LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, Schweighoffer E, Tybulewicz V, Brown GD, Ruland J, Reis e Sousa C

LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, Schweighoffer E, Tybulewicz V, Brown GD, Ruland J, Reis e Sousa C. tumor necrosis factor alpha (TNF-), the formation of neutrophil extracellular traps (NETs), phagocytosis, and neutrophil swarming, appear to be critically dependent on Syk. These results demonstrate an essential role for Syk in neutrophil responses to species and raise concern for increased fungal infections with the development of Syk-modulating therapeutics. species can be found as commensals on the skin, vagina, and in the human digestive tract, yet remain harmless in most healthy hosts (9). However, in the setting of a compromised immune system, these same species can become opportunistic pathogens and acquire Midecamycin invasive features resulting in morbidity and mortality (10, 11). Among the invasive infections caused by human-pathogenic yeasts, the majority are caused by species, among which and together account for approximately 90% of invasive cases in North America (4, 9, 11). More recently, has emerged as a new species demonstrating high rates of drug resistance associated with significant mortality (12). First recognized in Midecamycin Japan in 2009 2009, has now emerged as a cause of severe illness and outbreaks in hospitalized patients around the world, including the United States (13, 14). High rates of drug resistance have Midecamycin offered clinical difficulties and in turn resulted in significant mortality (15). In addition, persists around the surfaces in rooms and gear of health care facilities despite standard cleaning procedures, increasing the risk of patient to patient transmission (14, 16). Spleen tyrosine kinase (Syk) is usually a critical kinase that was first thought to be restricted to adaptive immunity but has since been shown to play crucial functions in innate immunity, including fungal immunity (17). Many cell surface receptors, such as Dectin-1, Dectin-2, match, Midecamycin and Fc receptors, that participate in acknowledgement of Rabbit polyclonal to Caspase 4 fungal components rely on Syk for downstream signaling (15, 18, 19). The central role of Syk in adaptive immune cell activation has made this kinase a promising target for the development of anti-inflammatory therapeutics (20, 21). Small molecule Syk inhibitors are currently in clinical development Midecamycin as therapies for autoimmune disorders such as rheumatoid arthritis (22, 23), immune thrombocytopenia, and autoimmune hemolytic anemia. Security reports from clinical trials demonstrate an increased infectious risk in patients treated with inhibitors of Syk and other tyrosine kinase inhibitors (24). While Syk does play a role in many innate immune cells, its specific role in neutrophil-fungus interactions has not been elucidated. In macrophages, Syk is an important signaling factor in reactive oxygen species (ROS) production, autophagy, and phagosomal maturation, leading to augmented fungicidal activity (25,C27). Syk also activates the CARD9 pathway and mediates NLRP3 inflammasome assembly, which can contribute to innate antifungal defense (28,C31). Lastly, Syk-dependent signaling can also trigger dendritic cell maturation, CD4+ T-cell differentiation, and induction of a cascade of inflammatory cytokines bridging innate and adaptive antifungal activities (31,C34). Thus, it is of crucial importance to better understand the possible outcomes of Syk modulation in the context of host immunity against contamination. Neutrophils, or polymorphonuclear cells (PMNs), are innate immune cells that constitute the first line of defense against bacterial and fungal pathogens (17). PMNs employ a variety of effector mechanisms to control (39). In studies of neutrophil fungal interactions with interactions has not been well characterized. Despite evidence suggesting a crucial role for Syk in PMNs, elucidation of a precise role for Syk in neutrophils has been challenging for a variety of reasons. Deletion of Syk is usually embryonic lethal. Early studies on Syk-deficient neutrophils have relied on implantation of chimeric Syk-deleted liver cells into wild-type recipients resulting in removal within all hematopoietic cells (37, 40). Other studies use murine models with cell lineage-specific deletion of Syk resulting in removal in mature neutrophils or monocytes (39, 42). The short life span and terminally differentiated state of PMNs present.