scholarly journals Immunodominant surface epitopes power immune evasion in the African trypanosome

2021 ◽  
Author(s):  
Anastasia Gkeka ◽  
Francisco Aresta-Branco ◽  
Gianna Triller ◽  
Evi P Vlachou ◽  
Mirjana Lilic ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Antigenic Variation ◽  
Cross Reactivity ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
African Trypanosome ◽  
Repetitive Nature ◽  
Variable Surface ◽  
Major Surface ◽  
Immunodominant Epitopes

The African trypanosome survives the immune response of its mammalian host by antigenic variation of its major surface antigen (the Variable Surface Glycoprotein, or VSG). Here we describe the antibody repertoires elicited by different VSGs. We show that the repertoires are highly restricted, directed predominantly to epitopes on the surface of the VSGs. They are also highly discriminatory: minor alterations within these exposed epitopes confer antigenically-distinct properties to these VSGs and elicit different repertoires. We propose that the patterned and repetitive nature of the VSG coat focuses host immunity to a restricted set of immunodominant epitopes per VSG, eliciting a highly stereotyped response, minimizing cross reactivity between different VSGs and facilitating prolonged immune evasion through epitope variation.

scholarly journals Trypanosoma brucei Interaction with Host: Mechanism of VSG Release as Target for Drug Discovery for African Trypanosomiasis

2019 ◽  
Vol 20 (6) ◽  
pp. 1484 ◽  
Author(s):  
Cláudia Moreno ◽  
Adriana Temporão ◽  
Taffarel Torres ◽  
Marcelo Sousa Silva
Keyword(s):  
Drug Discovery ◽  
Phospholipase C ◽  
Trypanosoma Brucei ◽  
Antigenic Variation ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
African Trypanosomiasis ◽  
Variable Surface Glycoprotein ◽  
Variable Surface ◽  
Major Surface

The protozoan Trypanosoma brucei, responsible for animal and human trypanosomiasis, has a family of major surface proteases (MSPs) and phospholipase-C (PLC), both involved in some mechanisms of virulence during mammalian infections. During parasitism in the mammalian host, this protozoan is exclusively extracellular and presents a robust mechanism of antigenic variation that allows the persistence of infection. There has been incredible progress in our understanding of how variable surface glycoproteins (VSGs) are organised and expressed, and how expression is switched, particularly through recombination. The objective of this manuscript is to create a reflection about the mechanisms of antigenic variation in T. brucei, more specifically, in the process of variable surface glycoprotein (VSG) release. We firstly explore the mechanism of VSG release as a potential pathway and target for the development of anti-T. brucei drugs.

scholarly journals Diversity and Complexity of the Large Surface Protein Family in the Compacted Genomes of Multiple Pneumocystis Species

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Liang Ma ◽  
Zehua Chen ◽  
Da Wei Huang ◽  
Ousmane H. Cissé ◽  
Jamie L. Rothenburger ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Disease Transmission ◽  
Antigenic Variation ◽  
The United States ◽  
Surface Proteins ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
Content Type ◽  
Multiple Functions ◽  
First Time

ABSTRACT Pneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multicopy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneumocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins and provide a detailed description of the classification, unique characteristics, and phylogenetic relatedness of five Msg families. We further describe, for the first time, the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. carinii from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests multiple functions for this superfamily rather than just conferring antigenic variation to allow immune evasion as previously believed. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology. IMPORTANCE Pneumocystis continues to be a major cause of disease in humans with immunodeficiency, especially those with HIV/AIDS and organ transplants, and is being seen with increasing frequency worldwide in patients treated with immunodepleting monoclonal antibodies. Annual health care associated with Pneumocystis pneumonia costs ∼$475 million dollars in the United States alone. In addition to causing overt disease in immunodeficient individuals, Pneumocystis can cause subclinical infection or colonization in healthy individuals, which may play an important role in species preservation and disease transmission. Our work sheds new light on the diversity and complexity of the msg superfamily and strongly suggests that the versatility of this superfamily reflects multiple functions, including antigenic variation to allow immune evasion and optimal adaptation to host environmental conditions to promote efficient infection and transmission. These findings are essential to consider in developing new diagnostic and therapeutic strategies.

