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NLRP3 with Mtb

Eduardo P Amaral, Nicolas Riteau, Mahtab Moayeri, Nolan Maier, Katrin D Mayer-Barber, Rosana M Pereira, Silvia L Lage, Andre Kubler, William R Bishai, Maria R D'Império-Lima, Alan Sher, Bruno B Andrade
Lysosomal cathepsin B (CTSB) has been proposed to play a role in the induction of acute inflammation. We hypothesised that the presence of active CTSB in the cytosol is crucial for NLRP3-inflammasome assembly and, consequently, for mature IL-1β generation after mycobacterial infection in vitro . Elevated levels of CTSB was observed in the lungs of mice and rabbits following infection with Mycobacterium tuberculosis (Mtb) H37Rv as well as in plasma from acute tuberculosis patients. H37Rv-infected murine bone marrow-derived macrophages (BMDMs) displayed both lysosomal leakage, with release of CTSB into the cytosol, as well as increased levels of mature IL-1β...
2018: Frontiers in Immunology
Haibo Su, Zhen Zhang, Zijian Liu, Baozhou Peng, Cong Kong, Honghai Wang, Zhi Zhang, Ying Xu
Targeting of Mycobacterium tuberculosis (MTB) PE/PPE antigens that induce type 1 helper T cell (Th1) and Th17 responses represents a crucial strategy for the development of tuberculosis (TB) vaccines. However, only a few PE/PPE antigens induce these responses. Here, we sought to determine how the cell wall-associated antigen PPE60 (Rv3478) activates dendritic cell (DC) maturation and T-cell differentiation. We observed that PPE60 induces DC maturation by augmenting the protein expression of cluster of differentiation 80 (CD80) and CD86 and major histocompatibility complex (MHC) class I and MHC class II on the cell surface...
June 29, 2018: Journal of Biological Chemistry
Naveed Sabir, Tariq Hussain, Syed Zahid Ali Shah, Deming Zhao, Xiangmei Zhou
Tuberculosis (TB) is a major health threat to the human population worldwide. The etiology of the disease is Mycobacterium tuberculosis (Mtb), a highly successful intracellular pathogen. It has the ability to manipulate the host immune response and to make the intracellular environment suitable for its survival. Many studies have addressed the interactions between the bacteria and the host immune cells as involving many immune mediators and other cellular players. Interferon-β (IFN-β) signaling is crucial for inducing the host innate immune response and it is an important determinant in the fate of mycobacterial infection...
December 16, 2017: International Journal of Molecular Sciences
Qingwen Zhang, Jinxia Sun, Yuli Wang, Weigang He, Lixin Wang, Yuejuan Zheng, Jing Wu, Ying Zhang, Xin Jiang
Tuberculosis (TB) remains a leading killer worldwide among infectious diseases and the effective control of TB is still challenging. Autophagy is an intracellular self-digestion process which has been increasingly recognized as a major host immune defense mechanism against intracellular microorganisms like Mycobacterium tuberculosis (Mtb) and serves as a key negative regulator of inflammation. Clinically, chronic inflammation surrounding Mtb can persist for decades leading to lung injury that can remain even after successful treatment...
2017: Frontiers in Microbiology
Andreas Kupz, Ulrike Zedler, Manuela Stäber, Carolina Perdomo, Anca Dorhoi, Roland Brosch, Stefan H E Kaufmann
IFN-γ is a critical mediator of host defense against Mycobacterium tuberculosis (Mtb) infection. Antigen-specific CD4+ T cells have long been regarded as the main producer of IFN-γ in tuberculosis (TB), and CD4+ T cell immunity is the main target of current TB vaccine candidates. However, given the recent failures of such a TB vaccine candidate in clinical trials, strategies to harness CD4-independent mechanisms of protection should be included in future vaccine design. Here, we have reported that noncognate IFN-γ production by Mtb antigen-independent memory CD8+ T cells and NK cells is protective during Mtb infection and evaluated the mechanistic regulation of IFN-γ production by these cells in vivo...
June 1, 2016: Journal of Clinical Investigation
D Souza de Lima, M M Ogusku, A Sadahiro, A Pontillo
Tuberculosis (TB) continues to be a major public health problem. An estimated one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb) but remains asymptomatic (latent TB) and only 5% to 10% of these latent individuals will develop active pulmonary TB. Factors affecting the balance between latent and active TB are mostly unknown, even if host genome has been shown to contribute to the outcome of Mtb response. Acute inflammation and Th1 response are important in the early clearance of the bacteria as it was emphasized by the association between immune genes (i...
July 2016: Infection, Genetics and Evolution
Anna K Coussens, Robert J Wilkinson, Adrian R Martineau
Adjunctive vitamin D treatment for pulmonary tuberculosis enhances resolution of inflammation but has modest effects on bacterial clearance. Sodium 4-phenylbutyrate (PBA) is in clinical use for a range of conditions and has been shown to synergise with vitamin D metabolites to upregulate cathelicidin antimicrobial peptide (CAMP) expression. We investigated whether clinically attainable plasma concentrations of PBA (0.4-4 mM) directly affect Mycobacterium tuberculosis (Mtb) growth and human macrophage and PBMC response to infection...
