MiR-342 controls Mycobacterium tuberculosis susceptibility by modulating inflammation and cell death
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Beibei Fu
PROVIDER: S-SCDT-EMBOR-2020-52252V1 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that places a heavy strain on public health. Host susceptibility to Mtb is modulated by macrophages, which regulate the balance between cell apoptosis and necrosis. However, the role of molecular switches that modulate apoptosis and necrosis during Mtb infection remains unclear. Here, we show that Mtb-susceptible mice and TB patients have relatively low miR-342-3p expression, while mice with miR-342-3p overexpression are more resistant to Mtb. We demonstrate that the miR-342-3p/SOCS6 axis regulates anti-Mtb immunity by increasing the production of inflammatory cytokines and chemokines. Most importantly, the miR-342-3p/SOCS6 axis participates in the switching between Mtb-induced apoptosis and necrosis through A20-mediated K48-linked ubiquitination and RIPK3 degradation. Our findings reveal several strategies by which the host innate immune system controls intracellular Mtb growth via the miRNA-mRNA network and pave the way for host-directed therapies targeting these pathways.
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Project description:The molecular mechanisms that control innate cell recruitment during chronic infection and inflammation, such as tuberculosis (TB), are incompletely understood. During TB, myeloid cells infiltrate the lung and sustain local inflammation. We identified microRNA (miR)-223 as one of the most abundant noncoding RNAs in lung parenchyma of TB patients and susceptible mice. MiR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation, by directly targeting the chemoattractants CXCL2, CCL3 and IL-6. Our study reveals an essential role for a single miR in TB. Moreover, we identify new targets for and assign novel biological functions to miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR223 is critical for control of TB and probably other nonresolving inflammatory diseases.
2014-04-21 | GSE39163 | GEO
Project description:The molecular mechanisms that control innate cell recruitment during chronic infection and inflammation, such as tuberculosis (TB), are incompletely understood. During TB, myeloid cells infiltrate the lung and sustain local inflammation. We identified microRNA (miR)-223 as one of the most abundant noncoding RNAs in lung parenchyma of TB patients and susceptible mice. MiR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation, by directly targeting the chemoattractants CXCL2, CCL3 and IL-6. Our study reveals an essential role for a single miR in TB. Moreover, we identify new targets for and assign novel biological functions to miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR223 is critical for control of TB and probably other nonresolving inflammatory diseases. MicroRNAs expression analysis in whole blood from 8 TB and 8 TST+ subjects. The samples were collected at Makerere University in Kampala, Uganda. Gene expression analysis of whole blood and lung tissue of C57/BL6 and miR-223-/- mouse strains (8-12 weeks of age) after Mtb aerosol infection. Samples were collected at 7, 14 and 21 days post infection.
2014-04-21 | E-GEOD-39163 | biostudies-arrayexpress
Project description:BackgroundDepletion of T cells following infection by Mycobacterium tuberculosis (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised.Methodology/principal findingsWe found that lymphopenia (<1.5 × 10(9) cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cell-free supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-α or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtb-secreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from Mycobacterium bovis Bacille de Calmette et Guerin (BCG)- infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system.ConclusionsMtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.
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