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Autophagy Jun 2022Mitophagy is a selective autophagy mechanism for eliminating damaged mitochondria and plays a crucial role in the immune evasion of some viruses and bacteria. Here, we...
Mitophagy is a selective autophagy mechanism for eliminating damaged mitochondria and plays a crucial role in the immune evasion of some viruses and bacteria. Here, we report that () utilizes host mitophagy to suppress host xenophagy to enhance its intracellular survival. is the causative agent of animal tuberculosis and human tuberculosis. In the current study, we show that induces mitophagy in macrophages, and the induction of mitophagy is impaired by PINK1 knockdown, indicating the PINK1-PRKN/Parkin pathway is involved in the mitophagy induced by . Moreover, the survival of in macrophages and the lung bacterial burden of mice are restricted by the inhibition of mitophagy and are enhanced by the induction of mitophagy. Confocal microscopy analysis reveals that induction of mitophagy suppresses host xenophagy by competitive utilization of p-TBK1. Overall, our results suggest that induction of mitophagy enhances growth while inhibition of mitophagy improves growth restriction. The findings provide a new insight for understanding the intracellular survival mechanism of in the host. BMDM: mouse bone marrow-derived macrophage; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; BCL2L13: BCL2-like 13 (apoptosis facilitator); CCCP: carbonyl cyanide m-cholorophenyl hydrazone; FUNDC1: FUN14 domain-containing 1; FKBP8: FKBP506 binding protein 8; HCV: hepatitis C virus; HBV: hepatitis B virus; IFN: interferon; ; Mtb: ; Mdivi-1: mitochondrial division inhibitor 1; PINK1: PTEN-induced putative kinase 1; TBK1: TANK-binding kinase 1; TUFM: Tu translation elongation factor, mitochondrial; TEM: transmission electron microscopy.
Topics: Animals; Macroautophagy; Macrophages; Membrane Proteins; Mice; Mitochondrial Proteins; Mitophagy; Mycobacterium bovis
PubMed: 34720021
DOI: 10.1080/15548627.2021.1987671 -
Cell Jan 2018The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for...
The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remain unknown. Here, we show that access of Bacillus Calmette-Guérin (BCG) to the bone marrow (BM) changes the transcriptional landscape of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), leading to local cell expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, BCG-educated HSCs generate epigenetically modified macrophages that provide significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice, as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCG-induced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.
Topics: Animals; Cell Line; Cells, Cultured; Epigenesis, Genetic; Hematopoiesis; Hematopoietic Stem Cells; Immunity, Innate; Immunologic Memory; Mice; Mice, Inbred C57BL; Mycobacterium bovis; Transcriptome; Tuberculosis
PubMed: 29328912
DOI: 10.1016/j.cell.2017.12.031 -
Cell Reports May 2023Bacillus Calmette-Guérin (BCG) vaccination is a prototype model for the study of trained immunity (TI) in humans, and results in a more effective response of innate...
Bacillus Calmette-Guérin (BCG) vaccination is a prototype model for the study of trained immunity (TI) in humans, and results in a more effective response of innate immune cells upon stimulation with heterologous stimuli. Here, we investigate the heterogeneity of TI induction by single-cell RNA sequencing of immune cells collected from 156 samples. We observe that both monocytes and CD8 T cells show heterologous transcriptional responses to lipopolysaccharide, with an active crosstalk between these two cell types. Furthermore, the interferon-γ pathway is crucial in BCG-induced TI, and it is upregulated in functional high responders. Data-driven analyses and functional experiments reveal STAT1 to be one of the important transcription factors for TI shared in all identified monocyte subpopulations. Finally, we report the role of type I interferon-related and neutrophil-related TI transcriptional programs in patients with sepsis. These findings provide comprehensive insights into the importance of monocyte heterogeneity during TI in humans.
