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Science Advances Sep 2023Trained immunity is a long-term memory of innate immune cells, generating an improved response upon reinfection. is an important human pathogen and inflammatory...
Trained immunity is a long-term memory of innate immune cells, generating an improved response upon reinfection. is an important human pathogen and inflammatory paradigm for which there is no effective vaccine. Using zebrafish larvae, we demonstrate that after training, neutrophils are more efficient at bacterial clearance. We observe that -induced protection is nonspecific and has differences with training by BCG and β-glucan. Analysis of histone ChIP-seq on trained neutrophils revealed that training deposits the active H3K4me3 mark on promoter regions of 1612 genes, dramatically changing the epigenetic landscape of neutrophils toward enhanced microbial recognition and mitochondrial ROS production. Last, we demonstrate that mitochondrial ROS plays a key role in enhanced antimicrobial activity of trained neutrophils. It is envisioned that signals and mechanisms we discover here can be used in other vertebrates, including humans, to suggest new therapeutic strategies involving neutrophils to control bacterial infection.
Topics: Enterobacteriaceae Infections; Animals; Zebrafish; Larva; Neutrophils; Trained Immunity; Shigella flexneri; Mycobacterium bovis; beta-Glucans; Epigenesis, Genetic; Mitochondria; Reactive Oxygen Species
PubMed: 37672585
DOI: 10.1126/sciadv.adf9706 -
Journal of Immunology (Baltimore, Md. :... Nov 2023Mycobacterium tuberculosis cell-wall glycolipids such as mannosylated lipoarabinomannan (ManLAM) can inhibit murine CD4+ T cells by blocking TCR signaling. This results...
Mycobacterium tuberculosis cell-wall glycolipids such as mannosylated lipoarabinomannan (ManLAM) can inhibit murine CD4+ T cells by blocking TCR signaling. This results in suppression of IL-2 production, reduced T cell proliferation, and induction of CD4+ T cell anergy. This study extended these findings to the interaction between primary human CD4+ T cells and macrophages infected by mycobacteria. Exposure of human CD4+ T cells to ManLAM before activation resulted in loss of polyfunctionality, as measured by IL-2, IFN-γ, and TNF-α expression, and reduced CD25 expression. This was not associated with upregulation of inhibitory receptors CTLA-4, PD-1, TIM-3, and Lag-3. By confocal microscopy and imaging flow cytometry, ManLAM exposure reduced conjugate formation between macrophages and CD4+ T cells. ManLAM colocalized to the immunological synapse (IS) and reduced translocation of lymphocyte-specific protein tyrosine kinase (LCK) to the IS. When CD4+ T cells and Mycobacterium bovis BCG-infected monocytes were cocultured, ManLAM colocalized to CD4+ T cells, which formed fewer conjugates with infected monocytes. These results demonstrate that mycobacterial cell-wall glycolipids such as ManLAM can traffic from infected macrophages to disrupt productive IS formation and inhibit CD4+ T cell activation, contributing to immune evasion by M. tuberculosis.
Topics: Humans; CD4-Positive T-Lymphocytes; Glycolipids; Immunological Synapses; Interleukin-2; Macrophages; Mycobacterium tuberculosis
PubMed: 37695687
DOI: 10.4049/jimmunol.2300107 -
Veterinary Journal (London, England :... Jun 2024Canine mycobacterial disease was first recognised over 100 years ago but is now an emerging concern. All reported cases of tuberculous disease in dogs have been caused... (Review)
Review
Canine mycobacterial disease was first recognised over 100 years ago but is now an emerging concern. All reported cases of tuberculous disease in dogs have been caused by infection with one of three Mycobacterium tuberculosis-complex (MTBC) organisms (M. tuberculosis, Mycobacterium bovis, and Mycobacterium microti). Molecular PCR and interferon-gamma release assays offer alternative or complementary diagnostic pathways to that of specialist culture, which is limited by availability, sensitivity, and the time it takes to get a result. Optimised triple antimicrobial protocols offer an excellent chance of a successful outcome in dogs where treatment can be considered and is attempted. In this review, the clinical presentation, diagnosis, treatment, and prognosis of canine tuberculosis are discussed.
Topics: Dogs; Dog Diseases; Animals; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis
PubMed: 38604331
DOI: 10.1016/j.tvjl.2024.106111 -
Frontiers in Veterinary Science 2023Bovine tuberculosis (bTB) is a chronic disease mainly caused by , a zoonotic pathogen with economic significance as it leads to reduced milk and meat production, and...
