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Overview of TLR-mycobacteria cross-talk. Binding of mycobacterial ligands to TLRs triggers the release of different immunomodulatory molecules; the cross-talk between these molecules induce pro-(inflammation and sterilizing immunity), pro-mycobacteria(immune evasion and disease prognosis) and comprehensive or pro-host/pro-bacteria effect (immune regulation favouring mycobacteria persistence with minimum immunopathology)
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Toll-like receptors (TLRs) play critical role in the innate recognition of pathogens besides orchestrating innate and adaptive immune responses. These receptors exhibit exquisite specificity for different pathogens or their products and, through a complex network of signalling, generate appropriate immune responses. TLRs induce both pro- and anti-i...
Citations
... Pathogen-induced macrophage apoptosis involves the initiation and amplification of both innate and adaptive immune responses [9]. Macrophages provide the first line of defense against mycobacteria by recognizing different conserved mycobacterial ligands with help of pathogen recognition receptors (PRRs), such as the Toll-like receptors (TLRs) [10]. There are also reports suggesting that the macrophages serve as safe havens for mycobacteria during the dormant period [11]. ...
... There are also reports suggesting that the macrophages serve as safe havens for mycobacteria during the dormant period [11]. Among the different TLRs, the role of TLR-2 in regulating mycobacterial-pathogenesis is well known [10]. TLR-2, in conjunction with adaptor proteins myeloid differentiation primary response gene 88 (Myd88) or TIR domain-containing adaptor-inducing interferon-β (TRIF) [12] activates downstream signal transduction pathways leading to activation of pro-inflammatory responses, thereby triggering apoptosis of infected macrophages to contain mycobacterial infection . ...
The role of microRNAs (miRNAs) in Mycobacterium fortuitum pathogenesis is not well illustrated. Using zebrafish kidney macrophages (ZFKM) we observed that M. fortuitum triggers miR-155 expression, and the TLR-2/NF-κB axis plays a key role in initiating the process. We report that mir-155 activates the pro-inflammatory Stat1/TBX21 pathway in M. fortuitum-infected ZFKM. Our results further reveal the role of miR-155 in M1-macrophage polarisation during M. fortuitum infection. We observed that miR-155 inhibits socs1 expression augmenting the expression of tnf-α, il-12 and ifn-γ in infected ZFKM. Additionally, attenuating miR-155 inhibited ZFKM apoptosis and increased the intracellular bacterial load implicating its pro-apoptotic and bactericidal role in M. fortuitum pathogenesis. This is the first report on the role of miRNA in regulating innate immunity to mycobacteria in fish. We propose that the TLR-2/NF-κB axis triggers miR-155 expression, which in turn represses socs1 and promotes the development of M1-macrophages. Thus, the functional miR-155/Stat1/TBX21pathway induces a pro-inflammatory milieu favouring ZFKM apoptosis and M. fortuitum clearance. Therefore, our study unveils the role of miR-155 in the hierarchy of events leading to M. fortuitum-induced apoptosis and bacterial clearance in fish that is still not explored in detail.
... They are known to regulate tissue damage and tumor progression processes [19]. They identify pathogen-associated molecular patterns (PAMPs), which are conserved microbial structures, such as peptidoglycan, lipopolysaccharide, synthetic double-stranded RNA, CpG DNA motifs associated with bacterial DNA, and agellin, which bind to TLR2, TLR4, TLR3, TLR9, TLR5, respectively [18,21]. Per previous studies, 10 functional human TLRs and 12 functional mice TLRs have been identi ed, with TLR1-9 being conserved in both species, whereas TLR10 in humans alone [20,22,23]. ...
Toll-like receptors (TLRs) are pattern recognition receptors that are found on both immune cells and cancerous cells. Gastric cancer (GC) cells/tissues have been shown to exhibit elevated levels of TLR4. Here, we examined the role of TLR4 on autophagy and growth in GC cells. Real-time quantitative PCR (RT-qPCR) and western blot (WB) were used to determine TLR4 levels at different stages of GC cells/tissues as well as the levels of autophagy-related proteins (ARPs) and determine the underlying signaling mechanism. Cellular growth was assessed via the CCK-8 assay. The protein and mRNA levels of ARPs were elucidated, followed by the estimation of the involved signaling pathways. Our results demonstrated that the modulation of the PI3K/AKT/mTOR pathway resulted from autophagy inhibition/induction, which was in turn induced by the overexpression and knockdown of TLR4. Thus, TLR4 played a vital role in GC progression.