Topics: Humans; Mycobacterium bovis; BCG Vaccine; Trained Immunity; CD8-Positive T-Lymphocytes; Interferon-gamma; Immunity, Innate
PubMed: 37155329
DOI: 10.1016/j.celrep.2023.112487 -
Vaccine Dec 2021The Mycobacterium bovis Bacillus Calmette et Guérin (BCG) vaccine was generated in 1921 with the efforts of a team of investigators, Albert Calmette and Camille... (Review)
Review
The Mycobacterium bovis Bacillus Calmette et Guérin (BCG) vaccine was generated in 1921 with the efforts of a team of investigators, Albert Calmette and Camille Guérin, dedicated to the determination to develop a vaccine against active tuberculosis (TB) disease. Since then, BCG vaccination is used globally for protection against childhood and disseminated TB; however, its efficacy at protecting against pulmonary TB in adult and aging populations is highly variable. Due to the BCG generated immunity, this vaccine later proved to have an antitumor activity; though the standing mechanisms behind are still unclear. Recent studies indicate that both innate and adaptive cell responses may play an important role in BCG eradication and prevention of bladder cancer. Thus, cells such as natural killer (NK) cells, macrophages, dendritic cells, neutrophils but also MHC-restricted CD4 and CD8 T cells and γδ T cells may play an important role and can be one the main effectors in BCG therapy. Here, we discuss the role of BCG therapy in bladder cancer and other cancers, including current strategies and their impact on the generation and sustainability of protective antitumor immunity against bladder cancer.
Topics: BCG Vaccine; CD8-Positive T-Lymphocytes; Child; Humans; Mycobacterium bovis; Tuberculosis; Urinary Bladder Neoplasms
PubMed: 34627626
DOI: 10.1016/j.vaccine.2021.09.053 -
Cells Aug 2023is a facultative intracellular bacterium that produces cellular necrosis in granulomatous lesions in bovines. Although -induced inflammation actively participates in...
is a facultative intracellular bacterium that produces cellular necrosis in granulomatous lesions in bovines. Although -induced inflammation actively participates in granuloma development, its role in necrotic cell death and in bovine macrophages has not been fully explored. In this study, we evaluate the effect of AN5 and its culture filtrate protein extract (CFPE) on inflammasome activation in bovine macrophages and its consequences on cell death. Our results show that both stimuli induce necrotic cell death starting 4 h after incubation. CFPE treatment and infection also induce the maturation of IL-1β (>3000 pg/mL), oligomerization of ASC (apoptosis-associated speck-like protein containing CARD), and activation of caspase-1, following the canonical activation pathway of the NLRP3 inflammasome. Inhibiting the oligomerization of NLRP3 and caspase-1 decreases necrosis among the infected or CFPE-stimulated macrophages. Furthermore, histological lymph node sections of bovines naturally infected with contained cleaved gasdermin D, mainly in macrophages and giant cells within the granulomas. Finally, the induction of cell death (apoptosis and pyroptosis) decreased the intracellular bacteria count in the infected bovine macrophages, suggesting that cell death helps to control the intracellular growth of the mycobacteria. Our results indicate that induces pyroptosis-like cell death that is partially related to the NLRP3 inflammasome activation and that the cell death process could control bacterial growth.
Topics: Cattle; Animals; Mycobacterium bovis; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Necrosis; Cell Death; Caspase 1; Macrophages
PubMed: 37626889
DOI: 10.3390/cells12162079 -
Emerging Infectious Diseases Mar 2021Mycobacterium bovis infection in wildlife species occurs worldwide. However, few cases of M. bovis infection in captive elephants have been reported. We describe 2...
Mycobacterium bovis infection in wildlife species occurs worldwide. However, few cases of M. bovis infection in captive elephants have been reported. We describe 2 incidental cases of bovine tuberculosis in free-ranging African elephants (Loxodonta africana) from a tuberculosis-endemic national park in South Africa and the epidemiologic implications of these infections.
Topics: Animals; Animals, Wild; Elephants; Mycobacterium bovis; South Africa; Tuberculosis
PubMed: 33622488
DOI: 10.3201/eid2703.204729 -
Emerging Infectious Diseases Mar 2021We analyzed 98 Mycobacterium tuberculosis complex isolates collected in 2 regions of Algeria in 2015-2018 from 93 cases of pulmonary tuberculosis. We identified 93/98...
We analyzed 98 Mycobacterium tuberculosis complex isolates collected in 2 regions of Algeria in 2015-2018 from 93 cases of pulmonary tuberculosis. We identified 93/98 isolates as M. tuberculosis lineage 4 and 1 isolate as M. tuberculosis lineage 2 (Beijing). We confirmed 4 isolates as M. bovis by whole-genome sequencing.
