scholarly journals Interplay between Attenuation- and Virulence-Factors of Babesia bovis and Their Contribution to the Establishment of Persistent Infections in Cattle

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 97 ◽  
Author(s):  
Gina M. Gallego-Lopez ◽  
Brian M. Cooke ◽  
Carlos E. Suarez
Keyword(s):  
Antigenic Variation ◽  
Immune Escape ◽  
Attenuation Factor ◽  
Protein A ◽  
Babesia Bovis ◽  
Bovine Babesiosis ◽  
Blood Capillaries ◽  
Persistent Infections ◽  
Neurological Signs ◽  
Immune Escape Mechanisms

Bovine babesiosis is an acute and persistent tick-borne global disease caused mainly by the intraerythrocytic apicomplexan parasites Babesia bovis and B. bigemina. B. bovis infected erythrocytes sequester in blood capillaries of the host (cytoadhesion), causing malaria-like neurological signs. Cytoadhesion and antigenic variation in B. bovis are linked to the expression of members of the Variant Erythrocyte Surface Antigen (VESA) gene family. Animals that survive acute B. bovis infection and those vaccinated with attenuated strains remain persistently infected, suggesting that B. bovis parasites use immune escape mechanisms. However, attenuated B. bovis parasites do not cause neurological signs in vaccinated animals, indicating that virulence or attenuation factors play roles in modulating parasite virulence phenotypes. Artificial overexpression of the SBP2t11 protein, a defined attenuation factor, was associated with reduced cytoadhesion, suggesting a role for this protein as a key modulator of virulence in the parasite. Hereby, we propose a model that might be functional in the modulation of B. bovis virulence and persistence that relies on the interplay among SBP2t, VESA proteins, cytoadhesion, and the immune responses of the host. Elucidation of mechanisms used by the parasite to establish persistent infection will likely contribute to the design of new methods for the control of bovine babesiosis.

scholarly journals Knockout of Babesia bovis rad51 ortholog and its complementation by expression from the BbACc3 artificial chromosome platform

2019 ◽  
Author(s):  
Erin A. Mack ◽  
Yu-Ping Xiao ◽  
David R. Allred
Keyword(s):  
Antigenic Variation ◽  
Genetic Manipulation ◽  
Artificial Chromosome ◽  
Babesia Bovis ◽  
Chromosome 1 ◽  
Gene Encoding ◽  
Persistent Infections ◽  
Essentially Normal ◽  
Regulated Gene Expression

AbstractBabesia bovis establishes persistent infections of long duration in cattle, despite the development of effective anti-disease immunity. One mechanism used by the parasite to achieve persistence is rapid antigenic variation of the VESA1 cytoadhesion ligand through segmental gene conversion (SGC), a phenomenon thought to be a form of homologous recombination (HR). To begin investigation of the enzymatic basis for SGC we initially identified and knocked out the Bbrad51 gene encoding the B. bovis Rad51 ortholog. BbRad51 was found to be non-essential for in vitro growth of asexual-stage parasites. However, its loss resulted in hypersensitivity to methylmethane sulfonate (MMS) and an apparent defect in HR. This defect rendered attempts to complement the knockout phenotype by reinsertion of the Bbrad51 gene into the genome unsuccessful. To circumvent this difficulty, we constructed an artificial chromosome, BbACc3, into which the complete Bbrad51 locus was inserted, for expression of BbRad51 under regulation by autologous elements. Maintenance of BbACc3 makes use of centromeric sequences from chromosome 3 and telomeric ends from chromosome 1 of the B. bovis C9.1 line. A selection cassette employing human dihydrofolate reductase enables recovery of transformants by selection with pyrimethamine. We demonstrate that the BbACc3 platform is stably maintained once established, assembles nucleosomes to form native chromatin, and expands in telomere length over time. Significantly, the MMS-sensitivity phenotype observed in the absence of Bbrad51 was successfully complemented at essentially normal levels. We provide cautionary evidence, however, that in HR-competent parasites BbACc3 can recombine with native chromosomes, potentially resulting in crossover. We propose that, under certain circumstances this platform can provide a useful alternative for the genetic manipulation of this group of parasites, particularly when regulated gene expression under the control of autologous elements may be important.

scholarly journals Isolation of viable Babesia bovis merozoites to study parasite invasion