scholarly journals Diversity and complexity of the large surface protein family in the compacted genomes of various Pneumocystis species

2019 ◽  
Author(s):  
Liang Ma ◽  
Zehua Chen ◽  
Da Wei Huang ◽  
Ousmane H. Cissé ◽  
Jamie L. Rothenburger ◽  
...  
Keyword(s):  
Antigenic Variation ◽  
Life Stage ◽  
Surface Protein ◽  
Opportunistic Pathogen ◽  
Surface Proteins ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
Expression Site ◽  
Phylogeny And Evolution ◽  
Major Surface

AbstractPneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multi-copy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneumocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins, and provide detailed description of the classification, unique characteristics and phylogenetic relatedness of five Msg families. We further describe the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. carinii from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests a wide variety of functions for this superfamily, not only conferring antigenic variation to allow immune evasion but also mediating life-stage development, optimizing cell mobility and adhesion, and adapting to specific host niches or environmental conditions. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology.

scholarly journals Targeting the Variable Surface of African Trypanosomes with Variant Surface Glycoprotein-Specific, Serum-Stable RNA Aptamers

2003 ◽  
Vol 2 (1) ◽  
pp. 84-94 ◽  
Author(s):  
Mihaela Lorger ◽  
Markus Engstler ◽  
Matthias Homann ◽  
H. Ulrich Göringer
Keyword(s):  
Antigenic Variation ◽  
Sleeping Sickness ◽  
Rna Aptamers ◽  
Surface Glycoprotein ◽  
Variant Surface Glycoprotein ◽  
Parasite Protein ◽  
African Trypanosomes ◽  
Variable Surface ◽  
New Strategy

ABSTRACT African trypanosomes cause sleeping sickness in humans and Nagana in cattle. The parasites multiply in the blood and escape the immune response of the infected host by antigenic variation. Antigenic variation is characterized by a periodic change of the parasite protein surface, which consists of a variant glycoprotein known as variant surface glycoprotein (VSG). Using a SELEX (systematic evolution of ligands by exponential enrichment) approach, we report the selection of small, serum-stable RNAs, so-called aptamers, that bind to VSGs with subnanomolar affinity. The RNAs are able to recognize different VSG variants and bind to the surface of live trypanosomes. Aptamers tethered to an antigenic side group are capable of directing antibodies to the surface of the parasite in vitro. In this manner, the RNAs might provide a new strategy for a therapeutic intervention to fight sleeping sickness.

scholarly journals Variable Surface Glycoprotein from Trypanosoma brucei Undergoes Cleavage by Matrix Metalloproteinases: An in silico Approach

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 178
Author(s):  
Cláudia Jassica Gonçalves Moreno ◽  
Taffarel Torres ◽  
Marcelo Sousa Silva
Keyword(s):  
Matrix Metalloproteinases ◽  
Trypanosoma Brucei ◽  
Cleavage Site ◽  
Surface Protein ◽  
Matrix Metalloproteases ◽  
Surface Glycoprotein ◽  
Mammalian Host ◽  
Variable Surface Glycoprotein ◽  
Biological Studies ◽  
Variable Surface

In order to survive as extracellular parasites in the mammalian host environment, Trypanosoma brucei has developed efficient mechanisms of immune system evasion, which include the abundant expression of a variable surface glycoprotein (VSG) coat. VSGs are anchored in the parasite membrane by covalent C-terminal binding to glycosylphosphatidylinositol and may be periodically removed by a phospholipase C (PLC) and a major surface protein (TbMSP). VSG molecules show extraordinary antigenic diversity and a comparative analysis of protein sequences suggests that conserved elements may be a suitable target against African trypanosomiasis. However, the cleavage mechanisms of these molecules remain unclear. Moreover, in protozoan infections, including those caused by Trypanosoma brucei, it is possible to observe an increased expression of the matrix metalloproteinases (MMPs). To address the cleavage mechanism of VSGs, the PROSPER server was used for the identification of VSG sequence cleavage sites. After data compilation, it was observed that 64 VSG consensus sequences showed a high conservation of hydrophobic residues, such as valine (V), methionine (M), leucine (L) and isoleucine (I) in the fifth position—the exact location of the cleavage site. In addition, the PROSPER server identified conserved cleavage site portions of VSG proteins recognized by three matrix metalloproteases (gelatinases: MMP-2, MMP-3 and MMP-9). However, further biological studies are needed in order to analyze and confirm this prediction.

