The term “microbiota” invokes images of mucosal surfaces densely populated with bacteria. These surfaces and the luminal compartments they form indeed predominantly harbor bacteria. However, research from this past decade has started to complete the picture by focusing on important but largely neglected constituents of the microbiota: fungi, viruses, and archaea. The community of commensal fungi, also called the mycobiota, interacts with commensal bacteria and the host. It is thus not surprising that changes in the mycobiota have significant impact on host health and are associated with pathological conditions like Inflammatory Bowel Disease (IBD). In this review we will give an overview of why the mycobiota is an important research area and different mycobiota research tools. We will specifically focus on distinguishing transient and actively colonizing fungi of the oral and gut mycobiota and their role in health and disease. In addition to correlative and observational studies, we will discuss mechanistic studies on specific cross-kingdom interactions of fungi, bacteria, and the host.
Nuclear factor of activated T cells (NFAT) is activated in innate immune cells downstream of pattern recognition receptors, but little is known about NFAT’s functions in innate immunity compared with adaptive immunity. We show that early activation of NFAT balances the two major phases of the innate response to Candida albicans skin infections: the protective containment (abscess) and the elimination (expulsion) phases. During the early containment phase, transforming growth factor–β (TGF-β) induces the deposit of collagen around newly recruited polymorphonuclear cells to prevent microbial spreading. During the elimination phase, interferon-γ (IFN-γ) blocks differentiation of fibroblasts into myofibroblasts by antagonizing TGF-β signaling. IFN-γ also induces the formation of plasmin that, in turn, promotes abscess capsule digestion and skin ulceration for microbial discharge. NFAT controls innate IFN-γ production and microbial expulsion. This cross-talk between the innate immune and the fibrinolytic systems also occurs during infection with Staphylococcus aureus and is a protective response to minimize tissue damage and optimize pathogen elimination.
Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or “Nissle”) exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin’s affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae.
Chronic inflammation is one of the causes of neurodegeneration in Amyotrophic lateral sclerosis (ALS). Here we examined whether circulating dendritic cells (DCs) can contribute to disease progression. We found ALS patients show a significant reduction in the number of circulating DCs. Also, patients’ DCs present an increased expression of CD62L and a tendency to overexpress CCR2 compared with healthy donors. Moreover, DCs derived from a subpopulation of ALS patients produced higher levels of IL-8 and CCL-2 upon lipopolysaccharide (LPS)-stimulation. Finally, we found a significant inverse correlation between the time from onset of the pathology to its diagnosis and the levels of IL-6 secretion induced by LPS. Our data support the hypothesis, in a subpopulation of patients, DCs recruited at the diseased tissue produce high levels of CCL-2 and IL-8 and contribute to the inflammatory process promoting the recruitment of other inflammatory cells. An increased efficiency of IL-6 production may accelerate only the initial phases of disease progression. Blood DC analysis can be used to identify ALS patients with an altered course of inflammatory cell recruitment at the diseased central nervous system (CNS). The high levels of CD62L expression suggests this molecule could be a target for treatment of CNS inflammation.
The skin is an extremely extended organ of the body and, due to this large surface, it is continuously exposed to microorganisms. Skin damage can easily lead to infections in the dermis which can, in turn, result in the dissemination of pathogens into the bloodstream. Understanding how the immune system fights infections at the very early stage and how the host can eliminate the pathogens is an important step to set the base for future therapeutic interventions. Here we describe a model of Candida albicans infection that can visualize the processes that occur early during an infection, including when the pathogen has passed the epithelial barrier, as well as the immune response elicited by the C. albicans invasion. We used this infection model to perform histological analyses that show the immune cells that infiltrate the skin as well as the presence and localization of the pathogen. Samples collected after the infection can be processed for RNA extraction.
The fungal gut microbiota (mycobiota) has been implicated in diseases that disturb gut homeostasis. However, little is known about functional relationships between bacteria and fungi in the gut during infectious colitis. We investigated the role of fungal metabolites during infection with the intestinal pathogen Salmonella enterica serovar Typhimurium. We found that in the gut lumen, both the mycobiota and fungi present in the diet can be a source of siderophores, small molecules that scavenge iron from the host. The ability to use fungal siderophores, such as ferrichrome and coprogen, conferred a competitive growth advantage to Salmonella strains expressing the fungal siderophore receptors FhuA or FhuE in vitro and in a mouse model. Our study highlights the role of inter-kingdom cross-feeding between fungi and Salmonella, and elucidates a new function for the gut mycobiota, revealing the importance of these under-studied members of the gut ecosystem during bacterial infection.
The study of bacterial competition systems has received significant attention in recent years. These systems are important in a multitude of polymicrobial environments and collectively shape the composition of complex ecosystems like the mammalian gut.
Salmonella enterica serovar Typhimurium ( Salmonella ) is one of the leading causes of food-borne illnesses worldwide. To colonize the gastrointestinal tract, Salmonella produces multiple virulence factors that facilitate cellular invasion. Chitinases have been recently emerging as virulence factors for various pathogenic bacterial species and the Salmonella genome contains two annotated chitinases: STM0018 ( chiA ) and STM0233. However, the role of these chitinases during Salmonella pathogenesis is unknown. The putative chitinase STM0233 has not been studied previously and only limited data exists on ChiA. Chitinases typically hydrolyze chitin polymers, which are absent in vertebrates. However, chiA expression was detected in infection models and purified ChiA cleaved carbohydrate subunits present on mammalian surface glycoproteins, indicating a role during pathogenesis. Here, we demonstrate that expression of chiA and STM0233 is upregulated in the mouse gut and that both chitinases facilitate epithelial cell adhesion and invasion. Salmonella lacking both chitinases showed a 70% reduction in invasion of small intestinal epithelial cells in vitro. In a gastroenteritis mouse model, chitinasedeficient Salmonella strains were also significantly attenuated in the invasion of small intestinal tissue. This reduced invasion resulted in significantly delayed Salmonella dissemination to the spleen and the liver, but chitinases were not required for systemic survival. The invasion defect of the chitinase-deficient strain was rescued by the presence of wild-type Salmonella , suggesting that chitinases are secreted. By analyzing N -linked glycans of small intestinal cells, we identified specific N -acetylglucosamine-containing glycans as potential extracellular targets of Salmonella chitinases. This analysis also revealed differential abundance of Lewis X-containing glycans that is likely a result of host cell modulation due to the detection of Salmonella chitinases. Similar glycomic changes elicited by chitinase deficient strains indicate functional redundancy of the chitinases. Overall, our results demonstrate that Salmonella chitinases contribute to intestinal adhesion and invasion through modulation of the host glycome.
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