There is increasing concern about potential long-term effects of antibiotics on children's health. Epidemiological studies have revealed that early-life antibiotic exposure can increase the risk of developing immune and metabolic diseases, and rodent studies have shown that administration of high doses of antibiotics has long-term effects on brain neurochemistry and behaviour. Here we investigate whether low-dose penicillin in late pregnancy and early postnatal life induces long-term effects in the offspring of mice. We find that penicillin has lasting effects in both sexes on gut microbiota, increases cytokine expression in frontal cortex, modifies blood–brain barrier integrity and alters behaviour. The antibiotic-treated mice exhibit impaired anxiety-like and social behaviours, and display aggression. Concurrent supplementation with Lactobacillus rhamnosus JB-1 prevents some of these alterations. These results warrant further studies on the potential role of early-life antibiotic use in the development of neuropsychiatric disorders, and the possible attenuation of these by beneficial bacteria.

Our results suggest that 2'-fucosyllactose and 6'-sialyllactose reduce the symptoms of food allergy through induction of IL-10(+) T regulatory cells and indirect stabilization of mast cells. Thus, human milk oligosaccharides may have therapeutic potential in allergic disease.

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The major vault protein (MVP) is the predominant component of a large cytoplasmic ribonucleoprotein particle, the vault complex [1,2]. The vault particle was originally identified as a barrel shaped body in preparations of clathrin-coated vesicles and named after its morphology reminiscent of the vaulted ceilings of cathedrals [3]. Vaults exist in thousands of copies per cell and are widely expressed in all eukaryotic organisms [4][5][6][7][8]. In both structure and composition vaults are highly conserved throughout evolution in diverse phylogenetic lineages including mammals, avians, amphibians and slime moulds [9]. They represent multimeric protein complexes with one predominant member, the MVP which constitutes more than 70% of the total complex. The remaining mass comprises vault RNA and two high molecular weight proteins, vault poly(ADP-ribose) polymerase (VPARP) and telomerase-associated protein 1 (TEP1) [10,11] Vaults are highly conserved, ubiquitous ribonucleoprotein (RNP) particles with an unidentified function. For the three protein species (TEP1, VPARP, and MVP) and a small RNA that comprises vault, expression of the unique 100-kDa major vault protein (MVP) is sufficient to form the basic vault structure. To identify and characterize proteins that interact with the Src homology 2 (SH2) domain of Src and potentially regulate Src activity, we used a pull-down assay using GST-Src-SH2 fusion proteins. We found MVP as a Src-SH2 binding protein in human stomach tissue. Interaction of Src and MVP was also observed in 253J stomach cancer cells. A subcellular localization study using immunofluorescence microscopy shows that epidermal growth factor (EGF) stimulation triggers MVP translocation from the nucleus to the cytosol and perinuclear region where it colocalizes with Src. We found that the interaction between Src and MVP is critically dependent on Src activity and protein (MVP) tyrosyl phosphorylation, which are induced by EGF stimulation. Our results also indicate MVP to be a novel substrate of Src and phosphorylated in an EGF-dependent manner. Interestingly, purified MVP inhibited the in vitro tyrosine kinase activity of Src in a concentration-dependent manner. MVP overexpression downregulates EGF-dependent ERK activation in Src overexpressing cells. To our knowledge, this is the first report of MVP interacting with a protein tyrosine kinase involved in a distinct cell signalling pathway. It appears that MVP is a novel regulator of Src-mediated signalling cascades.Abbreviations EGF, epidermal growth factor; GST, glutathione S-transferase; MVP, major vault protein; PAP, potato acid phosphatase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; SH2, Src homology 2; TCL, total cell lysate; TEP1, telomerase-associated protein 1; VPARP, vault poly(ADP-ribose) polymerase.

NK cells are a key antiviral component of the innate immune response to HSV-2, particularly through their production of IFN-γ. It is still commonly thought that type I IFN activates NK cell function; however, rather than requiring the type I IFN receptor themselves, we have previously found that type I IFN activates NK cells through an indirect mechanism involving inflammatory monocytes and IL-18. Here, we further show that direct action of type I IFN on NK cells, rather than inducing IFN-γ, negatively regulates its production during HSV-2 infection and cytokine stimulation. During infection, IFN-γ is rapidly induced from NK cells at day 2 post-infection and then immediately downregulated at day 3 post-infection. We found that this downregulation of IFN-γ release was not due to a loss of NK cells at day 3 post-infection, but negatively regulated through IFN signaling on NK cells. Absence of IFNAR on NK cells led to a significantly increased level of IFN-γ compared to WT NK cells after HSV-2 infection in vitro . Further, priming of NK cells with type I IFN was able to suppress cytokine-induced IFN-γ production from both human and mouse NK cells. We found that this immunosuppression was not mediated by IL-10. Rather, we found that type I IFN induced a significant increase in Axl expression on human NK cells. Overall, our data suggests that type I IFN negatively regulates NK cell IFN-γ production through a direct mechanism in vitro and during HSV-2 infection.

No abstract

The nervous and immune systems communicate bidirectionally, utilizing diverse molecular signals including cytokines and neurotransmitters to provide an integrated response to changes in the body’s internal and external environment. Although, neuro-immune interactions are becoming better understood under inflammatory circumstances and it has been evidenced that interaction between neurons and T cells results in the conversion of encephalitogenic T cells to T regulatory cells, relatively little is known about the communication between neurons and naïve T cells. Here, we demonstrate that following co-culture of naïve CD4+ T cells with superior cervical ganglion neurons, the percentage of Foxp3 expressing CD4+CD25+ cells significantly increased. This was mediated in part by immune-regulatory cytokines TGF-β and IL-10, as well as the neuropeptide calcitonin gene-related peptide while vasoactive intestinal peptide was shown to play no role in generation of T regulatory cells. Additionally, T cells co-cultured with neurons showed a decrease in the levels of pro-inflammatory cytokine IFN-γ released upon in vitro stimulation. These findings suggest that the generation of Tregs may be promoted by naïve CD4+ T cell: neuron interaction through the release of neuropeptide CGRP.

No abstract