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Table 1 Exosomes (vesicles) derived from Mycobacterium and host-derived (macrophages and neutrophils)

From: The emerging role of exosomal miRNAs as a diagnostic and therapeutic biomarker in Mycobacterium tuberculosis infection

Mycobacterium Macrophages/Neutrophils
The vesicles derived from mycobacterium were first visualized by scanning electron microscopy (SEM). These vesicles were discovered in the extracellular matrix of Mycobacterium ulcerans biofilm and from biopsies of Buruli ulcer-like lesions in infected mice. Also, these vesicles carried the sole virulence factor accountable for Bureli ulcer, the lipid toxin mycolactone, and, accordingly, presented potent cytotoxic activity (Marsollier et al. 2007; George et al. 1999) The exosomes originate from macrophages infected with Mycobacterium avium carry diverse antigens of both M. avium and the host cell. In macrophages, they are implicated in the initiation and creation of inflammatory responses. The interplay among the exosomes derived from macrophages infected with M. avium and phagocytosis (macrophage), cytokine production, immunostimulation, and apoptosis was investigated. In macrophages treated with exosomes (derived from macrophages infected with M. avium), the phagocytosis of dextran by macrophages was enhanced. Besides, the expression of CD40, CD80, CD81, CD86, Human Leukocyte Antigen (HLA)-DR, and most notably, CD195 was improved. Moreover, Interleukin (IL)-6, IL-8, IL-10, IFN-γ, and tumour necrosis factor α (TNFα) were increased by stimulated macrophages (Wang et al. 2015)
The investigation results showed that the extensive cell envelope restructuring associated with vesicle discharge correlated with modulation of cell surface lipid biosynthesis and peptidoglycan remodelings. Comparative transcriptomics explained common high expression of the iniBAC operon associated with high vesicle generation in Mycobacterium tuberculosis (Mtb) cells. Vesicle generation examination demonstrated that the dynamin-like proteins (DLPs) encoded by this operon, IniA, and IniC, are required to release extracellular vesicles (EVs) by Mtb in culture and infected macrophages (Gupta et al. 2020) EVs were originated from J774A.1 macrophages infected with Mtb H37Rv varied in size and phosphatidylserine content from directly discharged EVs. These EVs additionally had distinct physiological impacts: S-EV diminished the mycobacterial load and cytokine generation in vitro (through a phosphatidylserine-dependent mechanism). In contrast, both EVs decreased the bacterial lung load in vivo. These results are the foundation for more investigations to assess whether EVs enhance the efficacy of the conventional therapy for tuberculosis (TB) (García-Martínez et al. 2019)
The recent evidence has indicated that the Mtb infection can enhance microvesicle generation in response to iron limitation. These microvesicles carry mycobactin, which can work as an iron donor and promotes the replication of iron-starved mycobacteria. Finally, the study results revealed a function of microvesicles in iron attainment in Mtb, which can be significant for durability in the host (Prados-Rosales et al. 2014) The EVs derived from macrophages infected with M. bovis BCG are carriers of mycobacterial cell wall lipids such as lipoarabinomannan (LAM) and phosphatidylinositol mannoside (PIM). These molecules provoke the production of chemokines and cytokines, which leads to inflammation. The activation of nuclear factor-κB (NF-κB) is associated with the intracellular endurance of mycobacteria. In fact, the mycobacterial proteins Rv2456c, MPT64, PPE37, and Rv3402c activate NF-κB (Wang et al. 2019)
A study uncovered EVs were provided with pleasant quality composition with intact conformational construction during the isolation procedure. The isolated EVs had the initial qualifications as an immunogenic particle, such as safety, perseverance, inexpensiveness, and antigens possession, which, based on the relationships between Mycobacterium kansasii and Mtb, make them a proper competitor for prospective prophylactics, curative, detection, and adjuvants investigations against mycobacterial pulmonary diseases (Hoseini Tavassol et al. 2017) When exposed to uninfected macrophages, exosomes stimulate a proinflammatory response in a Toll-like receptor—and myeloid differentiation factor 88—dependent fashion. Besides, exosomes