Role of mitochondrial oxidative stress on lymphocyte homeostasis in patients diagnosed with extra-pulmonary tuberculosis (original) (raw)
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Scientific Reports, 2013
To probe how the pathogen Mycobacterium tuberculosis controls host cellular death pathways, we compared mitochondrial responses in human macrophages infected either with the avirulent mycobacterial strain H37Ra, or its virulent counterpart H37Rv. Following H37Ra infection, induction of the apoptotic response was foreshadowed by the early suppression of stress-induced mitochondrial activity. In contrast, mitochondria in H37Rv-infected cells displayed robust activity with increased membrane potential and ATP synthesis. An examination of the mitochondrial proteome revealed that attenuation of mitochondrial function was also coupled with the vigorous activation of bactericidal mechanisms in H37Ra-infected cells. In contrast, augmentation of mitochondrial activity by H37Rv enabled manipulation of host cellular mechanisms to inhibit apoptosis on the one hand, while ensuring fortification against anti-microbial pathways on the other. These results thus provide novel insights into the molecular interplay that facilitates adaptation of virulent mycobacteria within the hostile intracellular milieu of the host macrophage.
Apoptosis
PE/PPE proteins of Mycobacterium tuberculosis (Mtb) target the host organelles to dictate the outcome of infection. This study investigated the significance of PE6/Rv0335c protein's unique C-terminal in causing host mitochondrial perturbations and apoptosis. In-silico analysis revealed that similar to eukaryotic apoptotic Bcl2 proteins, Rv0335c had disordered, hydrophobic C-terminal and two BH3-like motifs in which one was located at C-terminal. Also, Rv0335c's N terminal had mitochondrial targeting sequence. Since, C-terminal of Bcl2 proteins are crucial for mitochondria targeting and apoptosis; it became relevant to evaluate the role of Rv0335c's C-terminal domain in modulating host mitochondrial functions and apoptosis. To confirm this, in-vitro experiments were conducted with Rv0335c whole protein and Rv0335c∆Cterm (C-terminal domain deleted Rv0335c) protein. Rv0335c∆Cterm caused significant reduction in mitochondrial perturbations and Caspasemediated apoptosis of THP1 macrophages in comparison to Rv0335c. However, the deletion of C-terminal domain didn't affect Rv0335c's ability to localize to mitochondria. Nine Ca 2+ binding residues were predicted within Rv0335c and four of them were at the C-terminal. In-vitro studies confirmed that Rv0335c caused significant increase in intracellular calcium influx whereas Rv0335c∆Cterm had insignificant effect on Ca 2+ influx. Rv0335c has been reported to be a TLR4 agonist and, we observed a significant reduction in the expression of TLR4-HLA-DR-TNF-α in response to Rv0335c∆Cterm protein also suggesting the role of Rv0335c's C-terminal domain in host-pathogen interaction. These findings indicate the possibility of Rv0335c as a molecular mimic of eukaryotic Bcl2 proteins which equips it to cause host mitochondrial perturbations and apoptosis that may facilitate pathogen persistence. Keywords Mycobacterium tuberculosis • Rv0335c • Unique C-terminal domain • BH3-like motif • Mitochondria-mediated intrinsic apoptosis Abbreviations (TB) Tuberculosis (Mtb) Mycobacterium tuberculosis (TLR4) Toll: like receptor 4 (MMP) Mitochondrial membrane potential (Cyt C) Cytochrome c (Ca 2+) Calcium
Indian Journal of Tuberculosis, 2019
Conclusion: This pilot study has been able to demonstrate that compared to controls, in newly diagnosed pulmonary tuberculosis patients some mtDNA damage did occur and was probably due to continuous generation of oxidative stress in tuberculous patients. However, sample size is too small to draw any conclusions but definitely a more comprehensive study, by recruiting more number of pulmonary tuberculosis patients is warranted to establish correlation between oxidative stress and mtDNA damage in PTB.
CD4 + T-cell mediated Th1 immune responses are critical for immunity to TB. The immuno-modulatory protein, lymphocyte activation gene-3 (LAG-3) decreases Th1-type immune responses in T-cells. LAG-3 expression is significantly induced in the lungs of macaques with active TB and correlates with increased bacterial burden. Overproduction of LAG-3 can greatly diminish responses and could lead to uncontrolled Mtb replication. To assess the effect of LAG-3 on the progression of Mtb infection, we developed a co-culture system wherein blood-derived macrophages are infected with Mtb and supplemented with macaque blood or lung derived CD4 + T-cells. Silencing LAG-3 signaling in macaque lung CD4 + T-cells enhanced killing of Mtb in co-cultures, accompanied by reduced mitochondrial electron transport and increased IFN-γ expression. Thus, LAG-3 may modulate adaptive immunity to Mtb infection by interfering with the mitochondrial apoptosis pathway. Better understanding this pathway could allow us to circumvent immune features that promote disease.
