scholarly journals Activation of Endocytosis as an Adaptation to the Mammalian Host by Trypanosomes

2007 ◽  
Vol 6 (11) ◽  
pp. 2029-2037 ◽  
Author(s):  
Senthil Kumar A. Natesan ◽  
Lori Peacock ◽  
Keith Matthews ◽  
Wendy Gibson ◽  
Mark C. Field
Keyword(s):  
Antigenic Variation ◽  
Subsequent Development ◽  
Tsetse Fly ◽  
Mammalian Host ◽  
Surface Coat ◽  
Down Regulation ◽  
African Trypanosomes ◽  
Endocytic Activity

ABSTRACT Immune evasion in African trypanosomes is principally mediated by antigenic variation, but rapid internalization of surface-bound immune factors may contribute to survival. Endocytosis is upregulated approximately 10-fold in bloodstream compared to procyclic forms, and surface coat remodeling accompanies transition between these life stages. Here we examined expression of endocytosis markers in tsetse fly stages in vivo and monitored modulation during transition from bloodstream to procyclic forms in vitro. Among bloodstream stages nonproliferative stumpy forms have endocytic activity similar to that seen with rapidly dividing slender forms, while differentiation of stumpy forms to procyclic forms is accompanied by rapid down-regulation of Rab11 and clathrin, suggesting that modulation of endocytic and recycling systems accompanies this differentiation event. Significantly, rapid down-regulation of endocytic markers occurs upon entering the insect midgut and expression of Rab11 and clathrin remains low throughout subsequent development, which suggests that high endocytic activity is not required for remodeling the parasite surface or for survival within the fly. However, salivary gland metacyclic forms dramatically increase expression of clathrin and Rab11, indicating that emergence of mammalian infective forms is coupled to reacquisition of a high-activity endocytic-recycling system. These data suggest that high-level endocytosis in Trypanosoma brucei is an adaptation required for viability in the mammalian host.

scholarly journals The GPI-Phospholipase C of Trypanosoma brucei Is Nonessential But Influences Parasitemia in Mice

1997 ◽  
Vol 139 (1) ◽  
pp. 103-114 ◽  
Author(s):  
Helena Webb ◽  
Nicola Carnall ◽  
Luc Vanhamme ◽  
Sylvie Rolin ◽  
Jakke Van Den Abbeele ◽  
...  
Keyword(s):  
Phospholipase C ◽  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Surface Glycoprotein ◽  
Covalent Attachment ◽  
Mammalian Host ◽  
Surface Coat ◽  
Null Mutant

In the mammalian host, the cell surface of Trypanosoma brucei is protected by a variant surface glycoprotein that is anchored in the plasma membrane through covalent attachment of the COOH terminus to a glycosylphosphatidylinositol. The trypanosome also contains a phospholipase C (GPI-PLC) that cleaves this anchor and could thus potentially enable the trypanosome to shed the surface coat of VSG. Indeed, release of the surface VSG can be observed within a few minutes on lysis of trypanosomes in vitro. To investigate whether the ability to cleave the membrane anchor of the VSG is an essential function of the enzyme in vivo, a GPI-PLC null mutant trypanosome has been generated by targeted gene deletion. The mutant trypanosomes are fully viable; they can go through an entire life cycle and maintain a persistent infection in mice. Thus the GPI-PLC is not an essential activity and is not necessary for antigenic variation. However, mice infected with the mutant trypanosomes have a reduced parasitemia and survive longer than those infected with control trypanosomes. This phenotype is partially alleviated when the null mutant is modified to express low levels of GPI-PLC.

scholarly journals Keith Vickerman. 21 March 1933—28 June 2016

2021 ◽  
Author(s):  
Francis Cox ◽  
Keith Gull
Keyword(s):  
Antigenic Variation ◽  
Morphological Changes ◽  
Tsetse Fly ◽  
Mammalian Host ◽  
Surface Coat ◽  
African Trypanosomes ◽  
Causative Agents ◽  
University College London ◽  
Variable Antigen ◽  
Commercially Important