separated from the bronchoalveolar lavage fluid (BALF) of mice infected with M. bovis BCG carry the mycobacteria components lipoarabinomannan and the 19-kDa lipoprotein. They can incite TNF-α generation in naive macrophages. Moreover, exosomes separated from M. bovis BCG- and Mtb-infected macrophages, when injected intranasally into mice, stimulate TNF-α and IL-12 production and neutrophil and macrophage recruitment in the lung. These investigations recognize an earlier undiscovered role for exosomes in developing intercellular signaling throughout an immune response to intracellular pathogens. They hypothesize that the extracellular release of exosomes carrying pathogen-associated molecular patterns (PAMPs) is a crucial immune surveillance mechanism (Bhatnagar et al. 2007)
EVs were also seen in macrophages and mice infected with Mtb and Mycobacterium bovis Bacille Calmette-Guérin (BCG)-mice. Recently, EVs of bacterial sources were separated from the tissue culture medium of macrophages infected with Mtb, designating that Mycobacterial extracellular vesicles (MEVs) are discharged into the extracellular milieu throughout intracellular infection. However, the molecular mechanisms implicated in MEVs trafficking out of the phagosome and through the macrophage plasma membrane are unexplained (Gupta and Rodriguez 2018) A study displayed that Mtb RNA is transported into EVs derived from macrophages through an Mtb SecA2‐dependent pathway. EVs released from macrophages infected with Mtb can incite a host RIG-I (Retinoic acid-inducible gene I)/Mitochondrial antiviral-signaling protein (MAVS)/TANK-binding kinase 1 (TBK1)/IFN regulatory factor 3 (IRF3) RNA sensing pathway, driving to type I interferon generation in receiver cells. In a RIG‐I/MAVS‐dependent manner, these EVs also promote the maturation of Mtb‐containing phagosomes through a noncanonical LC3 pathway, pointing to enhanced bacterial removal (Cheng and Schorey 2019)
A report revealed that the two medically essential species of mycobacteria, Mtb, and M. bovis BCG, release Mycobacterial vesicles (MVs) during growth in in-vitro and in-vivo conditions (both liquid culture and inside the murine phagocytic cells). They documented MV generation in different virulent and nonvirulent mycobacterial species, designating that the production of MVs is a characteristic conserved amongst mycobacterial species. Comprehensive proteomic investigation revealed that only MVs from the virulent strains carried Toll-like receptor (TLR)-2 lipoprotein agonists. The interplay of MVs with macrophages separated from mice stimulated the generation of cytokines and chemokines in a TLR2-dependent mode. The infusion of MVs toward mouse lungs evoked a florid inflammatory reaction in WT but not TLR2-deficient mice (Baena et al.) It has been designated that the several EVs generated by non-stimulated human neutrophils (EV-NS), EVs created by neutrophils incited with an activator (PMA), a peptide derived from bacterial proteins (fMLF) or Mtb; have differed in their size. In TB-EVs, the ligands for toll-like receptor (TLR) 2/6 were detected. These EVs promoted a moderate rise in the production of the co-stimulatory molecules CD80, a greater expression of CD86, higher volumes of TNF-α and IL-6, and lower masses of transforming growth factor beta (TGF-β), in autologous human macrophages, contrasted with the other EVs (Alvarez-Jiménez et al. 2018)
MVs released by Mtb carry lipoprotein LpqH, a central agonist for host TLR2. This study identifies a gene, rv0431, which appears to regulate mycobacterial MV formation, and therefore we suggest it be named “vasculogenesis and immune response regulator” (virR). This gene encodes a protein that holds a unique fold, as defined by nuclear magnetic resonance (NMR) spectroscopy, and a disordered domain indicative of cooperation in a higher-order network. By limiting the discharge of most of the material delivered by Mtb that stimulates host cells by TLR2, VirR declines Mtb’s immunostimulatory potential and enhances its virulence (Rath et al. 2013) Gonzalez-Cano et al. (2010) reported the exosomes generated from neutrophils infected with Mtb H37Rv, carried CD35, Rab5, Rab7, gp91phox, phosphatidylserine, and enzymes such as myeloperoxidase and elastase. This research combines another cell of the innate immune system to the representation of EVs as alleged effectors
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