Aspergillus fumigatus Stimulates the NLRP3 Inflammasome through a Pathway Requiring ROS Production and the Syk Tyrosine Kinase

Invasive aspergillosis (IA) is a life-threatening disease that occurs in immunodepressed patients when infected with Aspergillus fumigatus. This fungus is the second most-common causative agent of fungal disease after Candida albicans. Nevertheless, much remains to be learned about the mechanisms by which A. fulmigatus activates the innate immune system. We investigated the inflammatory response to conidia and hyphae of A. fumigatus and specifically, their capacity to trigger activation of an inflammasome. Our results show that in contrast to conidia, hyphal fragments induce NLRP3 inflammasome assembly, caspase-1 activation and IL-1β release from a human monocyte cell line. The ability of Aspergillus hyphae to activate the NLRP3 inflammasome in the monocytes requires K+ efflux and ROS production. In addition, our data show that NLRP3 inflammasome activation as well as pro-IL-1β expression relies on the Syk tyrosine kinase, which is downstream from the pathogen recognition receptor Dectin-1, reinforcing the importance of Dectin-1 in the innate immune response against fungal infection. Furthermore, we show that treatment of monocytes with corticosteroids inhibits transcription of the gene encoding IL-1β. Thus, our data demonstrate that the innate immune response against A. fumigatus infection involves a two step activation process, with a first signal promoting expression and synthesis of pro-IL-1β; and a second signal, involving Syk-induced activation of the NLRP3 inflammasome and caspase-1, allowing processing and secretion of the mature cytokine

Biological Function and Molecular Mapping of M Antigen in Yeast Phase of Histoplasma capsulatum

Histoplasmosis, due to the intracellular fungus Histoplasma capsulatum, can be diagnosed by demonstrating the presence of antibodies specific to the immunodominant M antigen. However, the role of this protein in the pathogenesis of histoplasmosis has not been elucidated. We sought to structurally and immunologically characterize the protein, determine yeast cell surface expression, and confirm catalase activity. A 3D-rendering of the M antigen by homology modeling revealed that the structures and domains closely resemble characterized fungal catalases. We generated monoclonal antibodies (mAbs) to the protein and determined that the M antigen is present on the yeast cell surface and in cell wall/cell membrane preparations. Similarly, we found that the majority of catalase activity was in extracts containing fungal surface antigens and that the M antigen is not significantly secreted by live yeast cells. The mAbs also identified unique epitopes on the M antigen. The localization of the M antigen to the cell surface of H. capsulatum yeast and the characterization of the protein's major epitopes have important implications since it demonstrates that although the protein may participate in protecting the fungus against oxidative stress it is also accessible to host immune cells and antibody

Splenectomy for splenomegaly and secondary hypersplenism

Splenomegaly and secondary hypersplenism may be associated with acute and chronic infections, autoimmune states, portal hypertension or splenic vein thrombosis, and a number of infiltrative and neoplastic conditions involving the spleen. Our experience and that of others with these various conditions demonstrates that the decision to perform splenectomy should be based on well-defined and often strictly limited indications. Except for idiopathic splenomegaly, the presence and severity of secondary hypersplenism or severely symptomatic splenomegaly should be well documented. In each case, the potential for palliation and known mean duration of expected response must be weighed against the increased morbidity and mortality of splenectomy (as compared to operation for “primary” hypersplenism) . La splénomégalie avec hypersplénisme secondaire relève de multiples causes: infection aigue ou chronique, états autoimmunologiques, hypertension portale, thrombose de la veine splénique, lésions tumorales spléniques. L'expérience de l'auteur qui rejoint celle de nombreux collègues lui permet d'affirmer que les indications de la splénectomie doivent être bien définies et sont strictement limitées. A l'exception de la splénomégalie idiopathique, l'existence et l'intensité de l'hypersplénisme, l'importance des symptomes provoqués par la splénomégalie doivent être aprréciées avec précision. Dans chaque cas le potentiel de la rémission de l'affection et la durée de la rémission doivent être pris en considération en fonction de l'éventuelle morbidité et de l'éventuelle mortalité de la splénectomie (par comparaison avec la splénectomie pour hypersplénisme primaire). Eplenomegalia e hiperesplenismo secundario pueden estar asociados con infecciones agudas y crónicas, estados autoinmunes (síndrome de Felty, lupus eritematoso sistémico), “esplenomegalia congestiva” por hipertensión portal o trombosis de la vena esplénica y con una variedad de entidades de tipo infiltrativo y neoplásico que afectan al bazo (sarcoidosis, enfermedad de Gaucher, varios desórdenes mieloproliferativos y linfomas). Nuestra experiencia, y aquella de otros autores, con tales condiciones demuestra que la decisión de realizar esplenectomía debe estar fundamentada en indicaciones bien definidas y estrictamente limitadas. Excepto en casos de esplenomegalia idiopática, la presencia y severidad del hiperesplenismo secundario o de esplenomegalia severamente sintomática debe ser bien documentada. En cada caso debe determinarse el potencial de paliación y la duración de la respuesta que se espera obtener frente a la incrementada morbilidad y mortalidad de la esplenectomía (en comparación con la operación que se realiza por hiperesplenismo “primario”).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41318/1/268_2005_Article_BF01655279.pd

The Impact of State Abortion Policies on Teen Pregnancy Rates

Restrictive abortion policies, Teen pregnancy rates,