Keith Vickerman was a parasitologist and protozoologist who made major contributions to our understanding of the biology of African trypanosomes, the causative agents of human sleeping sickness and nagana in cattle. His first academic post was at University College London, where he quickly mastered the techniques of electron microscopy (EM) and produced some of the best electron micrographs of parasitic protozoa at that time. He was a great believer in observation and deduction, and what began as an exercise in EM led him to investigate two of the then outstanding problems of trypanosome biology: how the parasites manage the transition from the tsetse fly vector to its mammalian host, and how they evade the host's immune response. Morphological changes, he found, were correlated with changes in the single mitochondrion and ensuring biochemical changes during the transition from a glucose-rich environment in mammalian blood to the glucose-poor tsetse gut. It was while comparing bloodstream and tsetse forms that he observed that the trypanosomes possessed a thick surface coat in the blood, which he subsequently identified as the variable antigen that was repeatedly formed and reformed and that this was the basis of antigenic variation—findings that stimulated a vast amount of interest among immunologists, biochemists and geneticists. In his later career a new problem emerged, and he found that a disease devastating stocks of the commercially important Norway lobster, Nephrops norvegicus , thought to be caused by a virus was actually caused by a protozoan, Hematodinium . Keith will always be remembered as one of the founders of modern parasitology.

scholarly journals Procyclin gene expression and loss of the variant surface glycoprotein during differentiation of Trypanosoma brucei.

1989 ◽  
Vol 108 (2) ◽  
pp. 737-746 ◽  
Author(s):  
I Roditi ◽  
H Schwarz ◽  
T W Pearson ◽  
R P Beecroft ◽  
M K Liu ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Tsetse Fly ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Mammalian Host ◽  
Cylindrical Shape ◽  
Surface Coat ◽  
Insect Vector ◽  
Molecular Arrangement

In the mammalian host, the unicellular flagellate Trypanosoma brucei is covered by a dense surface coat that consists of a single species of macromolecule, the membrane form of the variant surface glycoprotein (mfVSG). After uptake by the insect vector, the tsetse fly, bloodstream-form trypanosomes differentiate to procyclic forms in the fly midgut. Differentiation is characterized by the loss of the mfVSG coat and the acquisition of a new surface glycoprotein, procyclin. In this study, the change in surface glycoprotein composition during differentiation was investigated in vitro. After triggering differentiation, a rapid increase in procyclin-specific mRNA was observed. In contrast, there was a lag of several hours before procyclin could be detected. Procyclin was incorporated and uniformly distributed in the surface coat. The VSG coat was subsequently shed. For a single cell, it took 12-16 h to express a maximum level of procyclin at the surface while the loss of the VSG coat required approximately 4 h. The data are discussed in terms of the possible molecular arrangement of mfVSG and procyclin at the cell surface. Molecular modeling data suggest that a (Asp-Pro)2 (Glu-Pro)22-29 repeat in procyclin assumes a cylindrical shape 14-18 nm in length and 0.9 nm in diameter. This extended shape would enable procyclin to interdigitate between the mfVSG molecules during differentiation, exposing epitopes beyond the 12-15-nm-thick VSG coat.

scholarly journals Kinetics and In Vivo Induction of Genetic Variation of vlsE in Borrelia burgdorferi

1998 ◽  
Vol 66 (8) ◽  
pp. 3689-3697 ◽  
Author(s):  
Jing-Ren Zhang ◽  
Steven J. Norris
Keyword(s):  
Borrelia Burgdorferi ◽  
Sequence Variation ◽  
Antigenic Variation ◽  
Pcr Amplification ◽  
Scid Mice ◽  
Mammalian Host ◽  
Expression Site ◽  
Disease Agent

