Non-canonical signalling mediates changes in fungal cell wall PAMPs that drive immune evasion

This is the final version. Available from the publisher via the DOI in this record.To colonise their host, pathogens must counter local environmental and immunological challenges. Here, we reveal that the fungal pathogen Candida albicans exploits diverse host-associated signals to promote immune evasion by masking of a major pathogen-associated molecular pattern (PAMP), β-glucan. Certain nutrients, stresses and antifungal drugs trigger β-glucan masking, whereas other inputs, such as nitrogen sources and quorum sensing molecules, exert limited effects on this PAMP. In particular, iron limitation triggers substantial changes in the cell wall that reduce β-glucan exposure. This correlates with reduced phagocytosis by macrophages and attenuated cytokine responses by peripheral blood mononuclear cells. Iron limitation-induced β-glucan masking depends on parallel signalling via the iron transceptor Ftr1 and the iron-responsive transcription factor Sef1, and the protein kinase A pathway. Our data reveal that C. albicans exploits a diverse range of specific host signals to trigger protective anticipatory responses against impending phagocytic attack and promote host colonisation.Medical Research Council (MRC)European CommissionWellcome Trus

Immune cells fold and damage fungal hyphae

This is the final version. Available on open access from the Evolutionary Computation Journal via the DOI in this recordData Availability: All study data are included in the article and/or supporting information.Innate immunity provides essential protection against life-threatening fungal infections. However, the outcomes of individual skirmishes between immune cells and fungal pathogens are not a foregone conclusion because some pathogens have evolved mechanisms to evade phagocytic recognition, engulfment, and killing. For example, Candida albicans can escape phagocytosis by activating cellular morphogenesis to form lengthy hyphae that are challenging to engulf. Through live imaging of C. albicans-macrophage interactions, we discovered that macrophages can counteract this by folding fungal hyphae. The folding of fungal hyphae is promoted by Dectin-1, β2-integrin, VASP, actin-myosin polymerization, and cell motility. Folding facilitates the complete engulfment of long hyphae in some cases and it inhibits hyphal growth, presumably tipping the balance toward successful fungal clearance.Medical Research Council (MRC)Wellcome TrustEuropean Research Council (ERC)Netherlands Organization for Scientific Researc

Nature of β-1,3-Glucan-Exposing Features on Candida albicans Cell Wall and Their Modulation

Microbes that coexist with humans have evolved ways of avoiding or evading our immunological defenses. These include the masking by these microbes of their “pathogen-associated molecular patterns” (PAMPs), which are recognized as “foreign” and used to activate protective immunity.</jats:p

A CO ₂ sensing module modulates β-1,3-glucan exposure in <i>Candida albicans</i>

Our innate immune defenses have evolved to protect us against microbial infection in part via receptor-mediated detection of “pathogen-associated molecular patterns” (PAMPs) expressed by invading microbes, which then triggers their immune clearance. Despite this surveillance, many microbial species are able to colonize healthy, immune-competent individuals, without causing infection. To do so, these microbes must evade immunity. The commensal fungus Candida albicans exploits a variety of strategies to evade immunity, one of which involves reducing the exposure of a proinflammatory PAMP (β-1,3-glucan) at its cell surface. Most of the β-1,3-glucan is located in the inner layer of the C. albicans cell wall, hidden by an outer layer of mannan fibrils. Nevertheless, some β-1,3-glucan can become exposed at the fungal cell surface. However, in response to certain specific host signals, such as lactate or hypoxia, C. albican s activates an anticipatory protective response that decreases β-1,3-glucan exposure, thereby reducing the susceptibility of the fungus to impending innate immune attack. Here, we exploited the natural phenotypic variability of C. albicans clinical isolates to identify strains that do not display the response to β-1,3-glucan masking signals observed for the reference isolate, SC5314. Then, using genome-wide transcriptional profiling, we compared these non-responsive isolates with responsive controls to identify genes potentially involved in β-1,3-glucan masking. Mutational analysis of these genes revealed that a sensing module that was previously associated with CO 2 sensing also modulates β-1,3-glucan exposure in response to hypoxia and lactate in this major fungal pathogen of humans. </jats:p

