Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials

Immunogenetics and cellular immunology of bacterial infectious disease

alpha(1)-Antitrypsin Production by Proinflammatory and Antiinflammatory Macrophages and Dendritic Cells

Pathogenesis and treatment of chronic pulmonary disease

IFN-alpha cannot substitute lack of IFN-gamma responsiveness in cells of an IFN-gamma R1 deficient patient

Patients with complete IFN-gamma R deficiency are unable to respond to IFN-gamma and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-alpha and IFN-gamma share signalling pathways, treatment with IFN-alpha has been proposed in complete IFN-gamma R deficiency. We stimulated cells from healthy controls and from a patient lacking IFN-gamma R1 with IFN-alpha and IFN-gamma, to establish whether IFN-alpha would substitute for IFN-gamma effects. IFN-alpha induced STAT1 phosphorylation in monocytes of the IFN-gamma R1(-/-) patient, but did not prime for LPS-induced IL-12p70, IL-12p40, IL-23 or TNF production. In control cells, IFN-alpha inhibited the priming effect of IFN-gamma on LPS-induced pro-inflammatory cytokine release. Finally, IFN-gamma but not IFN-alpha induced killing of M. smegmatis in cultured macrophages. In conclusion, no evidence was found to support the use of IFN-alpha in IFN-gamma R-deficient patients as intervention against mycobacterial infection; on the contrary, treatment of individuals with IFN-alpha may even adversely affect host defence against Mycobacteria. (C) 2010 Elsevier Inc. All rights reserved.Immunogenetics and cellular immunology of bacterial infectious disease

Spaceship earth: take your classroom into space

Schools in Europe actively participated in the educational project "Spaceship Earth", part of ESA astronaut André Kuipers’ PromISSe mission. The initiative, conceptualized by the European Space Agency (ESA) and the Netherlands Space Office (NSO) also involved a unique collaboration of a team including NEMO Science Centre (Amsterdam, NL), Space Expo (Noordwijk, NL),World Wildlife Fund (WWF), the University of Amsterdam and the Vu-University of Amsterdam. André Kuipers launched from Baikonur to the ISS on 21 December 2011. By asking students aged 10-14 to ‘Join my mission’, he invited them to participate in "Spaceship Earth" or "Ruimteschip Aarde" (the Dutch version of "Spaceship Earth" specially targeting Dutch primary schools). Pupils were directly involved in this mission by following lessons developed by ESA and Science Center NEMO for the three Spaceship Earth themes: ‘Life’, ‘Biodiversity’ and ‘Weather and Climate’. Additionally the Spaceship Earth programme was represented in a longstanding exhibition in Space Expo, ESA’s Teacher Summer Workshop and the ESA Space Camp. A major part of Spaceship Earth project allowed students to compare results of experiments in the classroom with the results carried out by André in microgravity. To fulfil this objective, space hardware and ground demonstration kits were developed and delivered free of charge to schools that signed up to participate in the experiment. These kits enabled students to appreciate the role of gravity in the phenomena of convection and foam formation/stability. In addition, a direct interaction between the astronaut and the children during an inflight call allowed for a more direct contact to discuss the results both sets of experiments achieved - truly bringing the classroom into space. The NSO further tailored their Ruimteschip Aarde national programme by involving Dutch Schooltv and by maintaining a dedicated project website, where André challenged Dutch children with three specific problem solving tasks. The children submitted their solutions via short video clip or photo-shoot after which André selected the winners whilst in space. The teams with the best solution won a radio contact (ARISS) with the astronaut. The goals of the project were to make pupils, teachers and those in their social environment, aware of the conditions necessary for life and the systems that support these, both on Earth and the ISS. Furthermore the project was a tool to enhance interest in science and technology, bring attention to the importance of space exploration as well as highlight the beauty and vulnerability of planet Earth