ABSTRACT The Lyme disease agent, Borrelia burgdorferi, is able to persistently infect humans and animals for months or years in the presence of an active immune response. It is not known how the organisms survive immune attack in the mammalian host.vlsE, a gene localized near one end of linear plasmid lp28-1 and encoding a surface-exposed lipoprotein in B. burgdorferi B31, was shown recently to undergo extensive genetic and antigenic variation within 28 days of initial infection in C3H/HeN mice. In this study, we examined the kinetics of vlsEsequence variation in C3H/HeN mice at 4, 7, 14, 21, and 28 days and at 7 and 12 months postinfection. Sequence changes were detected by PCR amplification and sequence analysis as early as 4 days postinfection and accumulated progressively in both C3H/HeN and CB-17 severe combined immunodeficient (SCID) mice throughout the course of infection. The sequence changes were consistent with sequential recombination of segments from multiple silent vls cassette sites into thevlsE expression site. No vlsE sequence changes were detected in organisms cultured in vitro for up to 84 days. These results indicate that vlsE recombination is induced by a factor(s) present in the mammalian host, independent of adaptive immune responses. The possible inducing conditions appear to be present in various tissue sites because isolates from multiple tissues showed similar degrees of sequence variation. The rate of accumulation of predicted amino acid changes was higher in the immunologically intact C3H/HeN mice than in SCID mice, a finding consistent with immune selection of VlsE variants.

scholarly journals On The Surface Coat and Flagellar Adhesion in Trypanosomes

1969 ◽  
Vol 5 (1) ◽  
pp. 163-193 ◽  
Author(s):  
K. VICKERMAN
Keyword(s):  
Negative Charge ◽  
Wide Spectrum ◽  
Surface Membrane ◽  
Tsetse Fly ◽  
The Body ◽  
Mammalian Host ◽  
Surface Coat ◽  
Junctional Complexes ◽  
Antigenic Type

Pathogenic trypanosomes in their bloodstream phase have a smooth and compact coat 12-15 nm thick enveloping the entire surface membrane of the body and flagellum. In the sleeping-sickness trypanosome Trypanosoma rhodesiense this coat is absent from the stages of development in the midgut of the tsetse-fly vector and from their counterparts obtained by cultivation of the trypanosome in vitro. In the salivary glands of the vector, however, the coat is reacquired as the trypanosomes transform from epimastigote forms into the metacyclic stage which is infective to the mammalian host. This loss and acquisition of the surface coat can be correlated with the cyclical changes in net surface charge on the trypanosome which have been observed by other workers. The trypanosome populations of successive relapses in the blood are known to differ in their surface antigens (agglutinogens) and the loss of antigenic identity detected when any of these populations are put into culture indicates that these variable antigens are located in the surface coat. It is suggested that the coat in bloodstream trypanosomes constitutes a replaceable surface which, after being replaced, enables the trypanosome to escape the effects of host antibodies. The coat is therefore an adaptation to life in the bloodstream. Reacquisition of the surface coat by the metacyclic trypanosome after development in the vector may reflect reversion to a ‘basic’ antigenic type at this stage, preparatory to invading the blood of the mammalian host. The surface coat may be removed by the wide-spectrum proteolytic enzyme pronase, and this fact together with evidence from pH/mobility relationships and chemical analysis of the variable antigens suggest that the coat is basically proteinaceous. The coat may facilitate pinocytosis by binding proteins at sites within the pocket surrounding the base of the flagellum. In the non-pathogenic trypanosome T. lewisi a more diffuse filamentous coat is present in bloodstream forms and absent from culture forms. This trypanosome is said to carry a negative charge in both bloodstream and culture phases, so it seems likely that the nature of the coat in T. lewisi is different from that found in the pathogenic trypanosomes. In all these trypanosomes the flagellar membrane adheres to the surface membrane of the body throughout the life-cycle. Along the zone of adhesion lies a regular row of junctional complexes of the macula adherens type which, it is argued, serve in attachment. These attachments persist regardless of changes in the intervening cell surfaces.

