Mycobacterium tuberculosis infection drives a Type I IFN signature in lung lymphocytes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE200639 | GEO | 2022/06/24
REPOSITORIES: GEO
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Project description:Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), latently infects one quarter of the world’s population. The rise of multidrug resistant (MDR) Mtb infections worldwide presents a significant obstacle to curb TB globally. While human studies report dysregulated immune responses in MDR TB patients, there is a lack of clear understanding of the host-pathogen interactions following MDR Mtb infection. We recently showed that Mtb carrying a rifampicin drug resistance (RDR)-conferring single nucleotide polymorphism in the RNA polymerase-B gene (Mtb rpoB-H445Y) can modulate host macrophage metabolic reprogramming by production of Type I IFNs. Here, using a mouse model, we have characterized the host immune response in vivo following RDR Mtb infection. We show that despite establishment of Mtb infection in the lung and dissemination to the peripheral organs, lung myeloid and lymphoid immune responses to RDR Mtb is suppressed through a Type I IFN-dependent mechanism. These results coincide with a muted responses in the bone marrow hematopoietic stem and progenitor cells (HSPCs) and progenitors following RDR Mtb infection. These results suggest that host directed therapeutics and vaccines for drug resistant TB may need to be target specific host immune pathways for protection.
2022-06-01 | GSE176423 | GEO
Project description:Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), infects approximately one-fourth of the world’s population. The majority of infected persons are asymptomatic, but latent TB infection (LTBI) can progress to active clinical disease in 5-10% of infected individuals. The immune mechanisms that govern progression from latent to active pulmonary TB (PTB) remain poorly defined. An in-depth understanding of immune factors correlating with TB disease, as well as protection during TB, is necessary for developing new immunotherapies to promote immune control of Mtb. Experimentally Mtb-infected non-human primates (NHP) mirror the disease progression and pathology observed in humans and can recapitulate both PTB and LTBI. In the present study, we have characterized the lung immune landscape in NHPs with LTBI and PTB using high-throughput technologies including single-cell RNA sequencing (scRNA-seq) and Time of flight cytometry (CyTOF). We show that the three defining features of PTB in macaque lungs are the influx of plasmacytoid DCs (pDCs), an Interferon (IFN)-exhibiting alveolar macrophage population and predominant activated T cell responses. These features contribute to uncontrolled inflammation and disease without mediating Mtb control. In contrast, a CD27+ Natural killer (NK) cell subset accumulated in the lungs of LTBI macaques and in circulation in individuals with LTBI, thus providing novel insights into the protective lung landscape that functions during TB latency. A comprehensive understanding of the lung immune landscape as described here will improve our overall understanding of TB disease immunopathogenesis and provide novel targets for design of new therapies and vaccines for TB control.
2020-12-23 | GSE149758 | GEO
Project description:The critical role of type I IFN (IFN I ) in viral disease is thoroughly documented while their function in bacterial infection remains ambiguous. General interest in biological functions of IFN I in Mycobacterium tuberculosis (Mtb) infection was raised by the identification of a distinct IFN I gene expression signature in tuberculosis (TB) patients. Here we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Increased survival was accompanied by reduced bacterial burden and ameliorated lung pathology as well as diminished production of proinflammatory IL-1?, among other cytokines. IFNAR1 signaling did not affect T cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung during pulmonary TB. This process was orchestrated by presence of IFNAR1 in both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by CXCL5/CXCL1-driven accumulation of neutrophils into alveoli and subsequently a distinct compartmentalization of Mtb in lung phagocytes. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to unleashed inflammation. Hence, our data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB. dual-color color-swap
2013-12-31 | E-GEOD-44848 | biostudies-arrayexpress
Project description:Tuberculosis is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobacterium tuberculosis (MTB), is estimated to have infected up to a third of the world’s population; however, only approximately 10% of healthy individuals progress to active TB disease. Despite evidence for heritability, it is not currently possible to predict whether a healthy person is susceptible to TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from a past episode of active TB. We measured genome-wide gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms in proximity to the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. By intersecting the gene expression and GWAS data, we identified two promising candidate genes: CCL1 and UNC13A. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated decent performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility.