Bovine tuberculosis (bTB) is a chronic disease mainly caused by , a zoonotic pathogen with economic significance as it leads to reduced milk and meat production, and high costs for control measures. The Bacillus Calmette-Guérin (BCG) vaccine, primarily used to prevent tuberculosis in humans, has also been studied for controlling bTB. While showing effectiveness in preventing infection and disease in cattle, the BCG vaccine can induce non-specific effects on the immune system, enhancing responses to infections caused by unrelated pathogens, and also having non-specific effects on lactation. The aim of this study is to describe both the specific and non-specific effects of BCG vaccination in calves from a commercial dairy herd in central Chile. Diagnosis of infection was performed through the IFNγ release assay (IGRA) using ESAT6/CFP-10 and Rv3615c antigens. The records of milk production, somatic cell count (SCC), clinical mastitis (CM) and retained placenta (RP) during the first lactation were compared between vaccinated and non-vaccinated animals. The breed (Holstein Friesian [HF] v/s HF × Swedish Red crossbred [HFSR]) and the season (warm v/s cold) were also analyzed as categorical explanatory variables. Results of IGRA showed significant differences between vaccinated and control groups, indicating a vaccine efficacy of 58.5% at 18 months post vaccination in HFSR crossbred animals. Although milk production did not vary, SCC and CM showed differences between groups, associated to the breed and the season, respectively. When analyzing CM and RP as a whole entity of disease, BCG showed protection in all but the cold season variables. Overall, the BCG vaccine induced protective specific and non-specific effects on health parameters, which may be influenced by the breed of animals and the season. These results provide new features of BCG protection, supporting initiatives for its implementation as a complementary tool in bTB control.
PubMed: 37869491
DOI: 10.3389/fvets.2023.1278329 -
The Journal of Clinical Investigation Jul 2023Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin-induced...
Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin-induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.
Topics: Mice; Animals; Humans; BCG Vaccine; Tuberculosis; Mycobacterium tuberculosis; Mycobacterium bovis; Genetic Background
PubMed: 37200108
DOI: 10.1172/JCI167762 -
Veterinary Sciences Jul 2023This study addressed the need in Great Britain for supplementary blood tests for deer and pig herds under movement restrictions due to confirmed infection-to enhance...
This study addressed the need in Great Britain for supplementary blood tests for deer and pig herds under movement restrictions due to confirmed infection-to enhance the overall sensitivity and reliability of tuberculosis (TB) testing and contribute to an exit strategy for these herds. We evaluated four antibody tests (lateral flow DPP VetTB Assay for Cervids, IDEXX ELISA, Enferplex Cervid and Porcine antibody tests and an in-house comparative PPD ELISA) using serum samples from defined cohorts of TB-infected and TB-free deer and pigs. TB-infected deer included two separate cohorts; farmed deer that had received a tuberculin skin test less than 30 days prior, and park deer that had received no prior skin test. In this way, we were able to assess the effect of the skin test anamnestic boost upon antibody test sensitivity. We tested a total of 402 TB-free pigs and 416 TB-free deer, 77 infected farmed deer and 105 infected park deer, and 29 infected pigs (including 2 wild boar). For deer, we found an equivalent high performance of all four tests: specificity range 98.8-99.5% and sensitivity range 76.6-85.7% for skin test-boosted infected deer, and 51.4-58.1% for non-boosted infected deer. These data suggest an overall approximate 25% increase in test sensitivity for infected deer following a skin test boost. For pigs, the tests again had equivalent high specificity of 99-99.5% and a sensitivity range of 62.1-86.2%, with substantial agreement for three of the four tests. Retrospective application of the ELISA tests to individual culled park deer and wild boar that showed no obvious evidence of TB at larder inspection identified a significant seropositivity within wild boar suggestive of low-level infection that would otherwise not have been detected. Overall this investigation provided a robust evaluation of four antibody tests, which is essential to generate confidence in test performance before a wider deployment within TB control measures can be considered.
PubMed: 37624276
DOI: 10.3390/vetsci10080489 -
Microbiology Spectrum May 2024causes animal tuberculosis in livestock and wildlife, with an impact on animal health and production, wildlife management, and public health. In this work, we sampled a...
UNLABELLED
causes animal tuberculosis in livestock and wildlife, with an impact on animal health and production, wildlife management, and public health. In this work, we sampled a multi-host tuberculosis community from the official hotspot risk area of Portugal over 16 years, generating the largest available data set in the country. Using phylogenetic and ecological modeling, we aimed to reconstruct the history of circulating lineages across the livestock-wildlife interface to inform intervention and the implementation of genomic surveillance within the official eradication plan. We find evidence for the co-circulation of European 1 (Eu1), Eu2, and Eu3 clonal complexes, with Eu3 providing sufficient temporal signal for further phylogenetic investigation. The Eu3 most recent common ancestor (bovine) was dated in the 1990s, subsequently transitioning to wildlife (red deer and wild boar). Isolate clustering based on sample metadata was used to inform phylogenetic inference, unravelng frequent transmission between two clusters that represent an ecological corridor of previously unrecognized importance in Portugal. The latter was associated with transmission at the livestock-wildlife interface toward locations with higher temperature and precipitation, lower agriculture and road density, and lower host densities. This is the first analysis of Eu3 complex in Iberia, shedding light on background ecological factors underlying long-term transmission and informing where efforts could be focused within the larger hotspot risk area of Portugal.
