scholarly journals Harnessing Mycobacterium bovis BCG Trained Immunity to Control Human and Bovine Babesiosis

Vaccines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 123
Author(s):  
Reginaldo G. Bastos ◽  
Heba F. Alzan ◽  
Vignesh A. Rathinasamy ◽  
Brian M. Cooke ◽  
Odir A. Dellagostin ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Inflammatory Responses ◽  
Acute Infection ◽  
Innate Immune ◽  
Babesia Bovis ◽  
Babesia Microti ◽  
Bovine Babesiosis ◽  
Apicomplexan Parasites ◽  
Trained Immunity ◽  
Causative Agents

Babesiosis is a disease caused by tickborne hemoprotozoan apicomplexan parasites of the genus Babesia that negatively impacts public health and food security worldwide. Development of effective and sustainable vaccines against babesiosis is currently hindered in part by the absence of definitive host correlates of protection. Despite that, studies in Babesia microti and Babesia bovis, major causative agents of human and bovine babesiosis, respectively, suggest that early activation of innate immune responses is crucial for vertebrates to survive acute infection. Trained immunity (TI) is defined as the development of memory in vertebrate innate immune cells, allowing more efficient responses to subsequent specific and non-specific challenges. Considering that Mycobacterium bovis bacillus Calmette-Guerin (BCG), a widely used anti-tuberculosis attenuated vaccine, induces strong TI pro-inflammatory responses, we hypothesize that BCG TI may protect vertebrates against acute babesiosis. This premise is supported by early investigations demonstrating that BCG inoculation protects mice against experimental B. microti infection and recent observations that BCG vaccination decreases the severity of malaria in children infected with Plasmodium falciparum, a Babesia-related parasite. We also discuss the potential use of TI in conjunction with recombinant BCG vaccines expressing Babesia immunogens. In conclusion, by concentrating on human and bovine babesiosis, herein we intend to raise awareness of BCG TI as a strategy to efficiently control Babesia infection.

scholarly journals Endochin-like quinolone-300 and ELQ-316 inhibit Babesia bovis, B. bigemina, B. caballi and Theileria equi

2020 ◽  
Author(s):  
Carlos Suarez ◽  
Marta G. Silva ◽  
Reginaldo G. Bastos ◽  
J. Stone Doggett ◽  
Michael K. Riscoe ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Babesia Bovis ◽  
Host Cells ◽  
Bovine Babesiosis ◽  
Theileria Equi ◽  
Peripheral Blood Mononuclear ◽  
Equine Piroplasmosis ◽  
Apicomplexan Parasites ◽  
And Control

Abstract Background: The most common apicomplexan parasites causing bovine babesiosis are Babesia bovis and B. bigemina, while B. caballi and Theileria equi are responsible for equine piroplasmosis. Treatment and control of these diseases are usually achieved using potentially toxic chemotherapeutics, such as imidocarb diproprionate, but drug-resistant parasites are emerging, and alternative effective and safer drugs are needed. Endochin-like quinolones (ELQ)-300 and ELQ-316 proved safe and efficacious against related apicomplexans, such as Plasmodium spp., and ELQ-316 was also effective against B. microti, without showing toxicity in mammals.Methods: Inhibitory effects of ELQ-300 and ELQ-316 were assessed on the growth of cultured B. bovis, B. bigemina, B. caballi and T. equi. Percentage of parasitized erythrocytes was measured by flow cytometry. Effect of the ELQ drugs on the viability of actively replicating horse and bovine peripheral blood mononuclear cells (PBMC) was assessed by ELISA. Results: We calculated IC50 ranging from 0.04 to 0.37 nM for ELQ-300, and from 0.002 to 0.1 nM for ELQ-316 at 72 hr among all cultured parasites tested. None of the parasites tested were able to replicate in cultures in the presence of the ELQs-300 and ELQ-316 at IC100, which range from 1.3 to 5.7 nM for ELQ-300 and from 1.0 to 6.0 nM for ELQ-316 at 72 hours. Neither ELQ-300 nor ELQ-316 altered the viability of equine and bovine PBMC at their IC100 in in vitro testing. Conclusions: ELQ-300 and ELQ-316 have a significant inhibitory activity on the main parasites responsible for bovine babesiosis and equine piroplasmosis at doses that are tolerable to host cells. These ELQ drugs may be viable candidates for developing alternative protocols for the treatment of bovine babesiosis and equine piroplasmosis.

scholarly journals Gram-Positive Staphylococcus aureus LTA Promotes Distinct Memory-like Effects in Murine Bone Marrow Neutrophils

