Recognition of yeast ß-glucan particles triggers immunometabolic signaling required for trained immunity.

Fungal ß-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in ß-glucan source, structure, and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse ß-glucans, we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogram metabolism and thereby drive trained immunity in human monocyte-derived macrophages in vitro and mice bone marrow in vivo. Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming, and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive trained immunity. Thus, the investment of a cell in a trained response relies on specific recognition of ß-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.

Human MAIT Cells Respond to Staphylococcus aureus with Enhanced Anti-Bacterial Activity.

Mucosal-Associated Invariant T (MAIT) cells have been shown to play protective roles during infection with diverse pathogens through their propensity for rapid innate-like cytokine production and cytotoxicity. Among the potential applications for MAIT cells is to defend against Staphylococcus aureus, a pathogen of serious clinical significance. However, it is unknown how MAIT cell responses to S. aureus are elicited, nor has it been investigated whether MAIT cell cytotoxicity is mobilized against intracellular S. aureus. In this study, we investigate the capacity of human MAIT cells to respond directly to S. aureus. MAIT cells co-cultured with dendritic cells (DCs) infected with S. aureus rapidly upregulate CD69, express IFNγ and Granzyme B and degranulate. DC secretion of IL-12, but not IL-18, was implicated in this immune response, while TCR binding of MR1 is required to commence cytokine production. MAIT cell cytotoxicity resulted in apoptosis of S. aureus-infected cells, and reduced intracellular persistence of S. aureus. These findings implicate these unconventional T cells in important, rapid anti-S. aureus responses that may be of great relevance to the ongoing development of novel anti-S. aureus treatments.

Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies.

Staphylococcus aureus is one of the most important human pathogens worldwide. Its high antibiotic resistance profile reinforces the need for new interventions like vaccines in addition to new antibiotics. Vaccine development efforts against S. aureus have failed so far however, the findings from these human clinical and non-clinical studies provide potential insight for such failures. Currently, research is focusing on identifying novel vaccine formulations able to elicit potent humoral and cellular immune responses. Translational science studies are attempting to discover correlates of protection using animal models as well as in vitro and ex vivo models assessing efficacy of vaccine candidates. Several new vaccine candidates are being tested in human clinical trials in a variety of target populations. In addition to vaccines, bacteriophages, monoclonal antibodies, centyrins and new classes of antibiotics are being developed. Some of these have been tested in humans with encouraging results. The complexity of the diseases and the range of the target populations affected by this pathogen will require a multipronged approach using different interventions, which will be discussed in this review.

Targeting Skin-Resident Memory T Cells via Vaccination to Combat Staphylococcus aureus Infections.

Tissue-resident memory T cells are important in adaptive immunity against many infections, rendering these cells attractive potential targets in vaccine development. Genetic and experimental evidence highlights the importance of cellular immunity in protection from Staphylococcus aureus skin infections, yet skin-resident memory T cells are, thus far, an untested component of immunity during such infections. Novel methods of generating and sampling vaccine-induced skin memory T cells are paralleled by discoveries of global, skin-wide immunosurveillance. We propose skin-resident memory CD4+ T cells as a potential missing link in the search for correlates of protection during S. aureus infections. A better appreciation of their phenotypes and functions could accelerate the development of preventive vaccines against this highly virulent and antibiotic-resistant pathogen.