Differential antigen expression among strains of Bacille Calmette-Guérin
Bibliographic record
Abstract
Mycobacterium bovis Bacille Calmette-Guerin (BCG) strains are live attenuated vaccines. These strains are genetically heterogeneous and the accumulation of deletions and mutations, particularly those affecting regulatory and antigenic proteins, has been proposed to have contributed to overly-attenuated vaccines. To examine this possibility, the effects of the two mutations incurred by BCG vaccines was formally studied through gene-deletion and complementation studies. First, the effect of deletion of the RD2 region was examined by over-expressing the antigenic protein MPB64 in a late strain of BCG and by creating an RD2-knockout strain in M. tuberculosis. These two approaches revealed minimal changes attributable to the RD2 region, but stimulated further investigation for other differences contemporaneous with the loss of RD2. By examining differences in gene expression between RD2+ and RD2- strains of BCG, two regions, in addition to the RD2 region itself, that were significantly down-regulated in the latter strains were identified. One region contained genes encoding the highly antigenic proteins MPB70 and MPB83, and the second region contained the gene encoding the extracellular function (ECF) sigma factor, sigK. Sequencing of sigK across all BCG strains revealed a start codon single nucleotide polymorphism (SNP) in strains with low production of MPB70 and MPB83. Complementation of BCG Pasteur with wild-type sigK resulted in up-regulation of mpb70/mpb83 and increased production of MPB70 and MPB83 proteins. Further studies revealed that the in vitro growth rate of BCG Pasteur::sigK was slower than that of BCG Pasteur::pMV306 and that cytotoxicity to macrophage-like THP-1 cells was greater following infection with BCG Pasteur::sigK than with BCG Pasteur::pMV306. Infection of C57BU6J mice demonstrated differences between BCG Pasteur::sigK and BCG Pasteur::pMV306 in initial deposition, growth rates and persistence. Vaccination of C57BU6J mice with BCG Pasteur::sigK stimulated an MPB70-specific immune response, indicating that restored protein production resulted in increased immunogenicity. Finally, in challenge experiments, mice vaccinated with BCG Pasteur::sigK demonstrated equal, or slightly greater, protection than vaccination with BCG Pasteur::pMV306 against subsequent challenge with M. tuberculosis. Together, these findings provide an explanation for the loss of MPB70 and MPB83 production by BCG vaccines during prolonged in vitro passaging, and provide the oasis for further studies aimed at understanding the role of the sigK-mpb70 regulon in tuberculosis pathogenesis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".