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Abstract: Aberrant expression of microRNAs (miRNAs) is associated with tumour progression, extracellular matrix remodelling, and cell proliferation. miRNAs modulate host gene expression during infection by pathogens such as Helicobacter pylori, which is associated with varying degrees of gastric pathology. In order to gain insight into the regulation of gene expression by miRNAs during H. pylori infection of gastric epithelial cells and its likely downstream consequences, we analysed the transcriptomes and miRnomes of AGS cells infected with H. pylori. In silico analysis of miRNA–mRNA interactions suggested that miR‐29b‐1‐5p was a likely regulator of pathways associated with gastric epithelial cell pathology. We validated PH domain leucine rich phosphatase 1 (PHLPP1), a negative regulator of the Akt signalling pathway, as a target of miR‐29b‐1‐5p. In an in vivo mouse model, we observed that infection with H. pylori was associated with upregulation of miR‐29b‐1‐5p and downregulation of PHLPP1. Transfection with either a mimic or an inhibitor of miR‐29b‐1‐5p confirmed that downregulation of PHLPP1 upregulates Akt‐dependent NF‐κB signalling leading to activation of matrix metalloproteinases 2 and 9, players in the degradation of extracellular matrix during H. pylori infection. The secreted antigen HP0175 was associated with upregulation of miR‐29b‐1‐5p, regulation of metalloproteinase activity, and migration of AGS cells. Our study suggests that targeting the miR‐29b‐1‐5p/PHLPP1 signalling axis could be a potential host‐directed approach for regulating the outcome of H. pylori infection. [ABSTRACT FROM AUTHOR]

Abstract: Tuberculosis is a global health problem, with a third of the world's population infected with the bacillus, Mycobacterium tuberculosis. The problem is exacerbated by the emergence of multidrug resistant and extensively drug resistant strains. The search for new drug targets is therefore a priority for researchers in the field. The two‐component systems (TCSs) are central to the ability of the bacterium to sense and to respond appropriately to its environment. Here we summarize current knowledge on the paired TCSs of M. tuberculosis. We discuss what is currently understood regarding the signals to which each of the sensor kinases responds, and the regulons of each of the cognate response regulators. We also discuss what is known regarding attempts to inhibit the TCSs by small molecules and project their potential as pharmacological targets for the development of novel antimycobacterial agents. © 2018 IUBMB Life, 70(8):710–717, 2018 [ABSTRACT FROM AUTHOR]

Interleukin-32 (IL-32), which was previously called natural killer cell transcript 4, has recently been recognized as a proinflammatory cytokine (see Glossary) [1]. The main sources of IL-32 are natural killer [...]

Autophagy plays a crucial role in the control of bacterial burden during Mycobacterium tuberculosis infection. MicroRNAs (miRNAs) are small non-coding RNAs that regulate immune signalling and inflammation in response to challenge by pathogens. Appreciating the potential of host-directed therapies designed to control autophagy during mycobacterial infection, we focused on the role of miRNAs in regulating M. tuberculosis-induced autophagy in macrophages. Here, we demonstrate that M. tuberculosis infection leads to downregulation of miR-17 and concomitant upregulation of its targets Mcl-1 and STAT3, a transcriptional activator of Mcl-1. Forced expression of miR-17 reduces expression of Mcl-1 and STAT3 and also the interaction between Mcl-1 and Beclin-1. This is directly linked to enhanced autophagy, because Mcl-1 overexpression attenuates the effects of miR-17. At the same time, transfection with a kinase-inactive mutant of protein kinase C δ (PKCδ) (an activator of STAT3) augments M. tuberculosis-induced autophagy, and miR-17 overexpression diminishes phosphorylation of PKCδ, suggesting that an miR-17/PKC δ/STAT3 axis regulates autophagy during M. tuberculosis infection. [ABSTRACT FROM AUTHOR]