... PtpA and Mce3E of MTB regulate the MAPK and NF-kB signaling pathways. Interestingly, it has been reported that GRP160 can also regulate the entry of MTB into macrophages through the MAPK/ERK signaling pathway, indicating that the GPCR and TLR signaling pathways may play a synergistic role (Mercedes Romero et al., 2014;Mehta et al., 2021). The interaction between TLRs and MTB infection is shown in Figure 4. ...
Tuberculosis caused by Mycobacterium tuberculosis (MTB) is an ancient chronic infectious disease and is still the leading cause of death worldwide due to a single infectious disease. MTB can achieve immune escape by interacting with host cells through its special cell structure and secreting a variety of effector proteins. Innate immunity-related pattern recognition receptors (PPR receptors) play a key role in the regulation of signaling pathways.
In this review, we focus on the latest research progress on related signal transduction molecules in the interaction between MTB and the host. In addition, we provide new research ideas for the development of new anti-tuberculosis drug targets and lead compounds and provide an overview of information useful for approaching future tuberculosis host-oriented treatment research approaches and strategies, which has crucial scientific guiding significance and research value.
... For example, bacterial muramyl dipeptide and Neisseria porin as adjuvants can activate antigen-presenting cells through TLR2 [10], and TLR2-deficient mice produced significantly lower antibody titers to Borrelia burgdorferi OspA than wildtype mice after immunization [11]. TLR2 is involved in mycobacterial recognition, immune and antigen presentation which affects host defense against invading mycobacteria [12][13][14]. TLR2 also plays an essencial role in recognizing components including lipoprotein ligands of Mycobacterium tuberculosis (Rv3763, Rv1270c, LprA, and Rv1411c, LprG, and PhoS1) and other categories of TLR2 ligands (LAM, LM, PIMs and TDM) can activate macrophages by activating nuclear factor-κB through TLR2 [15,16], which plays an important role in humoral immunity and the expression of immunoglobulins. Therefore, evaluating the affinity between bTB protein and TLR2 is expected to become an important basis for the selection of antigens for the diagnosis of bTB based on humoral immunity. ...
Background:
There is an urgent need to find reliable and rapid bovine tuberculosis (bTB) diagnostics in response to the rising prevalence of bTB worldwide. Toll-like receptor 2 (TLR2) recognizes components of bTB and initiates antigen-presenting cells to mediate humoral immunity. Evaluating the affinity of antigens with TLR2 can form the basis of a new method for the diagnosis of bTB based on humoral immunity.
Objectives:
To develop a reliable and rapid strategy to improve diagnostic tools for bTB.
Methods:
In this study, we expressed and purified the sixteen bTB-specific recombinant proteins in Escherichia coli. The two antigenic proteins, MPT70 and MPT83, which were most valuable for serological diagnosis of bTB were screened. Molecular docking technology was used to analyze the affinity of MPT70, MPT83, dominant epitope peptide of MPT70 (M1), and dominant epitope peptide MPT83 (M2) with TLR2, combined with the detection results of enzyme-linked immunosorbent assay to evaluate the molecular docking effect.
Results:
The results showed that interaction surface Cα-atom root mean square deviation of proteins (M1, M2, MPT70, MPT83)-TLR2 protein are less than 2.5 A, showing a high affinity. It is verified by clinical serum samples that MPT70, MPT83, MPT70-MPT83 showed good diagnostic potential for the detection of anti-bTB IgG and M1, M2 can replace the whole protein as the detection antigen.
Conclusions:
Molecular docking to evaluate the affinity of bTB protein and TLR2 combined with ELISA provides new insights for the diagnosis of bTB.
... TLRs, a family of pattern recognition receptors, can recognize and bind to specific pathogen-associated molecular patterns to play an important role in host defense [1]. It is noteworthy that TLR2, a subclass of TLRs, recognizes a large number of lipid-containing molecules [4]. TLR2 activation is involved in the release of pro-inflammatory cytokines, and plays an important role in the pathogenesis of numerous chronic inflammatory diseases [5]. ...
... TLR2 activation is involved in the release of pro-inflammatory cytokines, and plays an important role in the pathogenesis of numerous chronic inflammatory diseases [5]. Previous works have indicated that TLR2-deficient mice are protected from insulin resistance by a high-fat diet (HFD) in adipose, liver, muscle and islet, and this process involves in regulation of tissue inflammation and attenuating local inflammatory cytokine expression [6,7], and reducing F4/80-positive macrophage accumulation in adipose tissue [4]. F4/80 is a specific surface marker of tissue macrophages in the mouse [4]. ...
