Class â histone deacetylase inhibitor regulate of Mycobacteria-Driven guanylate-binding protein 1 gene expression.

Guanylate-binding proteins (GBPs) are a class of interferon (IFN)-stimulated genes with well-established activity against viruses, intracellular bacteria, and parasites. The effect of epigenetic modification on GBP activity upon Mycobacterium tuberculosis (Mtb) infection is poorly understood. In this study, we found that Mtb infection can significantly increase the expression of GBPs. Class Ⅰ histone deacetylase inhibitor (HDACi) MS-275 can selectively inhibit GBP1 expression, ultimately affecting the release of inflammatory cytokines IL-1ß and suppressing Mtb intracellular survival. Moreover, interfering with GBP1 expression could reduce the production of IL-1ß and the level of cleaved-caspase-3 in response to Mtb infection. GBP1 silencing did not affect Mtb survival. Besides, using the bisulfite sequencing PCR, we showed that the CpG site of the GBP1 promoter was hypermethylated, and the methylation status of the GBP1 promoter did not change significantly upon Mtb infection. Overall, this study sheds light on the role of GBP in Mtb infection and provides a link between epigenetics and GBP1 activity.

Manganese enhances macrophage defense against Mycobacterium tuberculosis via the STING-TNF signaling pathway.

The host cell antiviral response pathway depends heavily on manganese (Mn), but its role in defense against Mycobacterium tuberculosis (M. tuberculosis) infection is rarely reported. In this study, we found that, in H37Ra-infected macrophages, Mn2+ increases the phosphorylation of stimulator of interferon genes (STING) and P65, as well as triggers the phosphorylation cascade of tumor necrosis factor (TNF) signaling pathway proteins, signal-regulated kinase (ERK), P38, and c-Jun N-terminal kinase (JNK). The activation of the TNF signaling pathway stimulated the expression of downstream inflammatory factors TNF-α, C-X-C Motif Chemokine Ligand 10(CXCL10), CC Motif Chemokine Ligand 20(CCL20), Colony Stimulating Factor 1(CSF1), Colony Stimulating Factor 2(CSF2), and Jagged Canonical Notch Ligand 1(JAG1), thereby triggering a strong inflammatory response in the cells. The excessive accumulation of TNF-α in macrophages induces necroptosis and inhibits the survival of M. tuberculosis in macrophages. When we treated macrophages with the STING inhibitor H-151, the phosphorylation of P38 was reduced, and the secretion of downstream inflammatory factors TNF-α and CXCL10, CCL20, CSF1, and CSF2 were also inhibited. Overall, this study reveals that Mn2+ plays a crucial role in host cell defense against M. tuberculosis infection, contributes to a deeper understanding of pathogen-host interactions, and offers theoretical support for the use of Mn2+ as a drug cofactor for the treatment of tuberculosis and the development of a new generation of drugs and vaccine adjuvants.

The role of neoantigens in tumor immunotherapy.

Tumor neoantigens are aberrant polypeptides produced by tumor cells as a result of genomic mutations. They are also tumor-specific antigens (TSA). Neoantigens are more immunogenic than tumor-related antigens and do not induce autoimmunity. Based on the rapid development of bioinformatics and the continuous update of sequencing technology, cancer immunotherapy with tumor neoantigens has made promising breakthroughs and progress. In this review, the generation, prediction, and identification of novel antigens, as well as the individualized treatments of neoantigens, were first introduced. Secondly, the mechanism of Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) therapy and immune checkpoint blockade therapy in the treatment of tumors were outlined, and the three treatment methods were compared. Thirdly, the application of neoantigens in CAR-T therapy and PD-1/PD-L1 blockade therapy was briefly described. The benefits of the neoantigen vaccines over common vaccines were summarized as well. Finally, the prospect of neoantigen therapy was presented.

Sulforaphane kills Mycobacterium tuberculosis H37Ra and Mycobacterium smegmatis mc2155 through a reactive oxygen species dependent mechanism.

Mycobacterium tuberculosis (M. tuberculosis) is a highly pathogenic intracellular pathogen that causes tuberculosis (TB), the leading cause of mortality from single infections. Redox homeostasis plays a very important role in the resistance of M. tuberculosis to antibiotic damage and various environmental stresses. The antioxidant sulforaphane (SFN) has been reported to exhibit anticancer activity and inhibit the growth of a variety of bacteria and fungi. Nonetheless, it remains unclear whether SFN exhibits anti-mycobacterial activity. Our results showed that the SFN against M. tuberculosis H37Ra exhibited bactericidal activity in a time and dose-dependent manner. The anti-tubercular activity of SFN was significantly correlated with bacterial reactive oxygen species (ROS) levels. In addition, SFN promoted the bactericidal effect of macrophages on intracellular bacteria in a dose-dependent manner, mediated by increasing intracellular mitochondrial ROS levels and decreasing cytoplasmic ROS levels. Taken together, our data revealed the previously unrecognized antimicrobial functions of SFN. Future studies focusing on the mechanism of SFN in macrophages against M. tuberculosis are essential for developing new host-directed therapeutic approaches against TB.