scholarly journals Experimental infection of cattle withMycobacterium tuberculosisisolates shows the attenuation of the human tubercle bacillus for cattle

2017 ◽  
Author(s):  
Bernardo Villarreal-Ramos ◽  
Stefan Berg ◽  
Adam Whelan ◽  
Sebastien Holbert ◽  
Florence Carreras ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Experimental Infection ◽  
Genetic Variants ◽  
One Health ◽  
Progressive Disease ◽  
Latent Infection ◽  
Vaccine Development ◽  
Tubercle Bacillus ◽  
Rna Seq ◽  
Mtbc Strain

AbstractTheMycobacterium tuberculosiscomplex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported thatM. tuberculosisH37Rv, a standard reference MTBC strain, is attenuated in cattle compared toMycobacterium bovis. However, asM. tuberculosisH37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation ofM. tuberculosisfor cattle by performing a bovine experimental infection with a recentM. tuberculosisisolate. Here we report infection of cattle usingM. bovisAF2122/97,M. tuberculosisH37Rv, andM. tuberculosisBTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that bothM. tuberculosisstrains caused reduced gross and histopathology in cattle compared toM. bovis. UsingM. tuberculosisH37Rv andM. bovisAF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation ofM. tuberculosisstrains for cattle, and emphasizes the potential of the bovine model as a ‘One Health’ approach to inform human TB biomarker development and post-exposure vaccine development.

scholarly journals Experimental infection of cattle with Mycobacterium tuberculosis isolates shows the attenuation of the human tubercle bacillus for cattle

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Bernardo Villarreal-Ramos ◽  
Stefan Berg ◽  
Adam Whelan ◽  
Sebastien Holbert ◽  
Florence Carreras ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Experimental Infection ◽  
Tubercle Bacillus

scholarly journals scSNV: accurate dscRNA-seq SNV co-expression analysis using duplicate tag collapsing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Gavin W. Wilson ◽  
Mathieu Derouet ◽  
Gail E. Darling ◽  
Jonathan C. Yeung
Keyword(s):  
Genetic Variants ◽  
False Positive ◽  
Variant Calling ◽  
Call Rate ◽  
Rna Seq ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Variant Call ◽  
Two Samples ◽  
Co Detection

AbstractIdentifying single nucleotide variants has become common practice for droplet-based single-cell RNA-seq experiments; however, presently, a pipeline does not exist to maximize variant calling accuracy. Furthermore, molecular duplicates generated in these experiments have not been utilized to optimally detect variant co-expression. Herein, we introduce scSNV designed from the ground up to “collapse” molecular duplicates and accurately identify variants and their co-expression. We demonstrate that scSNV is fast, with a reduced false-positive variant call rate, and enables the co-detection of genetic variants and A>G RNA edits across twenty-two samples.

Latent Haemobartonella muris infection: its transmission and decline in an inbred, ectoparasite-free strain of Wistar rat

Parasitology ◽  
1975 ◽  
Vol 71 (1) ◽  
pp. 35-40 ◽  
Author(s):  
Roberta Bartlett ◽  
Phyllis Pease
Keyword(s):  
Inbred Line ◽  
Experimental Infection ◽  
Wistar Rats ◽  
Latent Infection ◽  
Wistar Rat ◽  
Wild Rats ◽  
Free Strain

Ectoparasite-free, SPF Italian Wistar rats were consistently found to carry a latent infection with Haemobartonella muris, activable by splen ectomy. In an inbred line this diminished and eventually ceased in six generations. Experimental infection from wild rats demonstrated that this was not apparently due to immunity.

scholarly journals Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ–Syk–Card9–dependent innate immune activation

2009 ◽  
Vol 206 (1) ◽  
pp. 89-97 ◽  
Author(s):  
Kerstin Werninghaus ◽  
Anna Babiak ◽  
Olaf Groß ◽  
Christoph Hölscher ◽  
Harald Dietrich ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Subunit Vaccine ◽  
Vaccine Development ◽  
Adaptor Protein ◽  
Synthetic Analogue ◽  
Dependent Manner ◽  
Immunostimulatory Activity ◽  
Adjuvant Activity ◽  
Cord Factor

