Pulmonary infections with Aspergillus fumigatus (Af) are a significant cause of invasive fungal disease and lead to high morbidity and mortality in diverse populations throughout the world. Currently available antifungal drugs are often ineffective, thus contributing to unacceptably high mortality rates in patients suffering from invasive fungal infections. The use of cytokines as adjunctive immune therapies holds the promise of significantly improving patient outcomes in the future. In recent studies, we identified an essential role for type I and III interferons as regulators of optimal antifungal responses by pulmonary neutrophils during infection with Af. Although various membrane and cytosolic nucleic acid sensors are known to regulate interferon production in response to viruses, the pathways that regulate the production of these cytokines during fungal infection remain uncovered. In the current study, we demonstrate that dectin-1-mediated recognition of β-glucan on the cell wall of the clinically relevant fungal pathogen Aspergillus fumigatus promotes the activation of a protective cascade of type I and III interferon expression. We further demonstrate that exogenous administration of type I and III interferons can rescue inadequate antifungal responses in dectin-1 −/− mice, suggesting the potential therapeutic benefit of these cytokines as activators of antifungal defense in the context of innate defects.

The ubiquitin–proteasome system (UPS) mediates intracellular proteins degradation that influences various cellular functions in eukaryotic cells. The UPS is also involved in the development and virulence of pathogenic fungi. F-box proteins, which are part of the SCF (Skp1-Cullin-F-box protein) ligase, are a key component of UPS and are essential for the recognition of specific substrates. In this study, we identified 20 F-box proteins in C. neoformans and obtained deletion mutants for 19 of them. A comprehensive phenotypic analysis of these mutants revealed the diverse function of F-box proteins in stress response, cell size regulation, sexual reproduction, antifungal drug resistance, and fungal virulence in C. neoformans. The importance of three F-box proteins: Fbp4, Fbp8, and Fbp11, in these cellular functions were characterized in detail. This study provides an overall view of the F-box gene family in C. neoformans, which will lead to a better understanding of the function of fungal SCF E3 ligase-mediated UPS in fungal development and pathogenesis.

The bone morphogenic protein family (~20 BMPs in humans), are members of the transforming growth factor-β (TGF-β) superfamily. BMPs have been shown to exert important roles during development and organogenesis by delivering positional information in both vertebrates and invertebrates. We had previously observed early induction of mRNA for BMP10 in rat B cells soon after Aggregatibacter actinomycetemcomitans (Aa) bacterial infection, in studies conducted in a rat model for human periodontal disease. However, prior to the onset of bone resorption, BMP10 mRNA precipitously declined. Being the first demonstration that mRNA for BMP10 is expressed by lymphocytes, we examined the expression of BMP10, at the protein level. Peripheral blood lymphocytes from humans, rats and mice were purified, by micro-immunomagnetic bead separation, into B cell, CD4, and CD8 T cell fractions. Flow cytometry analysis conducted with anti-BMP10 antibody revealed cellular expression of BMP10 in all the fractions examined. Interestingly, activation of CD4 T cells by Con A, rodent B cells by LPS, or human B cells by S. Aureus, resulted in drastic shut-down of BMP10 expression at mRNA and protein levels. In conclusion, our studies demonstrate, for the first time, that lymphocytes express BMP10 protein. Furthermore, while activation of B cells by bacterial antigen induced early BMP10 expression, further chronic stimulation resulted in decline in BMP10 expression. Intriguingly, mitogen stimulation of B cells and CD4 T cells, led to a drastic reduction in BMP10 expression at mRNA and protein levels, suggesting that BMP10 might be a novel marker for naïve lymphocytes.

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