23 research outputs found
Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence
Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells’ oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells’ hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress
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Interferon (IFN)-λ Takes the Helm: Immunomodulatory Roles of Type III IFNs
Type III interferons (IFNs) (or IFN-λ) are the latest addition to the IFN family. Even though they share little protein homology with type I IFN, both exhibit remarkable functional similarities: each can be induced in response to viral infections, and both lead to Janus kinases (JAK) and signal transducer and activator of transcription (STAT) activation. The JAK/STAT pathway induces antiviral responses and IFN-stimulated gene transcription. However, despite the similarities in their effector functions with type I IFNs, IFN-λ also has a non-redundant role in protecting barrier organs: epithelial cells preferentially produce IFN-λ rather than type I IFNs; and interferon lambda receptor 1 (IFNLR1), the specific receptor for IFN-λ, is highly expressed on cells of epithelial lineage. Thus far, IFN-λ has been considered mainly as an epithelial cytokine, which restricts viral replication in epithelial cells and constitutes an added layer of protection at mucosal sites. However, it is now increasingly recognized that IFNLR1 is expressed broadly, and that immune cells such as neutrophils and dendritic cells also respond to IFN-λ. Moreover, in many in vivo models, IFN-λ modulates immune cell functions and thereby configures itself less as a cytokine that is only specific to the epithelium, and more as a cytokine that directly controls the inflammatory response at mucosal sites. Here, we critically review the recent literature on immune modulatory roles for IFN-λ, and distinguish between the direct and indirect effects of this IFN on immune cell functions in different inflammatory settings
Editorial: Type III interferons: Emerging roles beyond antiviral barrier defense
International audienceType III interferons or IFN-λs, are composed of 4 members: IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. IFN-λs are master protectors against mucosal viral infections due to the preferential expression of their cognate receptor, IFNLR1, to cells of epithelial lineage and to a restricted pool of immune cells. IFN-λ receptor activation induces intracellular signaling that overlaps with that of type I interferons (IFN-I) and culminates with the induction of Interferon-Stimulated-Genes (ISG) with antiviral functions. However, several studies have uncovered non-redundant functions of IFN-λs, compared to IFN-I, that go beyond viral restriction at epithelial barriers. In this topic, we highlighted several emerging aspects of IFN-λ biology, including: their ability to restrict non-viral infections, the mechanisms by which they modulate immune responses, and the enigmatic role of human IFN-λ4
Editorial: Type III interferons: Emerging roles beyond antiviral barrier defense
International audienceType III interferons or IFN-λs, are composed of 4 members: IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. IFN-λs are master protectors against mucosal viral infections due to the preferential expression of their cognate receptor, IFNLR1, to cells of epithelial lineage and to a restricted pool of immune cells. IFN-λ receptor activation induces intracellular signaling that overlaps with that of type I interferons (IFN-I) and culminates with the induction of Interferon-Stimulated-Genes (ISG) with antiviral functions. However, several studies have uncovered non-redundant functions of IFN-λs, compared to IFN-I, that go beyond viral restriction at epithelial barriers. In this topic, we highlighted several emerging aspects of IFN-λ biology, including: their ability to restrict non-viral infections, the mechanisms by which they modulate immune responses, and the enigmatic role of human IFN-λ4
Longitudinal Changes of Insulin Sensitivity in Essential Hypertension: Influence of Blood Pressure Control and Familial Predisposition to Hypertension
Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells
International audienc
Longitudinal study on insulin sensitivity in hypertension: influence of blood pressure control and genetic predisposition to hypertension
AORTIC STIFFNESS IN NEVER - TREATED HYPERTENSIVES: LACK OF RELATION WITH MYOCARDIAL HYPERTROPHY AND IMPAIRED LEFT VENTRICULAR RELAXATION
Zinc-dependent histone deacetylases drive neutrophil extracellular trap formation and potentiate local and systemic inflammation
International audienc