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Major intracellular pathways activated in macrophages following exposure to pathogenic mycobacteria or their components and leading to proinflammatory cytokine secretion.
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Mycobacterium tuberculosis is the etiological agent of tuberculosis. It is a pathogen that continues to draw international concerns particularly due to the emergence of multi-drug resistance and to the difficulties associated with the diagnosis and treatment of latent tuberculosis. A key process in the pathogenesis of this disease is the interactio...
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Tuberculosis is a severe contagious disease caused by Mycobacterium tuberculosis (Mtb). To develop new vaccines and medicine against TB, there is an urgent need to provide insights into the mechanisms by which Mtb induces tuberculosis. In this study, we found that secreted Mtb virulence factor MptpB significantly enhanced the survival of H37Rv in m...
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... Its ligand interaction has immunosuppressive effects by stimulating IL-10 production, which ultimately inhibits the production of IL-12. ManLAM also modulates M. tuberculosis-induced macrophage apoptosis, which allows the bacteria to survive and multiply within macrophages (52). ...
Although nontuberculous mycobacteria (NTM) are considered opportunistic infections, incidence and prevalence of NTM infection is increasing worldwide becoming a major public health threat. Innate immunity plays an essential role in mediating the initial host response against these intracellular bacteria. Specifically, macrophages phagocytose and eliminate NTM and act as antigen presenting cells which trigger downstream activation of cellular and humoral adaptive immune responses. Identification of macrophage receptors, mycobacterial ligands, phagosome maturation, autophagy/necrosis, and escape mechanisms are important components of this immunity network. The role of the macrophage in mycobacterial disease has mainly been studied in TB, but, limited information exists on its role in NTM. In this review, we focus on NTM immunity, the role of macrophages, and host interaction in NTM infection.
... Then, the phagosome proceeds to fuse with the lysosome which further acidifies and degrades bacteria via enzymatic processes. However, Mtb alters the phagosome trafficking pathway through numerous methods, preventing its own elimination by this process [22,23]. Mtb uses phosphatidylinositol mannoside (PIM) to stimulate Rab14, promoting phagosome fusion with an early endosome, resulting in the prevention of phagosomal maturation and acidification [24]. ...
Tuberculosis (TB) is a serious infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). The current therapy consists of a combination of antibiotics over the course of four months. Current treatment protocols run into problems due to the growing antibiotic resistance of Mtb and poor compliance to the multi-drug-resistant TB treatment protocol. New treatments are being investigated that target host intracellular processes that could be effective in fighting Mtb infections. Autophagy is an intracellular process that is involved in eliminating cellular debris, as well as intracellular pathogens. Mammalian target of rapamycin (mTOR) is an enzyme involved in inhibiting this pathway. Modulation of mTOR and the autophagy cellular machinery are being investigated as potential therapeutic targets for novel Mtb treatments. In this review, we discuss the background of Mtb pathogenesis, including its interaction with the innate and adaptive immune systems, the mTOR and autophagy pathways, the interaction of Mtb with these pathways, and finally, the drug everolimus, which targets these pathways and is a potential novel therapy for TB treatment.
... Alveolar macrophages represent the first line of defense against many airborne pathogens and inhaled environmental particles. The reaction of AMs after exposure to silica (70,(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115) has been extensively studied. The tissue remodeling and formation of granulomas in response to exposure to both silica and Mtb suggest that similar mechanisms are involved in the elimination process in individuals exposed to silica or Mtb separately (116)(117)(118). ...
Exposure to silica and the consequent development of silicosis are well-known health problems in countries with mining and other dust producing industries. Apart from its direct fibrotic effect on lung tissue, chronic and immunomodulatory character of silica causes susceptibility to tuberculosis (TB) leading to a significantly higher TB incidence in silica-exposed populations. The presence of silica particles in the lung and silicosis may facilitate initiation of tuberculous infection and progression to active TB, and exacerbate the course and outcome of TB, including prognosis and survival. However, the exact mechanisms of the involvement of silica in the pathological processes during mycobacterial infection are not yet fully understood. In this review, we focus on the host's immunological response to both silica and Mycobacterium tuberculosis, on agents of innate and adaptive immunity, and particularly on silica-induced immunological modifications in co-exposure that influence disease pathogenesis. We review what is known about the impact of silica and Mycobacterium tuberculosis or their co-exposure on the host's immune system, especially an impact that goes beyond an exclusive focus on macrophages as the first line of the defense. In both silicosis and TB, acquired immunity plays a major role in the restriction and/or elimination of pathogenic agents. Further research is needed to determine the effects of silica in adaptive immunity and in the pathogenesis of TB.