scholarly journals Towards a New Reference Test for Surra in Camels

2009 ◽  
Vol 16 (7) ◽  
pp. 999-1002 ◽  
Author(s):  
Thao Tran ◽  
Filip Claes ◽  
Didier Verloo ◽  
Henri De Greve ◽  
Philippe Büscher
Keyword(s):  
Antigenic Variation ◽  
Trypanosoma Evansi ◽  
Surface Glycoprotein ◽  
Antibody Detection ◽  
Enzyme Linked Immunosorbent Assay ◽  
Reference Test ◽  
Perfect Agreement ◽  
Cutoff Value ◽  
Variable Surface ◽  
Variable Antigen

ABSTRACT Current serological diagnosis of Trypanosoma evansi infection in camels is based on the native variable antigen type RoTat 1.2. The goal of this study was to develop a novel serological diagnostic test based on a nonvariable protein and freed from the use of rats or mice for its production. An enzyme-linked immunosorbent assay using a recombinant extracellular domain of invariant surface glycoprotein 75 (ELISA/rISG75) was developed and tested on a collection of 184 camel sera. The results were compared to those obtained from three established antibody detection tests based on variable surface glycoprotein RoTat 1.2: an ELISA for T. evansi (ELISA/T. evansi), a card agglutination test for trypanosomiasis (CATT/T. evansi), and an immune trypanolysis (TL) assay. The ELISA/rISG75 and the ELISA/T. evansi showed a sensitivity of 94.6% (95% confidence interval [CI], 87.8 to 98.2%, at 19% positivity cutoff value) and 98.9% (95% CI, 94.1 to 99.8, at 12% positivity cutoff value), respectively. The ELISA/rISG75 had 100% specificity (CI, 95.9 to 100%), while the ELISA/T. evansi showed 98.9% specificity (CI, 95.9 to 100%). The ELISA/rISG75 demonstrated an almost perfect agreement with the TL assay, the CATT/T. evansi, and the ELISA/T. evansi, with kappa scores of at least 0.94. The ELISA/rISG75, having a performance comparable to that of the gold standard (the TL assay) and being independent of antigenic variation, may become a new reference test for surra in camels. It opens avenues for the diagnosis of T. evansi infections in other hosts as well as for the development of a pan-Trypanozoon test for detection of Trypanosoma brucei brucei, T. b. gambiense, T. b. rhodesiense, T. evansi, and T. equiperdum.

scholarly journals Trypanosoma brucei PolIE suppresses telomere recombination

2021 ◽  
Author(s):  
Maiko Tonini ◽  
M. A. G. Rabbani ◽  
Marjia Afrin ◽  
Bibo Li
Keyword(s):  
Trypanosoma Brucei ◽  
Immune Evasion ◽  
Human African Trypanosomiasis ◽  
Antigenic Variation ◽  
Telomere Maintenance ◽  
Genome Integrity ◽  
Major Player ◽  
Elevated Rate ◽  
Major Surface ◽  
Telomere Structure

Telomeres are essential for genome integrity and stability. In T. brucei that causes human African trypanosomiasis, the telomere structure and telomere proteins also influence the virulence of the parasite, as its major surface antigen involved in the host immune evasion is expressed exclusively from loci immediately upstream of the telomere repeats. However, telomere maintenance mechanisms are still unclear except that telomerase-mediated telomere synthesis is a major player. We now identify PolIE as an intrinsic telomere complex component. We find that depletion of PolIE leads to an increased amount of telomere/subtelomere DNA damage, an elevated rate of antigenic variation, and an increased amount of telomere T-circles and C-circles, indicating that PolIE suppresses telomere recombination and helps maintain telomere integrity. In addition, we observe much longer telomere G-rich 3 prime overhangs in PolIE-depleted cells, which is not dependent on telomerase. Furthermore, the level of telomere DNA synthesis is slightly increased in PolIE-depleted cells, which is dependent on telomerase. Therefore, we identify PolIE as a major player for telomere maintenance in T. brucei.