2021 ◽  
Author(s):  
Trim Lajqi ◽  
David Frommhold ◽  
Maylis Braun ◽  
Simon Alexander Kranig ◽  
Johannes Pöschl ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Acute Infection ◽  
Lipoteichoic Acid ◽  
Innate Immune ◽  
High Dose ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Murine Bone Marrow ◽  
Neutrophil Priming

Neutrophils as innate immune cells primarily act as first responders in acute infection and directly maintain inflammatory responses. However, a growing body of evidence suggests that neutrophils also bear the potential to mediate chronic inflammation by exhibiting memory-like features. We recently showed that priming by serial doses of lipopolysaccharide (LPS) from gram-negative bacteria can trigger opposing memory-like responses (exaggerated inflammation, i.e. trained sensitivity or suppression of inflammation, i.e. tolerance) depending on the LPS-dose. We now asked whether this observation could also hold true for lipoteichoic acid (LTA) from gram-positive S. aureus. We found comparable effects of LTA on neutrophil priming as seen for LPS. Low-dose (1 ng/mL) LTA-priming promoted increased production of pro-inflammatory mediators (i.e., TNF-α, IL-6, ROS), whereas high-dose (10 µg/mL) results in contrary reactions supporting anti-inflammatory responses by increased IL-10 and declined pro-inflammatory capacity. In vitro neutrophil recruitment was similarly regulated by LTA -priming. Investigation of signalling patterns revealed TLR2/MyD88-mediated regulation of NFκB-p65 through intermediate PI3Ks/MAPK. Collectively, our data suggest a previously unknown capacity of neutrophils to be differentially primed by varying doses of LTA, endorsing memory-like features in neutrophils.

scholarly journals Controlled Human Malaria Infection Induces Long-Term Functional Changes in Monocytes

2020 ◽  
Vol 7 ◽  
Author(s):  
Jona Walk ◽  
Farid Keramati ◽  
L. Charlotte J. de Bree ◽  
Rob J. W. Arts ◽  
Bas Blok ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Oxidized Ldl ◽  
Acute Infection ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Human Malaria ◽  
Trained Immunity ◽  
Controlled Human Malaria Infection

Innate immune memory responses (also termed “trained immunity”) have been described in monocytes after BCG vaccination and after stimulation in vitro with microbial and endogenous ligands such as LPS, β-glucan, oxidized LDL, and monosodium urate crystals. However, whether clinical infections are also capable of inducing a trained immunity phenotype remained uncertain. We evaluated whether Plasmodium falciparum infection can induce innate immune memory by measuring monocyte-derived cytokine production from five volunteers undergoing Controlled Human Malaria Infection. Monocyte responses followed a biphasic pattern: during acute infection, monocytes produced lower amounts of inflammatory cytokines upon secondary stimulation, but 36 days after malaria infection they produced significantly more IL-6 and TNF-α in response to various stimuli. Furthermore, transcriptomic and epigenomic data analysis revealed a clear reprogramming of monocytes at both timepoints, with long-term changes of H3K4me3 at the promoter regions of inflammatory genes that remain present for several weeks after parasite clearance. These findings demonstrate an epigenetic basis of trained immunity induced by human malaria in vivo.

scholarly journals LPS Induces Opposing Memory-like Inflammatory Responses in Mouse Bone Marrow Neutrophils

2021 ◽  
Vol 22 (18) ◽  
pp. 9803
Author(s):  
Trim Lajqi ◽  
Maylis Braun ◽  
Simon Alexander Kranig ◽  
David Frommhold ◽  
Johannes Pöschl ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
In Vivo Studies ◽  
Mouse Bone Marrow ◽  
Innate Immune Cells ◽  
Trained Immunity

A growing body of evidence suggests that innate immune cells can respond in a memory-like (adaptive) fashion, which is referred to as trained immunity. Only few in vivo studies have shown training effects in neutrophils; however, no in vitro setup has been established to study the induction of trained immunity or tolerance in neutrophils by microbial agents. In light of their short lifespan (up to 48 h), we suggest to use the term trained sensitivity for neutrophils in an in vitro setting. Here, we firstly describe a feasible two-hit model, using different doses of lipopolysaccharide (LPS) in bone marrow neutrophils. We found that low doses (10 pg/mL) induce pro-inflammatory activation (trained sensitivity), whereas priming with high doses (100 ng/mL) leads to suppression of pro-inflammatory mediators such as TNF-α or IL-6 (tolerance) (p < 0.05). On a functional level, trained neutrophils displayed increased phagocytic activity and LFA-1 expression as well as migrational capacity and CD11a expression, whereas tolerant neutrophils show contrasting effects in vitro. Mechanistically, TLR4/MyD88/PI3Ks regulate the activation of p65, which controls memory-like responses in mouse bone marrow neutrophils (p < 0.05). Our results open a new window for further in vitro studies on memory-like inflammatory responses of short-lived innate immune cells such as neutrophils.

