Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection [ATAC-Seq]
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ABSTRACT: Currently there is limited knowledge of changes in genome-wide chromatin accessibility during Mycobacterium tuberculosis (Mtb) infection and whether host phosphatases such as PPM1A play a role in this process. Using combinatorial chromatin accessibility (ATAC-seq) and transcriptomics (RNA-seq) profiling of wild-type (WT), PPM1A knockout (△PPM1A) 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.
Project description:Currently there is limited knowledge of changes in genome-wide chromatin accessibility during Mycobacterium tuberculosis (Mtb) infection and whether host phosphatases such as PPM1A play a role in this process. Using combinatorial chromatin accessibility (ATAC-seq) and transcriptomics (RNA-seq) profiling of wild-type (WT), PPM1A knockout (△PPM1A) 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.
Project description:Mycobacterium tuberculosis (Mtb) has developed specialized mechanisms to parasitize its host cell, the macrophage. These mechanisms allow it to overcome killing by oxidative burst and persist in the wake of an inflammatory response. Mtb infection in the majority of those exposed is controlled in an asymptomatic form referred to as latent tuberculosis infection (LTBI). HIV is a well-known catalyst of reactivation of LTBI to active TB infection (ATB). Through the use of nonhuman primates (NHPs) co-infected with Mtb and Simian Immunodeficiency Virus (Mtb/SIV), we are able to simulate human progression of TB/AIDS comorbidity. The advantage of NHP models is that they recapitulate the breadth of human TB outcomes, including immune control of infection, and loss of this control due to SIV co-infection. Using macaques infected with Mtb or Mtb/SIV and with different clinical outcomes we attempted to identify signatures between those that progress to active infection after SIV challenge (reactivators) and those that control the infection (non-reactivators).
Project description:Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1-3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the mouse TB model and show that ULD infection recapitulates key features of human TB.
Project description:The aim of this study was to measure the impact of contained infection with Mycobacterium tuberculosis (CMTB) on the immune response of alveolar macrophages (AMs) to intracellular Mtb infection in vivo and on the circulatory cellularity. We characterized the transcriptional profile of murine AMs in CMTB and control mice by sorting cells from whole-lung lysates and performing RNA-sequencing (samples 1-6). We also characterized the transcriptional profile of murine Mtb-infected AMs after aerosol infection by sorting cells from bronchoalveolar lavage fluid and performing low-input RNA-sequencing (samples 7-12). In order to characterize changes in chromatin accessibility induced by CMTB, we performed ATAC-seq on AMs isolated from control and CMTB mice by BAL (samples 13-18). We also generated whole-blood transcriptomes from mice prior to and following the establishment of CMTB (samples 19-28) in order to characterize the circulatory cellularity.
2020-06-08 | GSE126355 | GEO
Project description:Asymmetrical nucleosomal DNA signatures regulate transcriptional directionality
Project description:In our rabbit model of pulmonary tuberculosis, infection with Mtb HN878, a hyper-virulent W-Beijing strain, results in progressive cavitary disease. However, infection of rabbit lungs with Mtb CDC1551, a hyper-immunogenic strain is effectively controlled overtime, establishing latent Mtb infection. Using these two Mtb strains, we tested the hypothesis that the initial host response in the lungs within hours of infection determines later outcome. The microarray experiments was performed to identify gene expression changes in the Mtb-HN878 or CDC1551- infected rabbit lungs at 3 hours post infection, compared to uninfected naïve rabbit lungs. New Zealand White rabbits were infected with Mtb HN878 or CDC1551 at ~3.5log10. At 3 hours post infection, lung tissue from Mtb-infected and uninfected rabbits were isolated and used for total RNA extraction. Total rabbit lung RNA was used for microarray analysis to determine infection induced changes in host gene expression.
Project description:We have found that drug-resistant (DR) Mtb infection alters the host pathogen interactions thought to occur during drug-sensitive (DS) Mtb infection. Recent data suggests that lack of IL-1, but not Type I IFN, signaling pathways leads to susceptibility to infection to DR Mtb infection. To understand the pathways involved in maintaining control of DS Mtb infection, we are sequencing the bulk lung cells early in infection.
Project description:We have found that drug-resistant (DR) Mtb infection alters the host pathogen interactions thought to occur during drug-sensitive (DS) Mtb infection. Recent data suggests that lack of both, Type I and IL-1, signaling pathways leads to susceptibility to infection to DR Mtb infection. To understand the pathways involved in maintaining control of DR Mtb infection, we are sequencing the bulk lung cells early in infection.
Project description:In our rabbit model of pulmonary tuberculosis, infection with Mtb HN878, a hyper-virulent W-Beijing strain, results in progressive cavitary disease. However, infection of rabbit lungs with Mtb CDC1551, a hyper-immunogenic strain is effectively controlled overtime, establishing latent Mtb infection. Using these two Mtb strains, we tested the hypothesis that the initial host response in the lungs within hours of infection determines later outcome. The microarray experiments was performed to identify gene expression changes in the Mtb-HN878 or CDC1551- infected rabbit lungs at 3 hours post infection, compared to uninfected naïve rabbit lungs.