scholarly journals RibonucleaseH1-targeted R-loops in surface antigen gene expression sites can direct trypanosome immune evasion

2018 ◽  
Author(s):  
Emma Briggs ◽  
Kathryn Crouch ◽  
Leandro Lemgruber ◽  
Craig Lapsley ◽  
Richard McCulloch
Keyword(s):  
Immune Evasion ◽  
Protein Gene ◽  
Antigenic Variation ◽  
Surface Protein ◽  
Surface Glycoprotein ◽  
Surface Coat ◽  
Loop Formation ◽  
New Host ◽  
Genome Damage ◽  
Surface Protein Gene

AbstractSwitching of the Variant Surface Glycoprotein (VSG) inTrypanosoma bruceiprovides a crucial host immune evasion strategy that is catalysed both by transcription and recombination reactions, each operating within specialised telomeric VSG expression sites (ES). VSG switching is likely triggered by events focused on the single actively transcribed ES, from a repertoire of around 15, but the nature of such events is unclear. Here we show that RNA-DNA hybrids, called R-loops, form preferentially within sequences termed the 70 bp repeats in the actively transcribed ES, but spread throughout the active and inactive ES in the absence of RNase H1, which degrades R-loops. Loss of RNase H1 also leads to increased levels of VSG coat switching and replication-associated genome damage, some of which accumulates within the active ES. This work indicates VSG ES architecture elicits R-loop formation, and that these RNA-DNA hybrids connectT. bruceiimmune evasion by transcription and recombination.Author summaryAll pathogens must survive eradication by the host immune response in order to continue infections and be passed on to a new host. Changes in the proteins expressed on the surface of the pathogen, or on the surface of the cells the pathogen infects, is a widely used strategy to escape immune elimination. Understanding how this survival strategy, termed antigenic variation, operates in any pathogen is critical, both to understand interaction between the pathogen and host and disease progression. A key event in antigenic variation is the initiation of the change in expression of the surface protein gene, though how this occurs has been detailed in very few pathogens. Here we examine how changes in expression of the surface coat of the African trypanosome, which causes sleeping sickness disease, are initiated. We reveal that specialised nucleic acid structures, termed R-loops, form around the expressed trypanosome surface protein gene and increase in abundance after mutation of an enzyme that removes them, leading to increased changes in the surface coat in trypanosome cells that are dividing. We therefore shed light on the earliest acting events in trypanosome antigenic variation.

scholarly journals Expression Pattern of the Pneumocystis jirovecii Major Surface Glycoprotein Superfamily in Patients with Pneumonia

2020 ◽  
Author(s):  
Emanuel Schmid-Siegert ◽  
Sophie Richard ◽  
Amanda Luraschi ◽  
Konrad Mühlethaler ◽  
Marco Pagni ◽  
...  
Keyword(s):  
Antigenic Variation ◽  
Single Gene ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
Pneumocystis Jirovecii ◽  
Clinical Samples ◽  
Single Nucleotide Variants ◽  
Rna Sequences ◽  
Major Surface ◽  
Cell Surface Structure

Abstract Background The human pathogen Pneumocystis jirovecii harbors 6 families of major surface glycoproteins (MSGs) encoded by a single gene superfamily. MSGs are presumably responsible for antigenic variation and adhesion to host cells. The genomic organization suggests that a single member of family I is expressed at a given time per cell, whereas members of the other families are simultaneously expressed. Methods We analyzed RNA sequences expressed in several clinical samples, using specific weighted profiles for sorting of reads and calling of single-nucleotide variants to estimate the diversity of the expressed genes. Results A number of different isoforms of at least 4 MSG families were expressed simultaneously, including isoforms of family I, for which confirmation was obtained in the wet laboratory. Conclusion These observations suggest that every single P. jirovecii population is made of individual cells with distinct surface properties. Our results enhance our understanding of the unique antigenic variation system and cell surface structure of P. jirovecii.

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