Biology subjects

Dagg, B.

Publications and source records attributed to Dagg, B..

3 recordsLinked to original sources

bioRxiv2023

Establishment of Tuberculosis Meningitis Mouse Model Using Aerosol Route of W. Beijing HN878 strain

In this study, we report the development of a tuberculosis meningitis (TBM) mouse model using the HN878 strain via the aerosol route. Three genetically different strains of mice, CB6F1, C57BL/6 and BALB/c mice, were used to determine the dissemination of HN878 in the brain. The 8 x 108 CFU/ml of HN878 dose was used to infect CB6F1 mice and deposited approximately 3.8 (0.07, SD) log10 CFU in the lungs. The burden of HN878 in the brain of the control group (administered saline) after approximately 16/17 days post-infection for CB6F1, C57BL/6 and BALB/c were 4.00 (0.47 SD), 3.79 (0.27, SD) and 2.12 (0.41, SD) log10 CFU/brain, respectively. The log10 CFU/brain in the BCG vaccinated CB6F1, C57BL/6 and BALB/c mice were 1.05 (0.61, SD), 2.13 (0.33, SD) and 1.42 (0.38, SD) respectively, which, if compared to the control groups, BCG vaccinated mice inhibited dissemination of HN878 in the brain by an impressive 2.94 (CB6F1), 1.66 (C57BL/6) and 0.69 (BALB/c) log10 CFU/brain reduction. In conclusion, we have established a relatively inexpensive TBM mouse model using an aerosol, a natural route of infection, which will advance research in understanding TBM dissemination to the brain, and preclinical tuberculosis vaccine/drug discovery/drug regimens against TBM.

developmental biology↗

bioRxiv2020

Efficacy and immunogenicity of different BCG doses in BALB/c and CB6F1 mice when challenged with H37Rv or Beijing HN878

In this study, 2 strains of mice (BALB/c and CB6F1) were vaccinated with a range of Bacille Calmette-Guerin (BCG) Danish doses from 3x105 to 30 CFU/mouse, followed by either immunogenicity evaluation or aerosol infection with Mycobacterium tuberculosis (a laboratory strain H37Rv or West-Beijing HN878 strain). The results indicated that both strains of mice when infected with HN878 exhibited significant protection in their lungs with BCG doses at 3x105 - 3000 CFU (BALB/c) and 3x105-300 CFU (CB6F1). Whereas, both strains of mice when infected with H37Rv, significant protection was seen in BCG doses at 3x105 - 300 CFU. Immunological evaluation revealed interesting results; i) both strains of mice demonstrated a significant increase in the frequencies of BCG-specific IFN{gamma}+ IL2+ TNF+ CD4 T cells in the BCG doses at 3x105 - 3000 CFU (BALB/c) and 3x105 - 300 CFU (CB6F1); ii) secretion of IL2 and IFN{gamma} were correlated with the bacterial burden in the lungs of HN878 infected CB6F1 mice. The study demonstrated a BCG dose at 3000 CFU (an equivalent single human dose in the mice by body weight index) is protective in both strains of mice and the use of a virulent clinical isolate in testing new tuberculosis vaccine/advancing research is recommended.

immunology↗

bioRxiv2018

Antibiotic resistance evasion is explained by rare mutation frequency and not by lack of compensatory mechanisms

Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for decades without appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low mutation frequency associated with D-cycloserine resistance is the dominant factor delaying the appearance of clinical resistance to this antibiotic in bacteria infecting humans, and not lack of potential compensatory mechanisms.\n\nOne Sentence SummaryWe show that the lack of D-cycloserine resistance in Mycobacterium tuberculosis is due its ultra-low mutation frequency rather than lack of compensatory mechanisms.

microbiology↗