Anti-inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors

We have made a detailed inventory of the immune infiltrate of gastrointestinal stromal tumors (GISTs), which originate from mesenchymal cells in the intestinal tract. These sarcomas are heavily infiltrated with macrophages and T cells, while immune cells of other lineages were much less abundant. Dissecting the functional subtypes of T cells with multicolor fluorescent microscopy revealed substantial populations of cytotoxic T cells, helper T cells and FoxP3(+) regulatory T cells. The balance of cytotoxic T cells and FoxP3(+) T cells was toward immune suppression. Analysis of the macrophage population also showed a dominance of anti-inflammatory cells, as the M2 type scavenger receptor CD163 was abundantly present. Other subsets of macrophages (CD14(+)CD163(-)) were occasionally detected. M2 type CD163(+) macrophages were associated with the number of infiltrating FoxP3(+) regulatory T cells and twice as many macrophages were found in metastatic GIST compared to primary lesions. Most metastatic GISTs had been treated with the tyrosine kinase inhibitors imatinib and sunitinib, but the high macrophage infiltrate was not related to this treatment. However, imatinib and sunitinib did induce secretion of anti-inflammatory IL-10 in macrophage cultures, indicating that treatment with these inhibitors might contribute to an immune suppressive microenvironment in GIST. Overall, our data reveal a picture of GIST as an active site of tumor-immune interaction in which suppressive mechanisms overrule potential antitumor responses. Tyrosine kinase inhibitors might promote this negative balance.MTG

Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species

The phagocyte NAPDH-oxidase complex consists of several phagocyte oxidase (phox) proteins, generating reactive oxygen species (ROS) upon activation. ROS are involved in the defense against microorganisms and also in immune regulation. Defective ROS formation leads to chronic granulomatous disease (CGD) with increased incidence of autoimmunity and disturbed resolution of inflammation. Because regulatory T cells (Tregs) suppress autoimmune T-cell responses and are crucial in down-regulating immune responses, we hypothesized that ROS deficiency may lead to decreased Treg induction. Previously, we showed that in p47(phox)-mutated mice, reconstitution of macrophages (Mph) with ROS-producing capacity was sufficient to protect the mice from arthritis. Now, we present evidence that Mph-derived ROS induce Tregs. In vitro, we showed that Mph ROS-dependently induce Treg, using an NADPH-oxidase inhibitor. This finding was confirmed genetically: rat or human CGD Mph with mutated p47(phox) or gp91(phox) displayed hampered Treg induction and T-cell suppression. However, basal Treg numbers in these subjects were comparable to those in controls, indicating a role for ROS in induction of peripheral Tregs. Induction of allogeneic delayed-type hypersensitivity with p47(phox)-mutated Mph confirmed the importance of Mph-derived ROS in Treg induction in vivo. We conclude that NAPDH oxidase activity in Mph is important for the induction of Tregs to regulate T cell-mediated inflammation.Nephrolog

Mycobacterial Secretion Systems ESX-1 and ESX-5 Play Distinct Roles in Host Cell Death and Inflammasome Activation

During infection of humans and animals, pathogenic mycobacteria manipulate the host cell causing severe diseases such as tuberculosis and leprosy. To understand the basis of mycobacterial pathogenicity, it is crucial to identify the molecular virulence mechanisms. In this study, we address the contribution of ESX-1 and ESX-5 - two homologous type VII secretion systems of mycobacteria that secrete distinct sets of immune modulators - during the macrophage infection cycle. Using wild-type, ESX-1- and ESX-5-deficient mycobacterial strains, we demonstrate that these secretion systems differentially affect subcellular localization and macrophage cell responses. We show that in contrast to ESX-1, the effector proteins secreted by ESX-5 are not required for the translocation of Mycobacterium tuberculosis or Mycobacterium marinum to the cytosol of host cells. However, the M. marinum ESX-5 mutant does not induce inflammasome activation and IL-1b activation. The ESX-5 system also induces a caspase-independent cell death after translocation has taken place. Importantly, by means of inhibitory agents and small interfering RNA experiments, we reveal that cathepsin B is involved in both the induction of cell death and inflammasome activation upon infection with wild-type mycobacteria. These results reveal distinct roles for two different type VII secretion systems during infection and shed light on how virulent mycobacteria manipulate the host cell in various ways to replicate and spread. Copyright © 2011 by The American Association of Immunologists, Inc

Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1

Bio-organic Synthesi