scholarly journals Endochin-like quinolone-300 and ELQ-316 inhibit Babesia bovis, B. bigemina, B. caballi and Theileria equi

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Marta G. Silva ◽  
Reginaldo G. Bastos ◽  
J. Stone Doggett ◽  
Michael K. Riscoe ◽  
Sovitj Pou ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Inhibitory Concentration ◽  
Colorimetric Assay ◽  
Babesia Bovis ◽  
Host Cells ◽  
Babesia Microti ◽  
Bovine Babesiosis ◽  
Theileria Equi ◽  
Peripheral Blood Mononuclear ◽  
Equine Piroplasmosis

Abstract Background The most common apicomplexan parasites causing bovine babesiosis are Babesia bovis and B. bigemina, while B. caballi and Theileria equi are responsible for equine piroplasmosis. Treatment and control of these diseases are usually achieved using potentially toxic chemotherapeutics, such as imidocarb diproprionate, but drug-resistant parasites are emerging, and alternative effective and safer drugs are needed. The endochin-like quinolones (ELQ)-300 and ELQ-316 have been proven to be safe and efficacious against related apicomplexans, such as Plasmodium spp., with ELQ-316 also being effective against Babesia microti, without showing toxicity in mammals. Methods The inhibitory effects of ELQ-300 and ELQ-316 were assessed on the growth of cultured B. bovis, B. bigemina, B. caballi and T. equi. The percentage of parasitized erythrocytes was measured by flow cytometry, and the effect of the ELQ compounds on the viability of horse and bovine peripheral blood mononuclear cells (PBMC) was assessed by monitoring cell metabolic activity using a colorimetric assay. Results We calculated the half maximal inhibitory concentration (IC50) at 72 h, which ranged from 0.04 to 0.37 nM for ELQ-300, and from 0.002 to 0.1 nM for ELQ-316 among all cultured parasites tested at 72 h. None of the parasites tested were able to replicate in cultures in the presence of ELQ-300 and ELQ-316 at the maximal inhibitory concentration (IC100), which ranged from 1.3 to 5.7 nM for ELQ-300 and from 1.0 to 6.0 nM for ELQ-316 at 72 h. Neither ELQ-300 nor ELQ-316 altered the viability of equine and bovine PBMC at their IC100 in in vitro testing. Conclusions The compounds ELQ-300 and ELQ-316 showed significant inhibitory activity on the main parasites responsible for bovine babesiosis and equine piroplasmosis at doses that are tolerable to host cells. These ELQ drugs may be viable candidates for developing alternative protocols for the treatment of bovine babesiosis and equine piroplasmosis.

scholarly journals The Role of Cell Metabolism in Innate Immune Memory

2020 ◽  
pp. 1-9
Author(s):  
Anaisa Valido Ferreira ◽  
Jorge Domiguéz-Andrés ◽  
Mihai Gheorghe Netea
Keyword(s):  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Trained Immunity ◽  
Health And Disease

Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined <i>trained immunity</i> or <i>innate immune memory</i>, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.

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 Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chia-Ching Lin ◽  
Yi-Ru Shen ◽  
Chi-Chih Chang ◽  
Xiang-Yi Guo ◽  
Yun-Yun Young ◽  
...  
Keyword(s):  
Posttranscriptional Regulation ◽  
Inflammatory Responses ◽  
Rna Stability ◽  
Innate Immune ◽  
Stem Loop ◽  
Stem Loop Structure ◽  
Tlr4 Activation ◽  
Harmful Effects ◽  
Different Levels

AbstractDifferent levels of regulatory mechanisms, including posttranscriptional regulation, are needed to elaborately regulate inflammatory responses to prevent harmful effects. Terminal uridyltransferase 7 (TUT7) controls RNA stability by adding uridines to its 3′ ends, but its function in innate immune response remains obscure. Here we reveal that TLR4 activation induces TUT7, which in turn selectively regulates the production of a subset of cytokines, including Interleukin 6 (IL-6). TUT7 regulates IL-6 expression by controlling ribonuclease Regnase-1 mRNA (encoded by Zc3h12a gene) stability. Mechanistically, TLR4 activation causes TUT7 to bind directly to the stem-loop structure on Zc3h12a 3′-UTR, thereby promotes Zc3h12a uridylation and degradation. Zc3h12a from LPS-treated TUT7-sufficient macrophages possesses increased oligo-uridylated ends with shorter poly(A) tails, whereas oligo-uridylated Zc3h12a is significantly reduced in Tut7-/- cells after TLR4 activation. Together, our findings reveal the functional role of TUT7 in sculpting TLR4-driven responses by modulating mRNA stability of a selected set of inflammatory mediators.

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.

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