This study highlights the importance of mycobactins in the growth and virulence of M. tuberculosis and establishes the enzymes of mycobactin biosynthesis as novel targets for the development of therapeutic interventions against tuberculosis.
BackgroundPrevious work from our laboratory has demonstrated that during acute viral brain infection, glial cells modulate antiviral T cell effector responses through the PD-1: PD-L1 pathway, thereby limiting the deleterious consequences of unrestrained neuroinflammation. Here, we evaluated the PD-1: PD-L1 pathway in development of brain-resident memory T cells (bTRM) following murine cytomegalovirus (MCMV) infection.MethodsFlow cytometric analysis of immune cells was performed at 7, 14, and 30 days post-infection (dpi) to assess the shift of brain-infiltrating CD8+ T cell populations from short-lived effector cells (SLEC) to memory precursor effector cells (MPEC), as well as generation of bTRMs.ResultsIn wild-type (WT) animals, we observed a switch in the phenotype of brain-infiltrating CD8+ T cell populations from KLRG1+ CD127− (SLEC) to KLRG1− CD127+ (MPEC) during transition from acute through chronic phases of infection. At 14 and 30 dpi, the majority of CD8+ T cells expressed CD127, a marker of memory cells. In contrast, fewer CD8+ T cells expressed CD127 within brains of infected, PD-L1 knockout (KO) animals. Notably, in WT mice, a large population of CD8+ T cells was phenotyped as CD103+ CD69+, markers of bTRM, and differences were observed in the numbers of these cells when compared to PD-L1 KOs. Immunohistochemical studies revealed that brain-resident CD103+ bTRM cells were localized to the parenchyma. Higher frequencies of CXCR3 were also observed among WT animals in contrast to PD-L1 KOs.ConclusionsTaken together, our results indicate that bTRMs are present within the CNS following viral infection and the PD-1: PD-L1 pathway plays a role in the generation of this brain-resident population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0860-3) contains supplementary material, which is available to authorized users.
The tumor suppressive activity of FOXP3 has been observed in tumor initiation, but the underlying mechanism still remains largely unknown. Here, we identified a FOXP3-microRNA-146 (miR-146)-NF-κB axis in vitro and in vivo in prostate cancer cells. We observed that FOXP3 dramatically induced the expression of miR-146a/b, which contributed to transcriptional inhibition of IRAK1 and TRAF6, in prostate cancer cell lines. Tissue-specific deletion of Foxp3 in mouse prostate caused a significant reduction of miR-146a and upregulation of NF-κB activation. In addition, prostatic intraepithelial neoplasia lesions were observed in miR-146a mutant mice as well as in Foxp3 mutant mice. Notably, the NF-κB inhibitor bortezomib inhibited cell proliferation and induced apoptosis in prostate epithelial cells, attenuating prostatic intraepithelial neoplasia formation in Foxp3 mutant mice. Our data suggest that the FOXP3-miR-146-NF-κB axis has a functional role during tumor initiation in prostate cancer. Targeting the miR-146-NF-κB axis may provide a new therapeutic approach for prostate cancers with FOXP3 defects.
BackgroundThe failure of Mycobacterium bovis Bacille Calmette-Guérin to impart satisfactory protection against adult pulmonary tuberculosis has necessitated the development of more effective TB vaccines. The assumption that the vaccine strain should be antigenically as similar as possible to the disease causing pathogen has led to the evaluation of M.tuberculosis mutants as candidate tuberculosis vaccines.Methods/Principal FindingsIn this study, we have generated a mutant of M.tuberculosis (Mtb∆mms) by disrupting 3 virulence genes encoding a mycobacterial secretory acid phosphatase (sapM) and two phosphotyrosine protein phosphatases (mptpA and mptpB) and have evaluated its protective efficacy in guinea pigs. We observed that Mtb∆mms was highly attenuated in THP-1 macrophages. Moreover, no bacilli were recovered from the lungs and spleens of guinea pigs after 10 weeks of Mtb∆mms inoculation, although, initially, the mutant exhibited some growth in the spleens. Subsequently, when Mtb∆mms was evaluated for its protective efficacy, we observed that similar to BCG vaccination, Mtb∆mms exhibited a significantly reduced CFU in the lungs of guinea pigs when compared with the unvaccinated animals at 4 weeks after challenge. In addition, our observations at 12 weeks post challenge demonstrated that Mtb∆mms exhibited a more sustainable and superior protection in lungs as compared to BCG. However, the mutant failed to control the hematogenous spread as the splenic bacillary load between Mtb∆mms vaccinated and sham immunized animals was not significantly different. The gross pathological observations and histopathological observations corroborated the bacterial findings. Inspite of disruption of phosphatase genes in MtbΔmms, the lipid profiles of M.tuberculosis and MtbΔmms were identical indicating thereby that the phenotype of the mutant was ascribed to the loss of phosphatase genes and the influence was not related to any alteration in the lipid composition.Conclusions/SignificanceThis study highlights the importance of M.tuberculosis mutants in imparting protection against pulmonary TB.
The dynamics of terrestrial ecosystems depends on interactions between carbon, nutrient and hydrological cycles. Terrestrial ecosystems retain carbon in live biomass (aboveground and belowground), decomposing organic matter, and soil. Carbon is exchanged naturally between these systems and the atmosphere through photosynthesis, respiration, decomposition, and combustion. Human activities change carbon stock in these pools and exchanges between them and the atmosphere through land-use, land-use change, and forestry.In the present study we estimated the wood (stem) biomass, growing stock (GS) and carbon stock of Indian forests for 1984 and 1994. The forest area, wood biomass, GS, and carbon stock were 63.86 Mha, 4327.99 Mm 3 , 2398.19 Mt and 1085.06 Mt respectively in 1984 and with the reduction in forest area, 63.34 Mha, in 1994, wood biomass (2395.12 Mt) and carbon stock (1083.69 Mt) also reduced subsequently. The Conifers, of temperate region, stocked maximum carbon in their woods, 28.88 to 65.21 t C ha −1 , followed by Mangrove forests, 28.24 t C ha −1 , Dipterocarp forests, 28.00 t C ha −1 , and Shorea robusta forests, 24.07 t C ha −1 . Boswellia serrata, with 0.22 Mha forest area, stocked only 3.91 t C ha −1 . To have an idea of rate of carbon loss the negative changes (loss of forest area) in forest area occurred during 1984-1994 (10yrs) and 1991-1994 (4yrs) were also estimated. In India, land-use changes and fuelwood requirements are the main cause of negative change. Total 24.75 Mt C was lost during 1984-1994 and 21.35 Mt C during 1991 at a rate of 2.48 Mt C yr −1 and 5.35 Mt C yr −1 respectively. While in other parts of India negative change is due to multiple reasons like fuelwood, extraction of non-wood forest products (NWFPs), illicit felling etc., but in the northeastern region of the country shifting cultivation is the only reason for deforestation. Decrease in forest area due to shifting cultivation accounts for 23.0% of the total deforestation in India, with an annual loss of 0.93 Mt C yr −1 .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.