Background: BCG is the most widely used vaccine of all time and remains the only licensed vaccine for use against tuberculosis in humans. BCG also protects other species such as cattle against tuberculosis, but due to its incompatibility with current tuberculin testing regimens remains unlicensed. BCG's efficacy relates to its ability to persist in the host for weeks, months or even years after vaccination. It is unclear to what degree this ability to resist the host's immune system is maintained by a dynamic interaction between the vaccine strain and its host as is the case for pathogenic mycobacteria.
Results: To investigate this question, we constructed transposon mutant libraries in both BCG Pasteur and BCG Danish strains and inoculated them into bovine lymph nodes. Cattle are well suited to such an assay, as they are naturally susceptible to tuberculosis and are one of the few animal species for which a BCG vaccination program has been proposed. After three weeks, the BCG were recovered and the input and output libraries compared to identify mutants with in vivo fitness defects. Less than 10% of the mutated genes were identified as affecting in vivo fitness, they included genes encoding known mycobacterial virulence functions such as mycobactin synthesis, sugar transport, reductive sulphate assimilation, PDIM synthesis and cholesterol metabolism. Many other attenuating genes had not previously been recognised as having a virulence phenotype. To test these genes, we generated and characterised three knockout mutants that were predicted by transposon mutagenesis to be attenuating in vivo: pyruvate carboxylase, a hypothetical protein (BCG_1063), and a putative cyclopropane-fatty-acyl-phospholipid synthase. The knockout strains survived as well as wild type during in vitro culture and in bovine macrophages, yet demonstrated marked attenuation during passage in bovine lymph nodes confirming that they were indeed involved in persistence of BCG in the host.
Conclusion: These data show that BCG is far from passive during its interaction with the host, rather it continues to employ its remaining virulence factors, to interact with the host's innate immune system to allow it to persist, a property that is important for its protective efficacy.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540422 | PMC |
http://dx.doi.org/10.1186/s12864-019-5791-1 | DOI Listing |
Eur J Pharm Sci
December 2024
Department of Infectious Diseases, LUCID, Leiden University Medical Center (LUMC), The Netherlands.
Tuberculosis (TB) remains a significant global health challenge, latently affecting around a quarter of the global population. The sole licensed TB vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), shows variable efficacy, particularly among adolescents and adults, underscoring the pressing need for more effective vaccination strategies. The administration route is crucial for vaccine efficacy, and administration via the skin, being rich in immune cells, may offer advantages over conventional subcutaneous routes, which lack direct access to abundant antigen-presenting cells.
View Article and Find Full Text PDFLancet Microbe
December 2024
Amsterdam University Medical Centres, Amsterdam, Netherlands; Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands.
Background: Tuberculosis vaccine trials using disease as the primary endpoint are large, time consuming, and expensive. An earlier immunological measure of the protection against disease would accelerate tuberculosis vaccine development. We aimed to assess whether the effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine for prevention of Mycobacterium tuberculosis infection was consistent with that for prevention of tuberculosis disease.
View Article and Find Full Text PDFBMC Urol
December 2024
Prokarium Ltd, 2 Royal College St, London, NW1 0NH, UK.
Background: Urine biomarkers are crucial for monitoring patient responses in treating urological pathologies, including non-muscle invasive bladder cancer (NMIBC). Yet, analysing urine biomarkers poses several challenges, including ensuring specimen stability during transportation and analytical processing. This prospective feasibility study aimed to investigate how urinary leukocytes and proteins are impacted by storing and refrigerating urine.
View Article and Find Full Text PDFGlob Health Sci Pract
December 2024
JSI Research & Training Institute, Inc., Ethiopia Data Use Partnership, Addis Ababa, Ethiopia.
Background: Health information systems (HIS) are vital in supporting all aspects of managing health systems, financing, policymaking, and service delivery. A package of priority HIS interventions was piloted in selected woredas across all regions in Ethiopia. This study examined the impact of HIS interventions on maternal and child health (MCH) service utilization.
View Article and Find Full Text PDFClin Cancer Res
December 2024
United States Food and Drug Administration, Silver Spring, Maryland, United States.
On December 16, 2022, the FDA approved the adenoviral vector-based gene therapy nadofaragene firadenovec-vncg (brand name Adstiladrin) for the treatment of adult patients with high-risk bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). The product represents the first approved adenoviral vector-based gene therapy and the first approved gene therapy for bladder cancer. Determination of efficacy was based on results from Study rAd-IFN-CS-003 (Study CS-003), a single-arm trial in 98 evaluable patients with BCG-unresponsive NMIBC with CIS who received intravesical instillations of the gene therapy product (75 mL of nadofaragene firadenovec at 3 × 1011 viral particles per mL) once every 3 months.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!