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Ziegler C.,Helmholtz Center for Infection Research | Goldmann O.,Helmholtz Center for Infection Research | Hobeika E.,Max Planck Institute for Immunobiology | Geffers R.,Helmholtz Center for Infection Research | And 2 more authors.
EMBO Molecular Medicine | Year: 2011

Staphylococcus aureus is an important human pathogen that can cause long-lasting persistent infections. The mechanisms by which persistent infections are maintained involve both bacterial escape strategies and modulation of the host immune response. So far, the investigations in this area have focused on strategies used by S. aureus to persist within the host. Here, we used an experimental mouse model to investigate the host response to persistent S. aureus infection. Our results demonstrated that T cells, which are critical for controlling S. aureus infection, gradually lost their ability to respond to antigenic stimulation and entered a state of anergy with the progression of infection towards persistence. The T cell hyporesponsiveness was reverted by co-stimulation with the phorbol ester PMA, an activator of protein kinase C, suggesting that a failure in the T cell receptor (TCR)-proximal signalling events underlie the hyporesponsive phenotype. The presence of these anergic antigen-specific T cells may contribute to the failure of the host immune response to promote sterilizing immunity during persistent S. aureus infection and also offers new possibilities for novel immunotherapeutic approaches. © 2011 EMBO Molecular Medicine. Source


Grouls S.,University of Heidelberg | Iglesias D.M.,McGill University | Wentzensen N.,U.S. National Cancer Institute | Moeller M.J.,RWTH Aachen | And 7 more authors.
Journal of the American Society of Nephrology | Year: 2012

β-Catenin/Wnt signaling is essential during early inductive stages of kidney development, but its role during postinductive stages of nephron development and maturation is not well understood. In this study, we used Pax8Cre mice to target β-catenin deficiency to renal epithelial cells at the late S-shaped body stage and the developing collecting ducts. The conditional β-catenin knockout mice formed abnormal kidneys and had reduced renal function. The kidneys were hypoplasticwith a thin cortex; a superficial layer of tubules was missing. A high proportion of glomeruli had small, underdeveloped capillary tufts. In these glomeruli, well differentiated podocytes replaced parietal epithelial cells in Bowman's capsule; capillaries toward the outer aspect of these podocytes mimicked the formation of glomerular capillaries. Tracing nephrogenesis in embryonic conditional β-catenin knockout mice revealed that these "parietal podocytes"derived from precursor cells in the parietal layer of the S-shaped body by direct lineage switch. Taken together, these findings demonstrate that β-catenin/Wnt signaling is important during the late stages of nephrogenesis and for the lineage specification of parietal epithelial cells. Copyright © 2012 by the American Society of Nephrology. Source


Ramezani-Rad P.,University of California at San Francisco | Geng H.,University of California at San Francisco | Hurtz C.,University of California at San Francisco | Chan L.N.,University of California at San Francisco | And 8 more authors.
Blood | Year: 2013

The Sox4 transcription factor mediates early B-cell differentiation. Compared with normal pre-B cells, SOX4 promoter regions in Ph+ ALL cells are significantly hypomethylated. Loss and gain-of-function experiments identified Sox4 as a critical activator of PI3K/AKT and MAPK signaling in ALL cells. ChIP experiments confirmed that SOX4 binds to and transcriptionally activates promoters of multiple components within the PI3K/AKT and MAPK signaling pathways. Cre-mediated deletion of Sox4 had little effect on normal pre-B cells but compromised proliferation and viability of leukemia cells, which was rescued by BCL2L1 and constitutively active AKT and p110 PI3K. Consistent with these findings, high levels of SOX4 expression in ALL cells at the time of diagnosis predicted poor outcome in a pediatric clinical trial (COG P9906). Collectively, these studies identify SOX4 as a central mediator of oncogenic PI3K/AKT and MAPK signaling in ALL. © 2013 by The American Society of Hematology. Source


Hoving J.C.,University of Cape Town | Kirstein F.,University of Cape Town | Nieuwenhuizen N.E.,University of Cape Town | Fick L.C.E.,University of Cape Town | And 5 more authors.
Gastroenterology | Year: 2012

Induction of colitis in mice by administration of oxazolone is mediated by T-helper (Th) 2 cells and has features of human ulcerative colitis. We investigated whether activation of interleukin (IL)-4Rα on T and B cells determines their effector functions and mediates oxazolone-induced colitis. We studied induction of colitis with oxazolone in wild-type mice and those with CD4 + T cells that did not express IL-4Rα (Lck creIL-4Rα -/lox). We also generated mice with B cells that did not express IL-4Rα (mb1 creIL-4Rα -/lox) and studied induction of colitis. Lck creIL- 4Rα -/lox mice did not develop colitis in response to oxazolone, and their levels of IL-4, IL-13, and immunoglobulin (Ig) E were reduced. Adoptive transfer of nave, wild-type CD4 + Th cells depleted of natural killer T cells to Lck creIL-4Rα -/lox mice restored their susceptibility to colitis. In contrast, Lck creIL- 4Rα -/lox mice maintained their protection against colitis when IL-13deficient CD4 + T cells were transferred. These findings indicate that development of colitis involves not only natural killer T-cell functions, but also requires IL-13 production by CD4 + T helper cells. Mb1 creIL-4Rα -/lox mice, which cannot produce IgE, were also protected against oxazolone-induced colitis. Blocking IgE binding significantly reduced mast cell numbers in colons and protected wild-type BALB/c mice from the onset of colitis. IL-4 appears to induce CD4 + Th2 cells to produce IL-13 and B cells to produce IgE, which together mediate oxazolone-induced colitis in mice. © 2012 AGA Institute. Source


Salomao R.,Federal University of Sao Paulo | Brunialti M.K.C.,Federal University of Sao Paulo | Rapozo M.M.,Federal University of Sao Paulo | Baggio-Zappia G.L.,Federal University of Sao Paulo | And 2 more authors.
Shock | Year: 2012

Since the definition of systemic inflammatory response syndrome/sepsis was originally proposed, a large amount of new information has been generated showing a much more complex scenario of inflammatory and counterinflammatory responses during sepsis. Moreover, some fundamental mechanisms of sensing and destroying invading microorganisms have been uncovered, which include the discovery of TLR4 as the lipopolysaccharide (LPS) gene, implications of innate immune cells as drivers of the adaptive response to infection, and the modulation of multiple accessory molecules that stimulate or inhibit monocyte/macrophage and lymphocyte interactions. The complexity of the infection/injury-induced immune response could be better appreciated with the application of genomics and proteomics studies, and LPS was a useful tool in many of these studies. In this review, we discuss aspects of bacterial recognition and induced cellular activation during sepsis. Because of the relevance of endotoxin (LPS) research in the field, we focus on LPS and host interactions as a clue to understand microorganisms sensing and cell signaling, then we discuss how this response is modulated in septic patients. © 2012 by the Shock Society. Source

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