Topics: Algeria; Beijing; Humans; Mycobacterium bovis; Mycobacterium tuberculosis; Tuberculosis, Pulmonary
PubMed: 33622469
DOI: 10.3201/eid2703.191823 -
CMAJ : Canadian Medical Association... Oct 2023
Topics: Female; Humans; Adolescent; Mycobacterium bovis; Mycobacterium Infections, Nontuberculous; Lymphadenitis
PubMed: 37903520
DOI: 10.1503/cmaj.230700-f -
Postepy Higieny I Medycyny... Dec 2016Tuberculosis was, and still is, one of the main causes of morbidity and mortality in the world. Thus it still remains a public health priority. Nonetheless, without a... (Review)
Review
Tuberculosis was, and still is, one of the main causes of morbidity and mortality in the world. Thus it still remains a public health priority. Nonetheless, without a newly developed vaccine, it is rather unlikely to be easily resolved. The only available vaccine against tuberculosis (BCG) has been used for nearly 100 years. Currently a variety of BCG substrains are used by many manufacturers in the world. All these substrains were obtained from a single parental strain of Mycobacterium bovis. Attempts to explain the complete mechanisms of attenuation, as well as tracing the microevolution resulting from the different distribution time and conditions of production of BCG vaccines in the different parts of the world, might explain the differences in the observed efficacy of vaccines produced with different substrains. The most important marker associated with attenuation of virulent M. bovis is the loss of the RD1 region observed in all BCG substrains. Among other attenuation markers, still not completely identified, accumulation of SNP mutations seems to be an important one. The different number of passages and culture conditions of the parental vaccine strain have led to there being about 50 different sister vaccine BCG substrains throughout the world. Among them, there are "early strains", distributed until 1927, and "later strains" with the RD2 deletion obtained during 1927‑1961. It has also been found that 22 regions containing 52 genes were lost during the distribution of sister substrains during the period 1924‑1966. Genetic differences due to selection pressure, revealing specific microevolutionary traits, may explain the variability in immunogenicity and residual virulence of each vaccine BCG substrain.
Topics: BCG Vaccine; Genome, Bacterial; Humans; Mycobacterium bovis; Mycobacterium tuberculosis; Tuberculosis; Virulence
PubMed: 28026828
DOI: No ID Found -
Saudi Medical Journal Jul 2021To optimize an enzyme-linked immunosorbent assay (ELISA) for measuring the HspX protein (α-crystallin) levels and then evaluate its correlation with the accumulation of...
OBJECTIVES
To optimize an enzyme-linked immunosorbent assay (ELISA) for measuring the HspX protein (α-crystallin) levels and then evaluate its correlation with the accumulation of lipid bodies in ( during hypoxia and exposure to nitric oxide.
METHODS
This study was conducted at Prince Sultan Military Medical City, Riyadh, Saudi Arabia between 2016 and 2017. We first optimized ELISA conditions for the detection of HspX. The optimization protocol focused on minimizing concentrations of the capture antibody, detection antibody, and conjugated secondary antibody, and determining the minimum detection limit of the antigen, HspX. Bacteria were grown either in shaking culture or in stationary flasks mimicking hypoxic environments. A standard Bradford assay was used to determine the total protein and HspX was detected using the optimized ELISA protocol. The effect of hypoxic environment and nitric oxide on the levels of HspX and lipid bodies, detected by staining with Nile red, was also evaluated.
RESULTS
An optimized ELISA protocol was established for the detection of HspX from . Exposure to nitric oxide and hypoxic conditions led to an increase in the levels of HspX protein. The increase in HspX associated with nitric oxide treatment and hypoxic conditions correlated with higher levels of lipid bodies mainly found in pathogenic mycobacteria.
CONCLUSIONS
The optimized ELISA protocol in this study can detect HspX protein levels in growing in normal and hypoxic environments. Importantly, hypoxia led to enhanced expression of HspX protein, which correlated with the enhanced production of lipid bodies. Lipid body production is a survival strategy of pathogenic mycobacteria.
Topics: Antigens, Bacterial; Bacterial Proteins; Enzyme-Linked Immunosorbent Assay; Humans; Mycobacterium bovis; Mycobacterium tuberculosis; Saudi Arabia
PubMed: 34187915
DOI: 10.15537/smj.2021.42.7.20200582