... Some strains of TB bacteria might be more transmissible. Other factors that can influence the risk of transmission include: [14] [15] Frequency and duration of exposure(s) to the case. ...
... Galectin 3 is also activated by NF-kB, which controls its expression [10]. As mycobacterial infection to the macrophage is known to regulate MAPK, NF-kB, ERK [11,12], this is the first report exhibiting the role of PtkA mediated Galectin 3 signaling after mycobacterial infection in macrophage. ...
Mycobacterium tuberculosis (MTB) is a successful pathogen which increases persistence inside the host macrophage by subverting its defence mechanism. Mycobacteria regulate the pathogenesis and intracellular survival by controlling its interaction with host protein(s). Galectin 3 is a member of the β-galactoside binding gene family which is involved in several biological functions. In the present study we have expressed the mycobacterial protein tyrosine kinase (PtkA) in the cytosol of host macrophages through a eukaryotic promoter vector and found that it down-regulates Galectin 3. Infection by ptkA knocked-out (KO) mycobacterial strain shows increased level of Galectin 3 in the cytosol of macrophages. PtkA regulates Galectin 3 level and stimulates host macrophage through MEK-JNK-cJUN pathway and initiates early apoptosis in H37Ra infected macrophage. The ptkA KO strain showed decreased progression of apoptosis confirming Galectin 3 as anti-apoptotic molecule. The intracellular survival was also found to be impaired in the mice infected with ptkA KO mycobacteria. The hypothesis was also confirmed by looking at the intracellular survival of mycobacteria in Galectin 3 silenced macrophages. The overall findings suggest the significance of Galectin 3 and PtkA interaction in intracellular persistence of mycobacteria.
... Galectin 3 is also activated by NF-kB, which controls its expression [10]. As mycobacterial infection to the macrophage is known to regulate MAPK, NF-kB, ERK [11,12], this is the first report exhibiting the role of PtkA mediated Galectin 3 signaling after mycobacterial infection in macrophage. ...
Mycobacterium tuberculosis (MTB) is a successful pathogen which increases persistence inside the host macrophage by subverting its defence mechanism. Mycobacteria regulate the pathogenesis and intracellular survival by controlling its interaction with host protein(s). Galectin 3 is a member of the β-galactoside binding gene family which is involved in several biological functions. In the present study, we have expressed the mycobacterial protein tyrosine kinase (PtkA) in the cytosol of host macrophages through a eukaryotic promoter vector and found that it down-regulates Galectin 3. Infection by ptkA knocked-out (KO) mycobacterial strain shows the increased level of Galectin 3 in the cytosol of macrophages. PtkA regulates Galectin 3 level and stimulates host macrophage through MEK-JNK-cJUN pathway and initiates early apoptosis in H37Ra infected macrophage. The ptkA KO strain showed the decreased progression of apoptosis confirming Galectin 3 as an anti-apoptotic molecule. The intracellular survival was also found to be impaired in the mice infected with ptkA KO mycobacteria. The hypothesis was also confirmed by looking at the intracellular survival of mycobacteria in Galectin 3 silenced macrophages. The overall findings suggest the significance of Galectin 3 and PtkA interaction in the intracellular persistence of mycobacteria
Tuberculosis (TB) remains a major global health problem. Conventional treatments fail either because of poor patient compliance with the drug regimen or due to the emergence of multidrug-resistant TB. Thus, not only has the discovery of new compounds and new therapeutic strategies been the focus of many types of research but also new routes of administration. Pulmonary drug delivery possesses many advantages, including the noninvasive route of administration, low metabolic activity, and control environment for systemic absorption, and avoids first-pass metabolism. The use of lipid nanocarriers provides several advantages such as protection of the compound's degradation, increased bioavailability, and controlled drug release. In this study, we review some points related to how the use of lipid nanocarriers can improve TB treatment with inhaled nanomedicines. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems with nanocarriers targeting alveolar macrophages.