July 2015: PLoS Pathogens
Henrik Andersson, Blanka Andersson, Daniel Eklund, Eyler Ngoh, Alexander Persson, Kristoffer Svensson, Maria Lerm, Robert Blomgran, Olle Stendahl
Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during the initial manifestation of tuberculosis. Since the adaptive immune response to Mtb is delayed, innate immune cells such as macrophages and neutrophils mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Since anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens, we therefore investigated how uptake of apoptotic neutrophils modulates the function of Mtb-activated human macrophages...
2014: PloS One
Volker Briken, Sarah E Ahlbrand, Swati Shah
The production of IL-1β during the infection with Mycobacterium tuberculosis (Mtb) is important for successful host immune defense. In macrophages and dendritic cells the host cell inflammasome is crucial for generation of secreted IL-1β in response to Mtb infections. In these cell types Mtb infection only activates the NLRP3-inflammasome. New reports demonstrate that nitric oxide has an important function in the negative regulation of the NLRP3-inflammasome to reduce tissue damage during Mtb infections. The type I interferon, IFN-β, is induced after Mtb infections and can also suppress NLRP3-inflammasome activation...
2013: Frontiers in Cellular and Infection Microbiology
Mark Verway, Manuella Bouttier, Tian-Tian Wang, Marilyn Carrier, Mario Calderon, Beum-Soo An, Emmanuelle Devemy, Fiona McIntosh, Maziar Divangahi, Marcel A Behr, John H White
Although vitamin D deficiency is a common feature among patients presenting with active tuberculosis, the full scope of vitamin D action during Mycobacterium tuberculosis (Mtb) infection is poorly understood. As macrophages are the primary site of Mtb infection and are sites of vitamin D signaling, we have used these cells to understand the molecular mechanisms underlying modulation of the immune response by the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D). We found that the virulent Mtb strain H37Rv elicits a broad host transcriptional response...
2013: PLoS Pathogens
Hye-Mi Lee, Junghee Kang, Sung Joong Lee, Eun-Kyeong Jo
The inflammasome is a multimolecular complex that orchestrates the activation of proinflammatory caspases and interleukin (IL)-1β, which is generally increased in the cerebrospinal fluids of patients with tuberculous meningitis. However, it has not been clarified whether mycobacteria can activate the inflammasome and induce IL-1β maturation in microglia. In this study, we found that the priming of primary murine microglial cells with conditioned media from cultures of macrophages infected with Mycobacterium tuberculosis (Mtb) led to robust activation of caspase-1 and IL-1β secretion after Mtb stimulation...
March 2013: Glia
Hana Abdalla, Lalitha Srinivasan, Swati Shah, Katrin D Mayer-Barber, Alan Sher, Fayyaz S Sutterwala, Volker Briken
BACKGROUND: Interleukin-1β (IL-1β) is important for host resistance against Mycobacterium tuberculosis (Mtb) infections. The response of the dendritic cell inflammasome during Mtb infections has not been investigated in detail. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that Mtb infection of bone marrow-derived dendritic cells (BMDCs) induces IL-1β secretion and that this induction is dependent upon the presence of functional ASC and NLRP3 but not NLRC4 or NOD2...
2012: PloS One
Anca Dorhoi, Geraldine Nouailles, Sabine Jörg, Kristine Hagens, Ellen Heinemann, Lydia Pradl, Dagmar Oberbeck-Müller, Maria Adelaida Duque-Correa, Stephen T Reece, Jürgen Ruland, Roland Brosch, Jürg Tschopp, Olaf Gross, Stefan H E Kaufmann
As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1β in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulence-associated RD1 locus of MTB...
February 2012: European Journal of Immunology
Amanda Welin, Daniel Eklund, Olle Stendahl, Maria Lerm
Mycobacterium tuberculosis (Mtb) infects lung macrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating an environment suitable for intracellular replication and spread to adjacent cells. The role of host cell death during Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keeping the host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the host macrophage to allow infection of neighboring cells. Since mycobacteria activate the NLRP3 inflammasome in macrophages, we investigated whether Mtb could induce one of the recently described inflammasome-linked cell death modes pyroptosis and pyronecrosis...
2011: PloS One
Erin McElvania Tekippe, Irving C Allen, Paul D Hulseberg, Jonathan T Sullivan, Jessica R McCann, Matyas Sandor, Miriam Braunstein, Jenny P-Y Ting
The NLR gene family mediates host immunity to various acute pathogenic stimuli, but its role in chronic infection is not known. This paper addressed the role of NLRP3 (NALP3), its adaptor protein PYCARD (ASC), and caspase-1 during infection with Mycobacterium tuberculosis (Mtb). Mtb infection of macrophages in culture induced IL-1beta secretion, and this requires the inflammasome components PYCARD, caspase-1, and NLRP3. However, in vivo Mtb aerosol infection of Nlrp3(-/-), Casp-1(-/-), and WT mice showed no differences in pulmonary IL-1beta production, bacterial burden, or long-term survival...
August 20, 2010: PloS One
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