IMPORTANCE
Efforts to strengthen surveillance and control of animal tuberculosis (TB) are ongoing worlwide. Here, we developed an eco-phylodynamic framework based on discrete phylogenetic approaches informed by whole-genome sequence data representing a multi-host transmission system at the livestock-wildlife interface, within a rich ecological landscape in Portugal, to understand transmission processes and translate this knowledge into disease management benefits. We find evidence for the co-circulation of several clades, with frequent transmission of the Eu3 lineage among cattle and wildlife populations. Most transition events between different ecological settings took place toward host, climate and land use gradients, underscoring animal TB expansion and a potential corridor of unrecognized importance for maintenance. Results stress that animal TB is an established wildlife disease without ecological barriers, showing that control measures in place are insufficient to prevent long-distance transmission and spillover across multi-host communities, demanding new interventions targeting livestock-wildlife interactions.
PubMed: 38771094
DOI: 10.1128/spectrum.03829-23 -
Veterinary Medicine and Science Jul 2023Tuberculosis (TB) has been an important public health concern in Bangladesh. The most common cause of human TB is Mycobacterium tuberculosis, while bovine TB is caused... (Observational Study)
Observational Study
BACKGROUND
Tuberculosis (TB) has been an important public health concern in Bangladesh. The most common cause of human TB is Mycobacterium tuberculosis, while bovine TB is caused by Mycobacterium bovis.
OBJECTIVE
The objective of this study was to determine the frequency of TB in individuals with occupational exposure to cattle and to detect Mycobacterium bovis among cattle in slaughterhouses in Bangladesh.
METHODS
Between August 2014 and September 2015, an observational study was conducted in two government chest disease hospitals, one cattle market, and two slaughterhouses. [Correction added on 27 June 2023, after first online publication: In the preceding sentence, the year "2014" has been added after the word "August".] Sputum samples were collected from individuals who met the criteria for suspected TB and had been exposed to cattle. Tissue samples were collected from cattle that had low body condition score(s). Both humans and cattle samples were screened for acid-fast bacilli (AFB) by Ziehl-Neelsen (Z-N) staining and cultured for Mycobacterium tuberculosis complex (MTC). Region of difference (RD) 9-based polymerase chain reaction (PCR) was also performed to identify Mycobacterium spp. We also conducted Spoligotyping to identify the specific strain of Mycobacterium spp.
RESULTS
Sputum was collected from a total of 412 humans. The median age of human participants was 35 (IQR: 25-50) years. Twenty-five (6%) human sputum specimens were positive for AFB, and 44 (11%) were positive for MTC by subsequent culture. All (N = 44) culture-positive isolates were confirmed as Mycobacterium tuberculosis by RD9 PCR. Besides, 10% of cattle workers were infected with Mycobacterium tuberculosis in the cattle market. Of all TB (caused by Mycobacterium tuberculosis) infected individuals, 6.8% of individuals were resistant to one or two anti-TB drugs. The majority of the sampled cattle (67%) were indigenous breeds. No Mycobacterium bovis was detected in cattle.
CONCLUSIONS
We did not detect any TB cases caused by Mycobacterium bovis in humans during the study. However, we detected TB cases caused by Mycobacterium tuberculosis in all humans, including cattle market workers.
Topics: Animals; Cattle; Humans; Bangladesh; Cattle Diseases; Coloring Agents; Mycobacterium bovis; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis, Bovine; Adult; Middle Aged
PubMed: 37327465
DOI: 10.1002/vms3.1178 -
EClinicalMedicine Oct 2023Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille...
BACKGROUND
Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects.
METHODS
In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2-8 x 10 colony forming units of , Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206.
FINDINGS
Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p = 0.02). There were no safety concerns.
INTERPRETATION
BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore.
FUNDING
Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.
PubMed: 37719417
DOI: 10.1016/j.eclinm.2023.102203 -
IScience Nov 2023Hunner-type interstitial cystitis (HIC) is a rare, enigmatic inflammatory disease of the urinary bladder with no curative treatments. In this study, we aimed to...
Hunner-type interstitial cystitis (HIC) is a rare, enigmatic inflammatory disease of the urinary bladder with no curative treatments. In this study, we aimed to characterize the unique cellular and immunological factors specifically involved in HIC by comparing with cystitis induced by bacillus Calmette-Guérin, which presents similar clinicopathological features to HIC. Here, we show that T helper 1/17 +polarized immune responses accompanied by prominent overexpression of interferon (IFN)-γ, enhanced cGAS-STING cytosolic DNA sensing pathway, and increased plasma cell infiltration are the characteristic inflammatory features in HIC bladder. Further, we developed a mouse anti-IFN-γ DNA aptamer and observed that the intravesical instillation of the aptamer significantly ameliorated bladder inflammation, pelvic pain and voiding dysfunction in a recently developed murine HIC model with little migration into the blood. Our study provides the plausible basis for the clinical translation of the anti-IFN-γ DNA aptamer in the treatment of human HIC.
PubMed: 38026177
DOI: 10.1016/j.isci.2023.108262