... Previous works have indicated that TLR2-deficient mice are protected from insulin resistance by a high-fat diet (HFD) in adipose, liver, muscle and islet, and this process involves in regulation of tissue inflammation and attenuating local inflammatory cytokine expression [6,7], and reducing F4/80-positive macrophage accumulation in adipose tissue [4]. F4/80 is a specific surface marker of tissue macrophages in the mouse [4]. Our previous work in vitro has showed that TLR2 deficiency promotes M2 polarization of macrophages [8]. ...
Background
Toll-like receptor 2 (TLR2) deficiency can increase insulin sensitivity and improves glucose tolerance. However, it is not yet fully understood about its underlying mechanism. The regulation of M1/M2 macrophage polarization has been verified to involve in insulin resistance. Here, we evaluated whether the beneficial effect of TLR2 deficiency is mediated by TLR2-associated macrophage polarization in mice fed with high-fat diet (HFD).Methods and resultsWild-type and TLR2 knockout (TLR2−/−) mice received HFD for two months. Following intraperitoneal glucose tolerance and insulin resistance tests, peripheral monocytes were isolated, and in vitro induced for differentiation into M1 and M2 macrophages, respectively. Macrophages polarization was evaluated using flow cytometry. The expression of macrophage polarization marker genes and cytokine production in visceral adipose tissue were measured by qRT-PCR and ELISA. Compared to wild-type mice, TLR2−/− mice showed higher glucose tolerance and insulin sensitivity, along with significantly reduced the population of M1 and increased M2 count in vitro. Additionally, TLR2−/− mice demonstrated higher expression of M2 marker iNOS mRNA and interleukin-10 level in adipose tissues.Conclusions
Our results reveal that TLR2 knockout-mediated macrophages M2 polarization is a crucial factor for preventing against diet-induced insulin resistance in mice. These findings deepen our knowledge about the mechanism underlying HFD-induced insulin resistance.
... TLRs affect host defense against invading mycobacteria by directly or indirectly participating in multiple biological processes, such as mycobacterial recognition, inflammatory responses, antimicrobial activity, and antigen presentation [99][100][101]. In mammals, TLR4 plays a role in defense against mycobacterial infection [38]. Immune cells can be activated by the interaction between TLR4 and Mtb components, such as secretory protein (Rv0335c), lipomannan (LM), HSPs 60, and 65 [65,102]. ...
... However, no pronounced susceptibility was found in TLR4 deficient mice in a high dose Mtb infection, compared to the wild-type controls [105]. Compared with TLR4, the function of TLR2 in mycobacterial infection is more complex, because TLR2 can recognize a large number of components on a mycobacterial membrane [99]. TLR2 forms a heterodimer with TLR1 or TLR6, which expands the range of its recognizable ligands [33,39]. ...
Innate immunity is considered the first line of defense against microbial invasion, and its dysregulation can increase the susceptibility of hosts to infections by invading pathogens. Host cells rely on pattern recognition receptors (PRRs) to recognize invading pathogens and initiate protective innate immune responses. Toll-like receptor 2 (TLR2) is believed to be among the most important Toll-like receptors for defense against mycobacterial infection. TLR2 has been reported to have very broad functions in infectious diseases and also in other diseases, such as chronic and acute inflammatory diseases, cancers, and even metabolic disorders. However, TLR2 has an unclear dual role in both the activation and suppression of innate immune responses. Moreover, in some studies, the function of TLR2 was shown to be controversial, and therefore its role in several diseases is still inconclusive. Therefore, although TLR2 has been shown to have an important function in innate immunity, its usefulness as a therapeutic target in clinical application is still uncertain. In this literature review, we summarize the knowledge of the functions of TLR2 in host–mycobacterial interactions, discuss controversial results, and suggest possibilities for future research.
... Toll-like receptors (TLRs) are a class of pathogen recognition receptors that recognize conserved molecular patterns expressed by pathogens triggering innate immune responses and inducing subsequent adaptive immune responses (4). Several TLRs have been reported to play critical roles in host immunity to mycobacterial pathogenesis, among which the involvement of TLR-2 is well studied (5,6). The role of TLR-2 in mycobacterial immunity is contentious. ...