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hassan Hakimi ◽  
Masahito Asada ◽  
Takahiro Ishizaki ◽  
Shinichiro Kawazu
Keyword(s):  
Control Strategies ◽  
Specific Inhibitor ◽  
Babesia Bovis ◽  
Parasite Development ◽  
Mammalian Host ◽  
Bovine Babesiosis ◽  
Binary Forms ◽  
Parasite Invasion ◽  
Dependent Protein ◽  
Basic Biology

AbstractBabesia parasite invades exclusively red blood cell (RBC) in mammalian host and induces alterations to host cell for survival. Despite the importance of Babesia in livestock industry and emerging cases in humans, their basic biology is hampered by lack of suitable biological tools. In this study, we aimed to develop a synchronization method for Babesia bovis which causes the most pathogenic form of bovine babesiosis. Initially, we used compound 2 (C2), a specific inhibitor of cyclic GMP-dependent protein kinase (PKG), and a derivative of C2, ML10. While both inhibitors were able to prevent B. bovis egress from RBC and increased percentage of binary forms, removal of inhibitors from culture did not result in a synchronized egress of parasites. Because using PKG inhibitors alone was not efficient to induce a synchronized culture, we isolated viable and invasive B. bovis merozoites and showed dynamics of merozoite invasion and development in RBCs. Using isolated merozoites we showed that BbVEAP, VESA1-export associated protein, is essential for parasite development in the RBC while has no significant role in invasion. Given the importance of invasion for the establishment of infection, this study paves the way for finding novel antigens to be used in control strategies against bovine babesiosis.

scholarly journals Applying Machine Learning to Predict the Exportome of Bovine and Canine Babesia Species That Cause Babesiosis

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 660
Author(s):  
Stephen J. Goodswen ◽  
Paul J. Kennedy ◽  
John T. Ellis
Keyword(s):  
Machine Learning ◽  
Severe Disease ◽  
Economic Loss ◽  
Babesia Bovis ◽  
Training Data ◽  
Babesia Bigemina ◽  
Bovine Babesiosis ◽  
Canine Babesiosis ◽  
Clinically Significant ◽  
Significant Disease

Babesia infection of red blood cells can cause a severe disease called babesiosis in susceptible hosts. Bovine babesiosis causes global economic loss to the beef and dairy cattle industries, and canine babesiosis is considered a clinically significant disease. Potential therapeutic targets against bovine and canine babesiosis include members of the exportome, i.e., those proteins exported from the parasite into the host red blood cell. We developed three machine learning-derived methods (two novel and one adapted) to predict for every known Babesia bovis, Babesia bigemina, and Babesia canis protein the probability of being an exportome member. Two well-studied apicomplexan-related species, Plasmodium falciparum and Toxoplasma gondii, with extensive experimental evidence on their exportome or excreted/secreted proteins were used as important benchmarks for the three methods. Based on 10-fold cross validation and multiple train–validation–test splits of training data, we expect that over 90% of the predicted probabilities accurately provide a secretory or non-secretory indicator. Only laboratory testing can verify that predicted high exportome membership probabilities are creditable exportome indicators. However, the presented methods at least provide those proteins most worthy of laboratory validation and will ultimately save time and money.

Translational Research in Cutaneous Melanoma: New Therapeutic Perspectives

2018 ◽  
Vol 18 (2) ◽  
pp. 166-181 ◽  
Author(s):  
Antonio Marra ◽  
Cristina R. Ferrone ◽  
Celeste Fusciello ◽  
Giosue Scognamiglio ◽  
Soldano Ferrone ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Poor Prognosis ◽  
Immune Escape ◽  
Checkpoint Inhibitor ◽  
Predictive Biomarkers ◽  
Driver Mutations ◽  
Targeted Agents ◽  
Therapeutic Approaches ◽  
Aggressive Form ◽  
Immune Escape Mechanisms

Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The development of targeted agents based on the discovery of driver mutations as well as the implementation of checkpoint inhibitor-based immunotherapy represents a major breakthrough in the treatment of metastatic melanoma. However, in both cases the development of drug resistance and immune escape mechanisms as well as the lack of predictive biomarkers limits their extraordinary clinical efficacy. In this article, we summarize the available therapeutic options for patients with metastatic melanoma, outline the mechanisms implicated in the resistance to both targeted agents and immunotherapy, discuss potential predictive biomarkers and outline future therapeutic approaches under investigation.

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