Mycobacterium tuberculosis carrying the rifampicin drug-resistance-conferring rpoB mutation H445Y is associated with suppressed immunity through type I interferons
Why this work is in the frame
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Bibliographic record
Abstract
Tuberculosis (TB) is one of the leading causes of death due to an infectious disease. The rise of multi-drug resistance (MDR) in Mycobacterium tuberculosis (Mtb), the causative agent of TB, presents a significant obstacle to TB control. While human studies report dysregulated immune responses during MDR TB, a clear understanding of the host-pathogen interactions of MDR Mtb is lacking. Here, we studied the immune responses induced by Mtb strains carrying two of the most common rifampicin drug-resistance (RDR)-conferring single-nucleotide polymorphisms (SNPs) in the RNA polymerase gene of Mtb, which accounts for nearly 90% of drug-resistance mutations found clinically in Mtb. During Mtb infection of primary human macrophages, we found that pro-inflammatory cytokine production was reduced upon infection with Mtb carrying the H445Y SNP but not the S450L SNP. Using a mouse model, we also characterized the host immune response in vivo following infection. Despite similar establishment of Mtb infection in the lung and dissemination to the peripheral organs, we show that infection with the RDR Mtb rpoB-H445Y strain, but not with the rpoB-S450L strain, resulted in a suppressed lung myeloid and lymphoid immune responses through type I IFN-dependent pathways, relative to wt Mtb. This suppressed host immunity had functional consequences in limiting control of RDR Mtb strains harboring rpoB-H445Y and led to worse pathology during chronic TB disease. Collectively, our results suggest that disease pathogenesis may be associated with specific RDR mutations in Mtb, which may differentially regulate immune responses. IMPORTANCE This study highlights the impact of specific rifampicin-resistance-conferring mutations on the host immune response to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Clinical reports have previously suggested that multi-drug-resistant) TB patients exhibit altered peripheral immune responses as compared with their drug-sensitive TB counterparts. The murine model of infection with Mtb strains carrying drug-resistance-conferring mutations recapitulated these findings and allowed us to mechanistically interrogate the pathways responsible for driving the divergent immune responses. Our findings underscore the need for greater investigation into bacterial heterogeneity to better appreciate the diversity in host-pathogen interactions during TB disease.
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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 | 0.001 |
| 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) | 0.000 | 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 it