The mechanisms underlying Mycobacterium fortuitum-induced mycobacteriosis remain unexplored. Using head kidney macrophages (HKM) from catfish (Clarias gariepinus), we report that Ca²⁺ surge across mitochondrial-Ca²⁺ uniporter (MICU), and consequent mitochondrial ROS (mtROS) production, is imperative for mycobactericidal activity. Inhibition of mtROS alleviated HKM apoptosis and enhanced bacterial survival. Based on RNA interference (RNAi) and inhibitor studies, we demonstrate that the Toll-like receptor (TLR)-2–endoplasmic reticulum (ER) stress–store-operated calcium entry (SOCE) axis is instrumental for activating the mt-Ca²⁺/mtROS cascade in M. fortuitum-infected HKM. Additionally, pharmacological inhibition of mtROS attenuated the expression of CHOP, STIM1, and Orai1, which suggests a positive feedback loop between ER-stress-induced SOCE and mtROS production. Elevated tumor necrosis factor alpha (TNF-α) levels and caspase-8 activity were observed in HKM consequent to M. fortuitum infection, and our results implicate that mtROS is crucial in activating the TNF-mediated caspase-8 activation. Our results for the first time demonstrate mitochondria as an innate immune signaling center regulating mycobacteriosis in fish. We conclude that M. fortuitum-induced persistent SOCE signaling leads to mtROS production, which in turn activates the TNF-α/caspase-8 axis culminating in HKM apoptosis and bacterial clearance.
... Toll-like receptors (TLRs) are a class of pathogen recognition receptors that recognize conserved molecular patterns expressed by pathogens triggering innate immune responses and inducing subsequent adaptive immune responses (4). Several TLRs have been reported to play critical roles in host immunity to mycobacterial pathogenesis, among which the involvement of TLR-2 is well studied (5,6). The role of TLR-2 in mycobacterial immunity is contentious. ...
... Bacteria encounter constantly changing environments that may threaten their survival and existence; hence, it is particularly important to study their survival strategies in different model systems [1][2][3]. These strategies include several sensory mechanisms and signaling pathways that are required to overcome such threats [4][5][6][7][8][9]. These mechanisms help bacteria to sense the environmental cues and generate an appropriate adaptive response. ...
Mycobacterium tuberculosis is a human pathogen that can thrive inside the host immune cells for several years and cause tuberculosis. This is due to the propensity of M. tuberculosis to synthesize a sturdy cell wall, shift metabolism and growth, secrete virulence factors to manipulate host immunity, and exhibit stringent response. These attributes help M. tuberculosis to manage the host response, and successfully establish and maintain an infection even under nutrient-deprived stress conditions for years. In this review, we will discuss the importance of mycobacterial stringent response under different stress conditions. The stringent response is mediated through small signaling molecules called alarmones “(pp)pGpp”. The synthesis and degradation of these alarmones in mycobacteria are mediated by Rel protein, which is both (p)ppGpp synthetase and hydrolase. Rel is important for all central dogma processes—DNA replication, transcription, and translation—in addition to regulating virulence, drug resistance, and biofilm formation. Rel also plays an important role in the latent infection of M. tuberculosis. Here, we have discussed the literature on alarmones and Rel proteins in mycobacteria and highlight that (p)ppGpp-analogs and Rel inhibitors could be designed and used as antimycobacterial compounds against M. tuberculosis and non-tuberculous mycobacterial infections.
... TLR, which belongs to the prominent type I transmembrane receptor protein family in mammals, plays an essential role in defense mechanisms by activating innate immunity and stimulating the adaptive immune system [39]. Cells recognize the peptidoglycan of resident microorganisms mainly via NOD1 or TLR [40]. ...
We evaluated the dietary effects of multiple probiotics in Jeju native pigs, using basal diet and multi-probiotic Lactobacillus (basal diet with 1% multi-probiotics) treatments (n = 9 each) for 3 months. We analyzed growth performance, feed efficiency, backfat thickness, blood parameters, hematological profiles, adipokines, and immune-related cytokines in pig tissues. Average daily gain, feed intake, feed efficiency, backfat thickness, and body weight were not significantly different between both groups. In Lactobacillus group, total protein (p < 0.08) and bilirubin (p < 0.03) concentrations increased; blood urea nitrogen (p < 0.08), alkaline phosphatase (p < 0.08), and gamma-glutamyltransferase (p < 0.08) activities decreased. Lactobacillus group showed decreased adiponectin (p < 0.05), chemerin (p < 0.05), and visfatin expression in adipose tissues, and increased TLR4 (p < 0.05), MYD88 (p < 0.05), TNF-α (p < 0.001), and IFN-γ (p < 0.001) expression in the liver. Additionally, NOD1 (p < 0.05), NOD2 (p < 0.01), and MYD88 (p < 0.05) mRNA levels in proximal colon tissue upregulated significantly. Colon, longissimus dorsi muscle, fat tissue, and liver histological analyses revealed no significant differences between the groups. Conclusively, Lactobacillus supplementation improved liver function and reduced cholesterol levels. Its application may treat metabolic liver disorders, especially cholesterol-related disorders.