Macrophages play an important role in the establishment of infection by intracellular pathogens. Mycobacterium tuberculosis is known to inhibit apoptosis and to downregulate immune responses of host cells using various strategies, including activation of peroxisome proliferator-activated receptor (PPAR)γ. Mannose-capped lipoarabinomannan (ManLAM) is one of the known bacterial effectors that plays a role in subversion of host immunity and activation of PPARγ. Here, we have used an unbiased global gene expression profiling approach to understand ( a) how ManLAM regulates host cell immune responses and ( b) the role of PPARγ in modulating ManLAM-induced host cell signaling. We have demonstrated that ManLAM-dependent inhibition of macrophage apoptosis is mediated by the upregulation of the antiapoptotic B-cell CLL/ lymphoma 2 (Bcl2) family member A1. Our in silico analyses suggested that ManLAM-mediated PPARγ signaling is linked to important functions such as phagocytosis, cytoskeleton remodeling, cell survival, and autophagy. We have validated that ManLAM upregulates signal transducer and activator of transcription ( STAT5) α, an important transcriptional regulator of cell survival in a PPARγ-dependent manner. © 2015 IUBMB Life, 67(9):726-736, 2015 [ABSTRACT FROM AUTHOR]

Autophagy is an intracellular catabolic process that is required to maintain cellular homeostasis. Pathogen-elicited host cell autophagy may favour containment of infection or may help in bacterial survival. Pathogens have developed the ability to modulate host autophagy. The secreted antigen HP0175, a peptidyl prolyl cis,trans isomerase of H elicobacter pylori, has moonlighting functions with reference to host cells. Here we show that it executes autophagy in gastric epithelial cells. Autophagy is dependent on the unfolded protein response ( UPR) that activates the expression of PKR-like ER kinase ( PERK). This is accompanied by phosphorylation of eukaryotic initiation factor 2α ( eIF-2α) and transcriptional activation of ATF4 and CHOP. Knockdown of UPR-related genes inhibits the conversion of LC3 I to LC3 II, a marker of autophagy. The autophagy-inducing ability of H . pylori is compromised when cells are infected with an isogenic hp0175 mutant. Autophagy precedes apoptosis. Silencing of BECLIN 1 augments cleavage of caspase 3 as well as apoptosis. Increased apoptosis of gastric epithelial cells is known to be linked to H . pylori-mediated gastric inflammation and carcinogenesis. To the best of our knowledge, this study provides the first demonstration of how HP0175 endowed with moonlighting functions links UPR-dependent autophagy and apoptosis during H . pylori infection. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis ( M.tb.) replicates in host macrophages to cause tuberculosis. We have investigated the role of miRNAs in M.tb.-infected murine RAW264.7 cells and bone marrow-derived macrophages ( BMDMs), focusing on miR-155, the most highly upregulated miRNA. We observed that miR-155 upregulation is directly linked to the attenuation of expression of BTB and CNC homology 1 ( Bach1) and SH2-containing inositol 5′-phosphatase ( SHIP1). Bach1 is a transcriptional repressor of haem oxygenase-1 ( HO-1), whereas SHIP1 inhibits the activation of the serine/threonine kinase AKT. We hypothesize that M.tb.-induced miR-155 induction leads to repression of Bach1, which augments the expression of HO-1, a documented activator of the M.tb. dormancyregulon. SHIP1 repression facilitates AKT activation, which is required for M.tb. survival. In addition, M.tb.-induced miR-155 inhibits expression of cyclooxygenase-2 ( Cox-2) and interleukin-6 ( Il-6), two modulators of the innate immune response. Importantly, we observed that the virulence-associated secreted protein ESAT-6 plays a key role in miR-155 induction and its subsequent effects on Bach1 and SHIP1 repression. Inhibition of miR-155 hindered survival of M.tb. in RAW264.7 and in murine BMDMs. Thus, our results offer new insights into the role of miRNAs in modulation of the host innate immune response by M.tb. for its own benefit. [ABSTRACT FROM AUTHOR]

Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIPS, which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIPS, which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis–triggered macrophage cell death. [ABSTRACT FROM AUTHOR]