Novel vaccination strategies against Mycobacterium tuberculosis (MTB) are urgently needed. The use of recombinant MTB antigens as subunit vaccines is a promising approach, but requires adjuvants that activate antigen-presenting cells (APCs) for elicitation of protective immunity. The mycobacterial cord factor Trehalose-6,6-dimycolate (TDM) and its synthetic analogue Trehalose-6,6-dibehenate (TDB) are effective adjuvants in combination with MTB subunit vaccine candidates in mice. However, it is unknown which signaling pathways they engage in APCs and how these pathways are coupled to the adaptive immune response. Here, we demonstrate that these glycolipids activate macrophages and dendritic cells (DCs) via Syk–Card9–Bcl10–Malt1 signaling to induce a specific innate activation program distinct from the response to Toll-like receptor (TLR) ligands. APC activation by TDB and TDM was independent of the C-type lectin receptor Dectin-1, but required the immunoreceptor tyrosine-based activation motif–bearing adaptor protein Fc receptor γ chain (FcRγ). In vivo, TDB and TDM adjuvant activity induced robust combined T helper (Th)-1 and Th-17 T cell responses to a MTB subunit vaccine and partial protection against MTB challenge in a Card9-dependent manner. These data provide a molecular basis for the immunostimulatory activity of TDB and TDM and identify the Syk–Card9 pathway as a rational target for vaccine development against tuberculosis.

scholarly journals Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

2017 ◽  
Vol 24 (11) ◽  
Author(s):  
Ahreum Kim ◽  
Yun-Gyoung Hur ◽  
Sunwha Gu ◽  
Sang-Nae Cho
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Interleukin 2 ◽  
T Cell Epitopes ◽  
Content Type ◽  
Complete Form ◽  
Ifn Γ

ABSTRACT The aim of this study was to evaluate the protective efficacy of MTBK_24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of Mycobacterium tuberculosis in South Korea. Mice were immunized with MTKB_24820, M. bovis Bacilli Calmette-Guérin (BCG), or adjuvant prior to a high-dosed Beijing/K strain aerosol infection. After 4 and 9 weeks, bacterial loads were determined and histopathologic and immunologic features in the lungs and spleens of the M. tuberculosis-infected mice were analyzed. Putative immunogenic T-cell epitopes were examined using synthetic overlapping peptides. Successful immunization of MTBK_24820 in mice was confirmed by increased IgG responses (P < 0.05) and recalled gamma interferon (IFN-γ), interleukin-2 (IL-2), IL-6, and IL-17 responses (P < 0.05 or P < 0.01) to MTBK_24820. After challenge with the Beijing/K strain, an approximately 0.5 to 1.0 log10 reduction in CFU in lungs and fewer lung inflammation lesions were observed in MTBK_24820-immunized mice compared to those for control mice. Moreover, MTBK_24820 immunization elicited significantly higher numbers of CD4+ T cells producing protective cytokines, such as IFN-γ and IL-17, in lungs and spleens (P < 0.01) and CD4+ multifunctional T cells producing IFN-γ, tumor necrosis factor alpha (TNF-α), and/or IL-17 (P < 0.01) than in control mice, suggesting protection comparable to that of BCG against the hypervirulent Beijing/K strain. The dominant immunogenic T-cell epitopes that induced IFN-γ production were at the N terminus (amino acids 85 to 102 and 217 to 234). Its vaccine potential, along with protective immune responses in vivo, may be informative for vaccine development, particularly in regions where the M. tuberculosis Beijing/K-strain is frequently isolated from TB patients.

scholarly journals Discovery of allele-specific protein-RNA interactions in human transcriptomes

2018 ◽  
Author(s):  
Emad Bahrami-Samani ◽  
Yi Xing
Keyword(s):  
Genetic Variants ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Specific Protein ◽  
Computational Method ◽  
Joint Analysis ◽  
Transcriptional Level ◽  
Rna Seq ◽  
Allele Specific ◽  
Rna Interaction

AbstractGene expression is tightly regulated at the post-transcriptional level through splicing, transport, translation, and decay. RNA-binding proteins (RBPs) play key roles in post-transcriptional gene regulation, and genetic variants that alter RBP-RNA interactions can affect gene products and functions. We developed a computational method ASPRIN (Allele-Specific Protein-RNA Interaction), that uses a joint analysis of CLIP-seq (cross-linking and immunoprecipitation followed by high-throughput sequencing) and RNA-seq data to identify genetic variants that alter RBP-RNA interactions by directly observing the allelic preference of RBP from CLIP-seq experiments as compared to RNA-seq. We used ASPRIN to systematically analyze CLIP-seq and RNA-seq data for 166 RBPs in two ENCODE (Encyclopedia of DNA Elements) cell lines. ASPRIN identified genetic variants that alter RBP-RNA interactions by modifying RBP binding motifs within RNA. Moreover, through an integrative ASPRIN analysis with population-scale RNA-seq data, we showed that ASPRIN can help reveal potential causal variants that affect alternative splicing via allele-specific protein-RNA interactions.