Scandinavian journal of immunology, 2018
The interaction of a pathogen with its host cell takes place at different levels, including the bioenergetics adaptation of both the pathogen and the host cell in the course of an infection. In this regard, Mycobacterium tuberculosis infection of macrophages induces mitochondrial membrane potential (Δψm) changes and cytochrome c release, depending on the bacteria strain's virulence, and the mitochondrial dynamics is modified by pathogens, such as Listeria monocytogenes. Here, we investigated whether two M. tuberculosis virulence factors are able to induce distinguishable bioenergetics traits in human monocyte-derived macrophages (MDMs). Results showed that Rv1411c (LprG, p27) induced mitochondrial fission, lowered the cell respiratory rate, and modified the kinetics of mitochondrial Ca uptake in response to agonist stimulation. In contrast, Rv1818c (PE_PGRS33) induced mitochondrial fusion, but failed to induce any appreciable effect on cell respiratory rate or mitochondrial Ca u...
Cell, 2019
Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.
PloS one, 2017
The mechanisms of mononuclear phagocyte death have been associated with the permissiveness and resistance to mycobacterial replication, but it remains unknown whether or not they help predict the risk of developing TB. To describe the factors associated with the induction of monocyte mitochondrial and membrane damage in response to PPD as well as determine if this type of damage might predict the susceptibility of developing active tuberculosis in a cohort of household contacts (HHCs) from Medellin, Colombia from 2005 to 2008. The prospective cohort study contains 2060 HHCs patients with pulmonary tuberculosis who were meticulously followed for two years. A survey of the socio-demographic, clinical, epidemiological factors and blood samples were collected. Mononuclear cell cultures were stimulated with or without PPD and the type of monocyte death was determined by the flow of cytometry, an indicator was also used for its analysis. Logistic regression was adjusted by the Generalized...
bioRxiv (Cold Spring Harbor Laboratory), 2024
Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (M.tb), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4 + T cell response, is central to host immunity against M.tb. Chronic infections, such as M.tb, as well as aging promote T cell exhaustion and senescence, which can impair immune control and promote progression to TB disease. Mitochondrial dysfunction contributes to T cell dysfunction, both in aging and chronic infections and diseases. Mitochondrial perturbations can disrupt cellular metabolism, enhance oxidative stress, and impair T-cell signaling and effector functions. This study examined the impact of mitochondrial transplantation (mito-transfer) on CD4 + T cell differentiation and function using aged mouse models and human CD4 + T cells from elderly individuals. Our study revealed that mito-transfer in naïve CD4 + T cells promoted the generation of protective effector and memory CD4 + T cells during M.tb infection in mice. Further, mito-transfer enhanced the function of elderly human T cells by increasing their mitochondrial mass and modulating cytokine production, which in turn reduced exhaustion and senescence cell markers. Our results suggest that mito-transfer could be a novel strategy to reestablish aged CD4 + T cell function, potentially improving immune responses in the elderly and chronic TB patients, with a broader implication for other diseases where mitochondrial dysfunction is linked to T cell exhaustion and senescence.
Cell, 2013
Tumor necrosis factor (TNF) constitutes a critical host defense against tuberculosis, but its excess is also implicated in tuberculosis pathogenesis in zebrafish and humans. Using the zebrafish, we elucidate the pathways by which TNF mediates tuberculosis pathogenesis. TNF excess induces mitochondrial reactive oxygen species (ROS) in infected macrophages through RIP1-RIP3-dependent pathways. While initially increasing macrophage microbicidal activity, ROS rapidly induce programmed necrosis (necroptosis) and release mycobacteria into the growth-permissive extracellular milieu. TNF-induced necroptosis occurs through two pathways: modulation of mitochondrial cyclophilin D, implicated in mitochondrial permeability transition pore formation, and acid sphingomyelinase-mediated ceramide production. Combined genetic blockade of cyclophilin D and acid sphingomyelinase renders the high TNF state hyperresistant by preventing macrophage necrosis while preserving increased microbicidal activity. Similarly, the cyclophilin D-inhibiting drug alisporivir and the acid sphingomyelinase-inactivating drug, desipramine, synergize to reverse susceptibility, suggesting the therapeutic potential of these orally active drugs against tuberculosis and possibly other TNF-mediated diseases.