The Slc26 family proteins, with one possible exception, transport anions across membranes in a wide variety of tissues in vertebrates, invertebrates, and plants. Mutations in human members of the family are a significant cause of disease. Slc26 family proteins are thought to be oligomers, but their stoichiometry of association is in dispute. A recent study, using sequential bleaching of single fluorophore-coupled molecules in membrane fragments, demonstrated that mammalian Slc26a5 (prestin) is a tetramer. In this report, the stoichiometry of two non-mammalian prestins and three human SLC26 proteins has been analyzed by the same method, including the evolutionarily-distant SLC26A11. The analysis showed that tetramerization is common and likely to be ubiquitous among Slc26 proteins, at least in vertebrates. The implication of the findings is that tetramerization is present for functional reasons.
Strain SC5314 is the most widely studied strain of Candida albicans. Despite C. albicans being the most commonly isolated yeast from the human gastrointestinal (GI) microbiome, strain SC5314 does not stably colonize the mouse GI tract long term, even after antibiotic disruption. In contrast, strain CHN1 will stably colonize the mouse GI tract long term. Comparative genomic analysis of strain CHN1 indicates that it belongs to a different evolutionary clade of C. albicans than strain SC5314. Previous studies from our laboratory have shown that colonization by strain CHN1 causes a change in the GI bacterial microbiome of mice and predisposes them to more robust Th2 immune responses. Despite this, little is known about the GI microbial ecology of SC5314 vs. CHN1 and subsequent host responses. Using a short-term antibiotic disruption model in C57BL/6 mice, we have been able to observe significantly different colonization kinetics between these two C. albicans strains, with CHN1 establishing stable long-term colonization. In contrast, colonization by SC5314 was lower, highly variable and cage-dependent. C. albicans colonization kinetics impacted the composition of the bacterial microbiome with a marked effect on the levels of Lactobacillus and Enterococcus. qPCR analysis of 46 host immune response genes did not detect significant differences in host gene expression between SC5134 and CHN1 colonized mice, except for chitinase expression. Thus, these studies suggest that yeast-bacteria interactions in the microbiome may be far more important in determining long-term colonization potential of C. albicans and secondary immunomodulatory effects.
Murine models of food allergy are useful tools for identifying potential pathways involved in the manifestation of anaphylactic reactions to food in humans. Individual mice exhibit inherent heterogeneity in their immune responses, including anaphylaxis, much like what is seen clinically in food allergic humans. The microbiome (MB) may be one major driver of this difference in individuals. MB dysbiosis by broad spectrum antibiotics and/or yeast colonization can alter systemic immunity and favor the development of mucosal Type 2 immunity to aeroallergens. Our objective was to use a well-characterized murine model of food allergies (chicken egg ovalbumin, OVA) and determine if dysbiosis could enhance the manifestation of food allergies and identify elements of the MB and host response associated with this heterogeneity. In our dataset, the intensity of anaphylaxis was most strongly associated with a disrupted MB that included C. albicans colonization, loss of a specific Lachnoclostridium species, development of a highly polarized Type 2 response in the intestines, and activation of mucosal mast cells. OVA-specific IgE serum levels were not predictive of the response and in germ-free mice the response was not fully recapitulated. Conventionalization of germ-free mice resulted in Akkermansia muciniphila outgrowth and more heterogeneity in the allergic response. We also observed that housing environment could induce MB changes that altered the response. Thus, our data recapitulate the heterogeneity in anaphylactic reactions, ranging from severe to none, seen in patients with circulating levels of food allergen-specific IgE and support the idea that alterations in the MB can be one factor underlying this heterogeneity. Supported by grants from NIH NIAID R01AI138348, Mary H. Weiser Food Allergy Center (MHWFAC), and the Nina and Jerry D. Liptak Endowment of the MHWFAC
There is heterogeneity inherent in the immune responses of individual mice in murine models of food allergy, including anaphylaxis, similar to the clinical heterogeneity observed in humans with food allergies to a defined food. One major driver of this heterogeneity may be differences in the microbiome between sensitized individuals. Our laboratory and others have reported that disruption of the microbiome (dysbiosis) by broad spectrum antibiotics and/or yeast colonization can alter systemic immunity and favor the development of mucosal Type 2 immunity to aeroallergens. Our objective was to use a well-characterized murine model (Balb/c mice) of food allergies (chicken egg ovalbumin, OVA) and determine if antibiotic-mediated dysbiosis (including C. albicans colonization) could enhance the manifestation of food allergies. Furthermore, we sought to identify elements of the microbiome and host response that were associated with this heterogeneity in the anaphylactic reaction between individual food allergen-sensitized mice. In our dataset, the intensity of the anaphylactic reactions was most strongly associated with a disrupted microbiome that included colonization by C. albicans, loss of a specific Lachnoclostridium species (tentatively, Lachnoclostridium YL32), development of a highly polarized Type 2 response in the intestinal mucosa and underlying tissue, and activation of mucosal mast cells. Serum levels of allergen-specific IgE were not predictive of the response and a complete absence of a microbiome did not fully recapitulate the response. Conventionalization of germ-free mice resulted in Akkermansia muciniphila outgrowth and a higher degree of heterogeneity in the allergic response. C57BL/6 mice remained resistant even under the same dysbiosis-inducing antibiotic regimens, while changes in the microbiome markedly altered the reactivity of Balb/c mice to OVA, as noted above. Strikingly, we also observed that genetically identical mice from different rooms in our vivarium develop different levels of a Type 2 response, as well as anaphylactic reactions. The intestinal microbiome in these mice also differed between rooms. Thus, our data recapitulate the heterogeneity in anaphylactic reactions, ranging from severe to none, seen in patients that have circulating levels of food allergen-reactive IgE and support the concept that alterations in the microbiome can be one factor underlying this heterogeneity.
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.