Tuberculosis

2010 ◽  
pp. 810-831 ◽  
Author(s):  
Richard E. Chaisson ◽  
Jean B. Nachega
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hiv Infection ◽  
Cause Of Death ◽  
Latent Infection

Tuberculosis is caused by organisms of the Mycobacterium tuberculosis complex, including M. tuberculosis (the most important), M. bovis, and M. africanum. It has been present since antiquity and is the second leading infectious cause of death after HIV infection. An estimated 2 billion people worldwide carry latent infection, when ...

scholarly journals Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2109
Author(s):  
Samuel T. Pasco ◽  
Juan Anguita
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Vaccine Development ◽  
Vaccine Design ◽  
Innate Immune ◽  
Bacillus Calmette Guerin ◽  
Adaptive Immune Responses ◽  
Trained Immunity ◽  
Adaptive Immune ◽  
Potential Methods

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.

scholarly journals Active Pulmonary Tuberculosis Triggered by Interferon Beta-1b Therapy of Multiple Sclerosis: Four Case Reports and a Literature Review

Medicina ◽  
2020 ◽  
Vol 56 (4) ◽  
pp. 202 ◽  
Author(s):  
Carmen Adella Sirbu ◽  
Elena Dantes ◽  
Cristina Florentina Plesa ◽  
Any Docu Axelerad ◽  
Minerva Claudia Ghinescu
Keyword(s):  
Multiple Sclerosis ◽  
Mycobacterium Tuberculosis ◽  
Literature Review ◽  
Interferon Beta ◽  
Latent Infection ◽  
Case Reports ◽  
Active Tuberculosis ◽  
Active Pulmonary Tuberculosis ◽  
Disease Modifying Therapies ◽  
Disease Modifying

In this paper, we reported on four cases of severe pulmonary active tuberculosis in patients with multiple sclerosis (MS) undergoing interferon beta-1b (IFNβ-1b) therapy. Disease-modifying therapies (DMTs) in MS may increase the risk of developing active tuberculosis (TB) due to their impact on cellular immunity. Screening for latent infection with Mycobacterium tuberculosis (LTBI) should be performed, not only for the newer DMTs (alemtuzumab, ocrelizumab) but also for IFNβ-1b, alongside better supervision of these patients.

scholarly journals Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis

mSystems ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Michelle M. Bellerose ◽  
Megan K. Proulx ◽  
Clare M. Smith ◽  
Richard E. Baker ◽  
Thomas R. Ioerger ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Outcome ◽  
Mouse Model ◽  
Genetic Variants ◽  
Drug Efficacy ◽  
Drug Susceptibility ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Bacterial Clearance

ABSTRACT Effective tuberculosis treatment requires at least 6 months of combination therapy. Alterations in the physiological state of the bacterium during infection are thought to reduce drug efficacy and prolong the necessary treatment period, but the nature of these adaptations remain incompletely defined. To identify specific bacterial functions that limit drug effects during infection, we employed a comprehensive genetic screening approach to identify mutants with altered susceptibility to the first-line antibiotics in the mouse model. We identified many mutations that increase the rate of bacterial clearance, suggesting new strategies for accelerating therapy. In addition, the drug-specific effects of these mutations suggested that different antibiotics are limited by distinct factors. Rifampin efficacy is inferred to be limited by cellular permeability, whereas isoniazid is preferentially affected by replication rate. Many mutations that altered bacterial clearance in the mouse model did not have an obvious effect on drug susceptibility using in vitro assays, indicating that these chemical-genetic interactions tend to be specific to the in vivo environment. This observation suggested that a wide variety of natural genetic variants could influence drug efficacy in vivo without altering behavior in standard drug-susceptibility tests. Indeed, mutations in a number of the genes identified in our study are enriched in drug-resistant clinical isolates, identifying genetic variants that may influence treatment outcome. Together, these observations suggest new avenues for improving therapy, as well as the mechanisms of genetic adaptations that limit it. IMPORTANCE Understanding how Mycobacterium tuberculosis survives during antibiotic treatment is necessary to rationally devise more effective tuberculosis (TB) chemotherapy regimens. Using genome-wide mutant fitness profiling and the mouse model of TB, we identified genes that alter antibiotic efficacy specifically in the infection environment and associated several of these genes with natural genetic variants found in drug-resistant clinical isolates. These data suggest strategies for synergistic therapies that accelerate bacterial clearance, and they identify mechanisms of adaptation to drug exposure that could influence treatment outcome.

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