Gonzalo G. Alvarez

Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. Mtb reprograms and disables key antibacterial response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, contribute to regulating chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Herein, we use combinatorial chromatin accessibility (ATAC-seq) and transcriptomic (RNA-seq) profiling of wild-type, PPM1A knockout and PPM1A overexpressing macrophages to demonstrate that Mtb infection induces global chromatin remodeling consistent with changes in gene expression. The strongest concordant changes to chromatin accessibility and gene expression triggered by Mtb infection were enriched for genes involved in type I interferon (IFN) signaling pathways. A panel of 15 genes with the strongest concordant changes in chromatin accessibility and gene expression were validated to be significantly upregulated in Mtb-infected human monocyte-derived macrophages. PPM1A expression affects chromatin accessibility profiles during Mtb infection reflected in the total number, chromosome location and directionality of change. Transcription factor binding motif analysis revealed enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including members of the IRF, MEF2 and AP-1 families. Our study shows that altered type I IFN responses in Mtb-infected macrophages occur due to genome-wide changes in chromatin accessibility, and that PPM1A could influence a subset of these signatures.

Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. The success of Mtb as a human pathogen depends on its ability to manipulate host immune response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, may play a role in the regulation of chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Using combinatorial chromatin accessibility (ATAC-seq) and transcriptomics (RNA-seq) profiling of wild-type (WT), PPM1A knockout (ΔPPM1A) and PPM1A overexpressing (PPM1A ⁺ ) macrophages, we demonstrate that Mtb infection induces global chromatin remodeling consistent with changes in gene expression signatures. The strongest concordant chromatin accessibility and gene expression signature triggered by Mtb infection was enriched for genes involved in the type I interferon (IFN) signaling pathways. Modulation of PPM1A expression results in altered chromatin accessibility signatures during Mtb infection that are reflected in the total number, chromosome location and directionality of change. Transcription factor motif analysis revealed an enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including IRF4, MEF2A, and JDP2. In contrast, both deletion and overexpression of PPM1A produced unique transcription factor enrichment signatures linked to the genomic regions with altered chromatin accessibility. Our study demonstrates that altered type I IFN responses in Mtb-infected macrophages occurs as a result of genome-wide changes in chromatin accessibility, and that PPM1A likely plays a role in a subset of these signatures.

Tuberculosis (TB) remains the leading cause of bacterial disease-related death and is among the top 10 overall causes of death worldwide. The complex nature of this infectious lung disease has proven difficult to treat, and significant research efforts are now evaluating the feasibility of host-directed, adjunctive therapies.

For tuberculosis preventive treatment (TPT):Either once-weekly rifapentine and isoniazid for 3 months (3HP), or daily rifampin for 4 months (4R) is recommended.When rifamycin based regimens cannot ...

Health care workers providing services on Indigenous lands and/or working with Indigenous Peoples to do tuberculosis-related work should:educate themselves about the epidemiology of tuberculosis (T...

Background: Prevention of TB is paramount to achieving elimination targets as recommended by the World Health Organization’s action framework for low incidence countries striving to eliminate TB. Although the rates of TB in Canada are low, understanding the latent TB infection (LTBI) cascade is paramount to identifying gaps in care and treatment barriers, thereby increasing the effectiveness of preventive strategies. The purpose of this study was to examine the LTBI cascade of care and identify barriers to treatment completion in adults referred from primary care to a regional tertiary care TB clinic in Ottawa, Canada. Methods: Electronic medical records between January 2010 and December 2016 were reviewed retrospectively and an LTBI cascade of care was constructed from The Ottawa Hospital TB clinic and surrounding primary care clinics. A cohort of 2207 patients with untreated LTBI was used to ascertain the associations between demographic and clinical factors for both treatment non-initiation and non-completion using log-binomial univariable and multivariable regression models. Results: Of 2207 patients with untreated LTBI who were seen in the clinic during the study period, 1771 (80.2%) were offered treatment, 1203 (67.9% of those offered) started treatment, and 795 (66.1% of those started) completed treatment. In multivariable analysis, non-initiation of treatment was associated with older age (adjusted risk ratio [aRR] 1.06 per 5-year increase, 95% CI: 1.03–1.08) and female gender (aRR 1.28, 95% CI: 1.11–1.47). Non completion of treatment was associated with referral from the TB Clinic back to the primary care team following initial consult (aRR 1.62, 95% CI: 1.35–1.94) and treatment with the standard of 9 months of Isoniazid (9H) compared to 4 months of Rifampin (4R) (aRR 1.45, 95% CI:1.20–1.74). Conclusions: LTBI treatment completion was significantly decreased among patients who were referred back to primary care from the TB clinic. The 4R regimen resulted in more people completing LTBI treatment compared to 9H in keeping with a recently published RCT. Improved education, communication, and collaboration between tertiary care TB clinics and primary care teams may improve treatment completion rates and address the TB burden in low incidence communities in Canada.