Analysis of trypanosome variable antigen types in cultures of metacyclic and mammalian forms of Trypanosoma congolense

Parasitology ◽  
1986 ◽  
Vol 93 (1) ◽  
pp. 99-109 ◽  
Author(s):  
A. G. Luckins ◽  
I. A. Frame ◽  
M. A. Gray ◽  
J. S. Crowe ◽  
C. A. Ross
Keyword(s):  
Antigenic Variation ◽  
Antigen Expression ◽  
Trypanosoma Congolense ◽  
Tsetse Fly ◽  
The Other ◽  
Surface Coat ◽  
Differentiation Process ◽  
Variable Antigen

SUMMARYCultured metacyclic forms of Trypanosoma congolense display a characteristic repertoire of metacyclic variable antigen types (M-VATs) similar to that exhibited in vitro in the tsetse fly. There appeared to be no change in expression of M-VATs in cultures of two stocks of T. congolense even after several passages, cryopreservation or long-term cultivation in vitro. Metacyclic forms transformed into mammalian forms when transferred to cultures of bovine aorta endothelial cells and whilst one stock retained expression of M-VATs without change even after 4 months, the other stock underwent antigenic variation within 14 days of transfer. Analysis of the M-VAT composition of mammalian forms of this stock using monoclonal antibodies showed that although the proportion of mammalian forms expressing certain M-VATs declined considerably, trypanosomes expressing one M-VAT increased proportionally to comprise 50 % of the population. In contrast, only small changes were seen in antigen expression in cultures of metacyclic trypanosomes from which mammalian-form cultures were derived. It was possible to produce in vitro, loss and reacquisition of variable antigen surface coat, similar to the differentiation process occurring when bloodstream trypanosomes are ingested by the tsetse fly and eventually develop into metacyclic forms.

scholarly journals Stage-specific Requirement of a Mitogen-activated Protein Kinase by Trypanosoma brucei

2002 ◽  
Vol 13 (11) ◽  
pp. 3787-3799 ◽  
Author(s):  
Ingrid B. Müller ◽  
Debora Domenicali-Pfister ◽  
Isabel Roditi ◽  
Erik Vassella
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Phosphorylation Site ◽  
Tsetse Fly ◽  
Mitogen Activated Protein Kinase ◽  
Mammalian Host ◽  
Null Mutant ◽  
African Trypanosomes ◽  
Mitogen Activated Protein

In cycling between the mammalian host and the tsetse fly vector, African trypanosomes undergo adaptive differentiation steps that are coupled to growth control. The signaling pathways underlying these cellular processes are largely unknown. Mitogen-activated protein kinases (MAPKs) are known mediators of growth and differentiation in other eukaryotic organisms. To establish the function of a MAPK homologue, TbMAPK2, in T. brucei, a null mutant was constructed. Bloodstream forms of aΔmapk2/Δmapk2 clone were able to grow normally and exhibited no detectable phenotype. When these cells were triggered to differentiate in vitro, however, they developed to the procyclic (fly midgut) form with delayed kinetics and subsequently underwent cell cycle arrest. Introduction of an ectopic copy of theTbMAPK2 gene into the null mutant restored its ability to differentiate and to divide. In contrast, a TbMAPK2mutant, in which the T190 and Y192 residues of the activating phosphorylation site were replaced by A and F, was unable to restore the growth and differentiation phenotypes. Analysis of the DNA content and the nucleus/kinetoplast configuration of individual cells showed that the null mutant was arrested in all phases of the cell cycle and that 25–30% of the cells had failed to segregate their nucleus and kinetoplast correctly. This implies that cell cycle progression by the procyclic form depends on a constitutive stimulus exerted by the signaling cascade operating through TbMAPK2.

Polyamines and Related Nitrogen Compounds in the Chemotherapy of Neglected Diseases Caused by Kinetoplastids

2018 ◽  
Vol 18 (5) ◽  
pp. 321-368 ◽  
Author(s):  
Juan A. Bisceglia ◽  
Maria C. Mollo ◽  
Nadia Gruber ◽  
Liliana R. Orelli
Keyword(s):  
Drug Targets ◽  
Redox Homeostasis ◽  
Cost Effective ◽  
Structural Features ◽  
Mammalian Host ◽  
Neglected Diseases ◽  
Nitrogen Compounds ◽  
Chemical Structures

Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed.

scholarly journals LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3

Human Cell ◽  
2021 ◽  
Author(s):  
Jiaying Zhu ◽  
Zhu Zhu ◽  
Yipin Ren ◽  
Yukang Dong ◽  
Yaqi Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Mice Model ◽  
Down Regulation

AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

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