Neonatal fungi promote lifelong metabolic health through macrophage-dependent β cell development.

Loss of early-life microbial diversity is correlated with diabetes, yet mechanisms by which microbes influence disease remain elusive. We report a critical neonatal window in mice when microbiota disruption results in lifelong metabolic consequences stemming from reduced β cell development. We show evidence for the existence of a similar program in humans and identify specific fungi and bacteria that are sufficient for β cell growth.

Fungal impacts on Earth's ecosystems.

Over the past billion years, the fungal kingdom has diversified to more than two million species, with over 95% still undescribed. Beyond the well-known macroscopic mushrooms and microscopic yeast, fungi are heterotrophs that feed on almost any organic carbon, recycling nutrients through the decay of dead plants and animals and sequestering carbon into Earth's ecosystems. Human-directed applications of fungi extend from leavened bread, alcoholic beverages and biofuels to pharmaceuticals, including antibiotics and psychoactive compounds.

Clec12a controls colitis by tempering inflammation and restricting expansion of specific commensals.

Microbiota composition regulates colitis severity, yet the innate immune mechanisms that control commensal communities and prevent disease remain unclear. We show that the innate immune receptor, Clec12a, impacts colitis severity by regulating microbiota composition. Transplantation of microbiota from a Clec12a animal is sufficient to worsen colitis in wild-type mice.

Controlling : immune regulation of commensal fungi in the gut.

The intestinal microbiome harbors fungi that pose a significant risk to human health as opportunistic pathogens and drivers of inflammation. Inflammatory and autoimmune diseases are associated with dysbiotic fungal communities and the expansion of potentially pathogenic fungi. The gut is also the main reservoir for disseminated fungal infections.

Commensal fungi in intestinal health and disease.

The microbiota is known to influence several facets of mammalian development, digestion and disease. Most studies of the microbiota have focused on the bacterial component, but the importance of commensal fungi in health and disease is becoming increasingly clear. Although fungi account for a smaller proportion of the microbiota than bacteria by number, they are much larger and therefore account for a substantial proportion of the biomass.

Clec12a tempers inflammation while restricting expansion of a colitogenic commensal.

Regulation of the microbiota is critical to intestinal health yet the mechanisms employed by innate immunity remain unclear. Here we show that mice deficient in the C-Type-lectin receptor, Clec12a developed severe colitis, which was dependent on the microbiota. Fecal-microbiota-transplantation (FMT) studies into germfree mice revealed a colitogenic microbiota formed within Clec12a mice that was marked by expansion of the gram-positive organism, .

Adaptive immunity induces mutualism between commensal eukaryotes.

Pathogenic fungi reside in the intestinal microbiota but rarely cause disease. Little is known about the interactions between fungi and the immune system that promote commensalism. Here we investigate the role of adaptive immunity in promoting mutual interactions between fungi and host.

Communication Between the Microbiota and Mammalian Immunity.

Mammalian immune systems evolved within a diverse world dominated by microbes, making interactions between these two life-forms inevitable. Adaptive immunity protects against microbes through antigen-specific responses. In classical studies, these responses were investigated in the context of pathogenicity; however, we now know that they have significant effects on our resident microbes.

Identifying a novel connection between the fungal plasma membrane and pH-sensing.

The mechanisms by which micro-organisms sense and internalize extracellular pH signals are not completely understood. One example of a known external pH-sensing process is the fungal-specific Rim/Pal signal transduction pathway. Fungi, such as the opportunistic pathogen Cryptococcus neoformans, use Rim signaling to sense and respond to changes in environmental pH.

Defects in intracellular trafficking of fungal cell wall synthases lead to aberrant host immune recognition.

The human fungal pathogen, Cryptococcus neoformans, dramatically alters its cell wall, both in size and composition, upon entering the host. This cell wall remodeling is essential for host immune avoidance by this pathogen. In a genetic screen for mutants with changes in their cell wall, we identified a novel protein, Mar1, that controls cell wall organization and immune evasion.

Characterization of additional components of the environmental pH-sensing complex in the pathogenic fungus .

Pathogenic microorganisms must adapt to changes in their immediate surroundings, including alterations in pH, to survive the shift from the external environment to that of the infected host. In the basidiomycete fungal pathogen , these pH changes are primarily sensed by the fungus-specific, alkaline pH-sensing Rim/Pal pathway. The Rim pathway has diverged significantly from that described in ascomycete fungi.

HDAC genes play distinct and redundant roles in Cryptococcus neoformans virulence.

The human fungal pathogen Cryptococcus neoformans undergoes many phenotypic changes to promote its survival in specific ecological niches and inside the host. To explore the role of chromatin remodeling on the expression of virulence-related traits, we identified and deleted seven genes encoding predicted class I/II histone deacetylases (HDACs) in the C. neoformans genome.

A Few Good Commensals: Gut Microbes Use IFN-γ to Fight Salmonella.

Whereas strong evidence supports the notion that the microbiota promotes immune system maturation in multiple tissues, the identity of the specific microbes that elicit protective immunity to different infections is less clear. In a recent issue of Cell Host & Microbe, Thiemann et al. (2017) report the identification of specific gut bacteria that protect from Salmonella infection by priming host IFN-γ responses.

Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation.

Unlabelled: Compared to other fungal pathogens, Cryptococcus neoformans is particularly adept at avoiding detection by innate immune cells. To explore fungal cellular features involved in immune avoidance, we characterized cell surface changes of the C. neoformans rim101Δ mutant, a strain that fails to organize and shield immunogenic epitopes from host detection.

Relative Contributions of Prenylation and Postprenylation Processing in Cryptococcus neoformans Pathogenesis.

Prenyltransferase enzymes promote the membrane localization of their target proteins by directing the attachment of a hydrophobic lipid group at a conserved C-terminal CAAX motif. Subsequently, the prenylated protein is further modified by postprenylation processing enzymes that cleave the terminal 3 amino acids and carboxymethylate the prenylated cysteine residue. Many prenylated proteins, including Ras1 and Ras-like proteins, require this multistep membrane localization process in order to function properly.

Impact of Protein Palmitoylation on the Virulence Potential of Cryptococcus neoformans.

The localization and specialized function of Ras-like proteins are largely determined by posttranslational processing events. In a highly regulated process, palmitoyl groups may be added to C-terminal cysteine residues, targeting these proteins to specific membranes. In the human fungal pathogen Cryptococcus neoformans, Ras1 protein palmitoylation is essential for growth at high temperature but is dispensable for sexual differentiation.

The Cryptococcus neoformans alkaline response pathway: identification of a novel rim pathway activator.

The Rim101/PacC transcription factor acts in a fungal-specific signaling pathway responsible for sensing extracellular pH signals. First characterized in ascomycete fungi such as Aspergillus nidulans and Saccharomyces cerevisiae, the Rim/Pal pathway maintains conserved features among very distantly related fungi, where it coordinates cellular adaptation to alkaline pH signals and micronutrient deprivation. However, it also directs species-specific functions in fungal pathogens such as Cryptococcus neoformans, where it controls surface capsule expression.