic information, now available for the malaria parasites, their mosquito vectors, and human host, can be leveraged to both develop these tools and monitor their effectiveness. Although knowledge of genomic sequences for the malaria parasites, Plasmodium falciparum and Plasmodium vivax, have helped advance our understanding of malaria biology, simply knowing this sequence information has not yielded a plethora of new interventions to reduce the burden of malaria. Here we review and provide specific examples of how genomic information has increased our knowledge of parasite biology, focusing on P. falciparum malaria. We then discuss how population genetics can be applied toward the epidemiological and transmission-related goals outlined by the International Centers of Excellence for Malaria Research groups recently established by the National Institutes of Health. Finally, we propose genomics is a research area that can promote coordination and collaboration between various ICEMR groups, and that working together as a community can significantly advance the value of this information toward reduction of the global malaria burden.