2017-01-31 | GSE94116 | GEO
Project description:Individuals exposed to Mycobacterium tuberculosis (Mtb) may become infected and are classified as with latent tuberculosis infection (LTBI) and remain whole time life in this condition or develop active tuberculosis (TB). Among the multiple factors governing the outcome of the infection, dendritic cells (DC) play a major role in dictating protective immunity. However, current knowledge on the role of the diverse components of human DC in shaping specific T cell response during Mtb infection is limited. In this study, we performed a comparative evaluation of peripheral blood circulating DC subsets along with the functional capability of monocyte-derived IFN-α DC to induce Mtb antigen-specific T cell response in patients with active TB, subjects with LTBI and healthy donors (HD). The percentage of BDCA3+ mDC2 and CD123+ pDC declined significantly in active TB patients with respect HD whereas the same subsets displayed a remarkable activation in LTBI. Simultaneously, IFN-α-driven differentiation of DC resulted profoundly impaired from monocytes of active TB patients as compared to LTBI and HD individuals. Importantly, the specific altered developmental trait of IFN-α DC from active TB patients was associated with a marked change of molecular signalings conveying antigen presentation as well as full inability to induce antigen-specific T cell response. Thus, these data unravel an unavoidable role of IFN-α in determining the induction of Mtb-specific protective immunity which is essential to control Mtb infection.
2017-12-18 | GSE84344 | GEO
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.
2020-11-06 | GSE158807 | GEO
Project description:Induced lymphoid structures associated with pulmonary granulomas have been observed during TB in both humans and mice and could orchestrate host defense. In order to determine whether granulomas perform lymphoid functions, mice lacking secondary lymphoid organs (SLOs) were infected with Mycobacterium tuberculosis (MTB). As in wild type mice (WT), granulomas developed, MTB was controlled, and antigen-specific T cell responses including T central memory (TCM) cells were generated in the complete absence of SLOs. Moreover, T cell activation correlated with granuloma formation in these mice and TCM cells accumulated in lungs and participated in protection against secondary MTB infection. Lung granulomas may therefore represent tertiary lymphoid organs (TLOs) capable of priming robust T cell responses and mediating host defense during chronic MTB at the site of infection.
2010-12-22 | GSE15335 | GEO
Project description:Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). we have used human monocyte and a mouse model of pulmonary TB to investigate whether treatment with PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection. Mice were infected with Mtb and treatment with PZA was started at 28 days post-infection. At 42 days and 63 days post-infection, group of animals were euthanized and lung tissue was collected to isolate total RNA and used in microarray experiments. Mtb-infected, untreated animals served as controls.
2013-06-28 | E-GEOD-48027 | biostudies-arrayexpress
Project description:The critical role of type I IFN (IFN I ) in viral disease is thoroughly documented while their function in bacterial infection remains ambiguous. General interest in biological functions of IFN I in Mycobacterium tuberculosis (Mtb) infection was raised by the identification of a distinct IFN I gene expression signature in tuberculosis (TB) patients. Here we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Increased survival was accompanied by reduced bacterial burden and ameliorated lung pathology as well as diminished production of proinflammatory IL-1?, among other cytokines. IFNAR1 signaling did not affect T cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung during pulmonary TB. This process was orchestrated by presence of IFNAR1 in both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by CXCL5/CXCL1-driven accumulation of neutrophils into alveoli and subsequently a distinct compartmentalization of Mtb in lung phagocytes. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to unleashed inflammation. Hence, our data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB.
2013-12-31 | GSE44848 | GEO
Project description:Tuberculosis (TB) remains the world’s top infectious killer. Understanding how immune mediators determine the outcome of Mycobacterium tuberculosis infection could facilitate the design of better therapies against this devastating disease. GM-CSF mediates protective immunity against TB but the underlying mechanisms remain elusive. To determine the molecular mechanisms underlying the protective role of GM-CSF during M. tuberculosis infection we performed RNA-sequencing analyses of whole blood and lung samples obtained from C57Bl/6 mice infected with HN878 and treated with anti-GM-CSF monoclonal antibody or isotype control. Uninfected mice were also treated and used as uninfected controls. Three weeks post-infection, whole blood and lungs were harvested from each individual mouse and processed for RNA-sequencing. Transcriptomic analyses revealed that during M. tuberculosis infection GM-CSF regulates the expression of genes associated with neutrophil recruitment and activation and type I IFN-inducible genes, which have been previously associated with TB pathogenesis. Further mechanistical studies showed that disease exacerbation driven by GM-CSF blockade during M. tuberculosis infection was type I IFN and neutrophil-dependent and that over-activation of neutrophils by type I IFN induced NET formation at the site of infection. NETs were also found in necrotic lung lesions from patients with pulmonary TB and type I IFN-driven NET formation correlated with increased disease susceptibility in different mouse models of TB. Our findings reveal an important immune network that may play a central role in determining TB outcome.
2020-09-07 | GSE141205 | GEO