Statistical and network analyses reveal mechanisms for the enhancement of macrophage immunity by manganese in Mycobacterium tuberculosis infection.

Tuberculosis is a significant infectious disease that poses a serious risk to human health. Our previous research has indicated that manganese ions reduce the bacterial load of Mycobacterium tuberculosis in macrophages, but the exact immune defense mechanism remains unknown. Several critical proteins and pathways involved in the host's immune response during this process are still unidentified. Our research aims to identify these proteins and pathways and provide a rationale for the use of manganese ions in the adjuvant treatment of tuberculosis. We downloaded GSE211666 data from the GEO database and selected the RM (Post-infection manganese ion treatment group) and Ra (single-infection group) groups for comparison and analysis to identify differential genes. These differential genes were then enriched and analyzed using STRING, Cytoscape, and NDEx tools to identify the two most relevant pathways of the "Host Response Signature Network." After conducting an in-depth analysis of these two pathways, we found that manganese ions mainly mediate (1) the interferon -gamma (IFN-γ) and its receptor IFNGR and the downstream JAK-STAT pathway and (2) the NFκB pathway to enhance macrophage response to interferon, autophagy, polarization, and cytokine release. Using qPCR experiments, we verified the increased expression of CXCL10, MHCII, IFNγ, CSF2, and IL12, all of which are cytokines that play a key role in resistance to Mycobacterium tuberculosis infection, suggesting that macrophages enter a state of pro-inflammatory and activation after the addition of manganese ions, which enhances their immunosuppressive effect against Mycobacterium tuberculosis. We conclude that our study provides evidence of manganese ion's ability to treat tuberculosis adjuvantly.

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 potential of mineral weathering of halophilic-endophytic bacteria isolated from Suaeda salsa and Spartina anglica.

Bacteria have the abilities of salt tolerant, mineral weathering and plant growth promoting can promote the growth of plants in saline lands. However, few reports of the mineral weathering capacity of halophilic-endophytic bacteria, raising the question of whether the halophilic-endophytic weathering bacteria are fundamentally distinct from those in plants communities. In this study, we isolated and characterized halophilic bacterial strains from the roots and leaves of Suaeda salsa and Spartina anglica with respect to their mineral weathering pattern, role in the promoting plant growth, community structure, and their changes in these two plants. Using improved Gibbson medium, we obtained 156 halophilic bacterial strains, among which 92 and 64 strains were isolated from the S. salsa and S. anglica samples, respectively. The rock weathering patterns of the isolates were characterized using batch cultures that measure the quantity of Si, Al, K, and Fe released from crystal biotite under aerobic conditions. Significantly, the biomass and capacity of the mineral weathering of the halophilic-endophytic bacteria were different in the plants. The abundance of the halophilic-endophytic bacterials in the Suaeda salsa was significantly greater than Spartina anglica, whereas the mineral weathering bacterial in the Suaeda salsa was similar to the Spartina anglica. Furthermore, the proportion of plant growth-promoting bacteria in the Suaeda salsa was higher than Spartina anglica. Phylogenetic analyses show that the weathered minerals were inhabited by specific functional groups of bacteria (Halomonas, Acinetobacter, Burkholderia, Alcaligenes, Sphingobium, Arthrobacter, Chryseobacterium, Paenibacillus, Microbacterium, Ensifer, Ralstonia and Enterobacter) that contribute to the mineral weathering. The changes in halophilic endophytes weathering communities between the two plants were attributable not only to major bacterial groups but also to a change in the minor population structure.

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.

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.