Streptococcus pneumoniae is an important bacterial pathogen that causes a range of noninvasive and invasive diseases. The mechanisms underlying variability in the ability of S. pneumoniae to transition from nasopharyngeal colonization to disease-causing pathogen are not well defined. Mucosal-associated invariant T (MAIT) cells are prevalent in mucosal tissues such as the airways and are believed to play an important role in the early response to infection with bacterial pathogens. The ability of MAIT cells to recognize and contain infection with S. pneumoniae is not known. In the present study, we analyzed MAIT-cell responses to infection with clinical isolates of S. pneumoniae serotype 19A, a serotype linked to invasive pneumococcal disease. We found that although MAIT cells were capable of responding to human dendritic and airway epithelial cells infected with S. pneumoniae, the magnitude of response to different serotype 19A isolates was determined by genetic differences in the expression of the riboflavin biosynthesis pathway. MAIT-cell release of cytokines correlated with differences in the ability of MAIT cells to respond to and control S. pneumoniae in vitro and in vivo in a mouse challenge model. Together, these results demonstrate first that there are genetic differences in riboflavin metabolism among clinical isolates of the same serotype and second that these likely determine MAIT-cell function in response to infection with S. pneumoniae. These differences are critical when considering the role that MAIT cells play in early responses to pneumococcal infection and determining whether invasive disease will develop.

Plasma concentration time curves following intravenous (i.v.) administration of 1.5 mg/kg of ranitidine, 0.2 mg/kg, 0.4 mg/kg and 0.8 mg/kg of omeprazole, respectively, were analysed in six llamas. Plasma profiles after i.v. administration of both drugs showed plasma concentrations declining in a biexponential manner with a rapid distribution phase. Pharmacokinetics parameters after ranitidine administration to six llamas showed a mean elimination half-life of 1.53 +/- 0.26 h. The mean volume of distribution (Vdss) in llamas was 1.77 +/- 0.31 L/kg, and mean body clearance in llamas was 0.778 +/- 0.109 L/kg/h. Ranitidine produced only a small transitory (<1 h) decline in acid production when administered i.v. at a dose of 1.5 mg/kg. Omeprazole showed dose-dependent nonlinear pharmacokinetics. The mean half-life of 0.2 mg/kg i.v. omeprazole was shorter than that of 0.4 and 0.8 mg/kg i.v. omeprazole, i.e. 0.61, 0.72 and 1.07 h, respectively. The area under the curve (AUC) and mean residence time (MRT) increased with increasing dose, while clearance decreased as dose increased. The decline in acid production following 0.2 mg/kg i.v. omeprazole was highly variable and did not produce a clinically useful suppression of third compartment acid production. In contrast, both 0.4 mg/kg and 0.8 mg/kg omeprazole i.v. administration significantly reduced third compartment acid production. The reduction in acid production following 0.8 mg/kg omeprazole was not significantly greater than the reduction observed following 0.4 mg/kg dosage. Misoprostol (10 microg/kg) was administered i.v. in an absolute alcohol solution. Two animals collapsed following drug administration. While the side-effects could have been produced by either misoprostol or the alcohol vehicle, the clinical changes were more consistent with an adverse drug reaction. Unfortunately, the limitation of UV detection did not provide the sensitivity needed to quantify the amount of misoprostol in llama plasma, and the pharmacokinetics could not be evaluated.

Fungal pigments, specifically those generated from spalting fungi, are being developed for broader use in the wood and textile industry, and due to their coloration properties, may also be useful as aesthetic bamboo dyes. This paper evaluates the potential use of fungal pigments in bamboo (Phyllostachys spp.), and compares the difference between natural spalting and the direct application of extracted fungal pigments of three known spalting fungi: Scytalidium cuboideum, Scytalidium ganodermophthorum, and Chlorociboria aeruginosa. Bamboo was significantly spalted by S. cuboideum under live inoculation, while the other two fungi did not colonize. For the direct application of fungal pigments, bamboo did not develop internal pigmentation with any pigment, but did develop visible surface color for S. cuboideium and C. aeruginosa. Light microscopy and scanning electron microscopy confirmed the presence of hyphae in bamboo vessels and parenchyma. An HPLC analysis for simple sugars showed the presence of glucose but no sucrose. Results indicate that the extracted pigments of the aforementioned fungi are ideal for the surface treatment of bamboo, while only direct inoculation of S. cuboideum is appropriate for internal coloration.

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Mucosal Associated Invariant T (MAIT) cells can sense intracellular infection by a broad array of pathogens. These cells are activated upon encountering microbial antigen(s) displayed by MR1 on the surface of an infected cell. Human MR1 undergoes alternative splicing. The full-length isoform, MR1A, can activate MAIT cells, while the function of the isoforms, MR1B and MR1C, are incompletely understood. In this report, we sought to characterize the expression and function of these splice variants. Using a transcriptomic analysis in conjunction with qPCR, we find that that MR1A and MR1B transcripts are widely expressed. However only MR1A can present mycobacterial antigen to MAIT cells. Coexpression of MR1B with MR1A decreases MAIT cell activation following bacterial infection. Additionally, expression of MR1B prior to MR1A lowers total MR1A abundance, suggesting competition between MR1A and MR1B for either ligands or chaperones required for folding and/or trafficking. Finally, we evaluated CD4/CD8 double positive thymocytes expressing surface MR1. Here, we find that relative expression of MR1A/MR1B transcript is associated with the prevalence of MR1 + CD4/CD8 cells in the thymus. Our results suggest alternative splicing of MR1 represents a means of regulating MAIT activation in response to microbial ligand(s).

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Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset important in the early response to bacterial and viral lung pathogens. MAIT cells recognize bacterial small molecule metabolites presented on the Class I-like molecule MR1. As with other Class I and Class II molecules, MR1 can likely sample ligands in the intracellular environment through multiple cellular pathways. Rab6, a small GTPase that regulates a number of endosomal trafficking pathways including retrograde transport to the trans-Golgi network (TGN), is involved in the presentation of ligands from Mycobacterium tuberculosis (Mtb) to MAIT cells. The Rab6-mediated trafficking pathway contains endosomal compartments that share features with the Mtb intracellular compartment. Using inducible expression of MR1, this study demonstrates that Rab6 regulates the recycling of MR1 molecules from the cell surface through endosomal trafficking compartments to the TGN. This Rab6-dependent pool of recycled MR1, which is available for reloading with ligands from bacterial pathogens like Mtb, may be important for early recognition of infected cells by MAIT cells in the lung.