Reintroducing URA3 to its native locus in Candida albicans not5, not3, bur2, and kel1 disruption mutants enabled us to directly compare strains with control strain CAI-12. We showed that URA3 position affected orotidine 5-monophosphate decarboxylase activity, hyphal morphogenesis, adherence, and mortality in murine disseminated candidiasis. After URA3 was reintroduced to its native locus, only NOT5 could be conclusively ascribed a role in virulence.In a previous article, using the ura blaster method of targeted gene disruption, we demonstrated that NOT5, a gene that is induced during thrush, encodes a newly identified factor important in candidal pathogenesis (2). Although the ura blaster method has been the conventional strategy for studying candidal virulence, mutant strains are not isogenic to control strains, since they do not express the selection marker URA3 from its native locus. It has recently been demonstrated that differences in URA3 position can alter virulence potential (1,5,6,10,11). In this study, we reinserted URA3 in its native locus in the not5 null mutant background, in order to systematically study the effects of URA3 position on morphogenesis, activity of orotidine 5Ј-monophosphate decarboxylase (OMP, the enzyme encoded by URA3), and virulence. In addition, we studied URA3 positional effects in null mutant strains of three other Candida albicans genes (NOT3, BUR2, and KEL1
Summary Lymphocyte homing to draining lymph nodes is critical for the initiation of immune responses. Secondary lymphoid organs of germ-free mice are underdeveloped. How gut commensal microbes remotely regulate cellularity and volume of secondary lymphoid organs remains unknown. We report here that driven by commensal fungi, a wave of CD45+CD103+RALDH+ cells migrated to the peripheral lymph nodes after birth. The arrival of these cells introduced a high amounts of retinoic acid, mediated the neonatal to adult addressin switch on endothelial cells, and directed the homing of lymphocytes to both gut-associated lymphoid tissues and peripheral lymph nodes. In adult mice, a small number of these RALDH+ cells may serve to maintain the volume of secondary lymphoid organs. Homing deficiency of these cells was associated with lymph node attrition in Vitamin A-deficient mice, suggesting a perpetual dependence on retinoic acid signaling for structural and functional maintenance of peripheral immune organs.
Tuberculosis (TB) has been the leading lethal infectious disease worldwide since 2014, and about one third of the world’s population has a latent TB infection (LTBI). This is largely attributed to the difficulties in diagnosis and treatment of TB and LTBI patients. Exosomes offer a new perspective on investigation of the process of TB infection. In this study, we performed small RNA sequencing to explore small RNA profiles of serum exosomes derived from LTBI and TB patients and healthy controls (HC). Our results revealed distinct miRNA profile of the exosomes in the three groups. We screened 250 differentially expressed miRNAs including 130 specifically expressed miRNAs. Some miRNAs were further validated to be specifically expressed in LTBI (hsa-let-7e-5p, hsa-let-7d-5p, hsa-miR-450a-5p, and hsa-miR-140-5p) and TB samples (hsa-miR-1246, hsa-miR-2110, hsa-miR-370-3P, hsa-miR-28-3p, and hsa-miR-193b-5p). Additionally, we demonstrated four expression panels in LTBI and TB groups, and six expression patterns among the three groups. These specifically expressed miRNAs and differentially expressed miRNAs in different panels and patterns provide potential biomarkers for detection/diagnosis of latent and active TB using exosomal miRNAs. Additionally, we also discovered plenty of small RNAs derived from genomic repetitive sequences, which might play roles in host immune responses along with Mtb infection progresses. Overall, our findings provide important reference and an improved understanding about miRNAs and repetitive region-derived small RNAs in exosomes during the Mtb infectious process, and facilitate the development of potential molecular targets for detection/diagnosis of latent and active tuberculosis.
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