Redes de política no combate à fome e à pobreza: a estratégia Comunidade Solidária no Brasil Policy networks combating hunger and poverty: the Solidarity Community strategy in Brazil

Este estudo analisou a estratégia de combate à pobreza da Comunidade Solidária (Governo Federal Brasileiro -1995-2003), examinando os mecanismos institucionais utilizados para aprimorar a focalização do Programa de Distribuição de Alimentos (PRODEA) e do Programa de Combate à Desnutrição Materno Infantil (PCDMI). Foram realizadas 97 entrevistas com atores governamentais e societários integrantes da CS nos níveis federal (9), estadual (6) e municipal (82 entrevistas em oito municípios do Estado do Rio de Janeiro), no ano de 2000. Concluiu-se que a CS avançou em identificar e convergir os programas para os municípios mais pobres e torná-los mais visíveis aos gestores. A inserção dos diferentes atores na rede da CS variou de acordo com o poder político e a capacidade institucional de cada setor. As estratégias utilizadas foram: a negociação com cada ministério para alocação prioritária de recursos a partir de um critério técnico (indigência); maior apoio técnico e acesso à informação para os municípios mais pobres, fortalecendo sua habilidade em captar recursos. O papel da CS no nível local foi limitado devido a deficiências na articulação intersetorial e a dificuldades no monitoramento da implementação dos programas e na seleção de beneficiários, limitando seu direcionamento para os grupos mais vulneráveis.<br>This paper analyzes a strategy deployed by the Brazilian Government for combating hunger and poverty: the Solidarity Community (1995-2003), particularly institutional mechanisms used to fine-tune targeting processes and allocate resources to the Food Stocks Distribution Program (PRODEA) and the Undernourished Child and High-Risk Pregnancy Program (PCDMI). Primary data were obtained through interviews with policy network players, including segments of government and society: nine Federal; six State and 82 from eight Municipalities in Rio de Janeiro state. Moving towards its goal of converging programs for the poorest municipalities, the Solidarity Community made them more visible to executive civil servants. The introduction of different sectors into the Solidarity Community network varied, according to the political clout and institutional capacity of each sector. The Solidarity Community strategy was: to negotiate criteria with Ministries for setting priorities and provide technical support and information for local governments, improving their skills for obtaining federal funding. The role of the Solidarity Community was thus limited at the local level, due to poor intersectoral networking and difficulties in monitoring program implementation and beneficiary selection processes, blunting its advantages for more vulnerable groups

Developing an (Al,Ti)NxCy interlayer to improve the durability of the Ta-C coating on magnetic recording heads

10.1007/s11249-013-0115-0Tribology Letters502233-24

Caracterização de cepas de referência de Leptospira sp utilizando a técnica de pulsed field gel electrophoresis Characterization of Leptospira sp reference strains using the pulsed field gel electrophoresis technique

INTRODUÇÃO: A leptospirose é uma zoonose endêmica, mundialmente distribuída, causada por bactérias do gênero Leptospira. Este gênero compreende espécies patogênicas e saprofíticas, com mais de 200 sorovares distintos, dificultando sua caracterização. A técnica de pulsed field gel electrophoresis tem sido empregada como uma ferramenta para auxiliar nesta caracterização. Os objetivos deste trabalho foram padronizar a técnica de PFGE, determinar os perfis moleculares das cepas de referência utilizadas pelo Laboratório de Referência Nacional para Leptospirose/Centro Colaborador da Organização Mundial de Saúde para Leptospirose e criar um banco de dados com estes perfis. MÉTODOS: Foram analisadas, por PFGE, dezenove cepas utilizando a enzima de restrição NotI. RESULTADOS: Cada cepa apresentou um perfil único que pode ser considerado como uma identidade genômica específica, com exceção dos sorovares Icterohaemorrhagiae e Copenhageni, cujos perfis foram indistinguíveis. CONCLUSÕES: Dessa forma, foi possível a criação de um banco de perfis moleculares que está sendo utilizado no Laboratório para a comparação e identificação de cepas isoladas de quadros clínicos.<br>INTRODUCTION: Leptospirosis is an endemic zoonosis of worldwide distribution, caused by bacteria of the genus Leptospira. This genus includes pathogenic and saprophytic species, with more than 200 different serovars, thus making it difficult to characterize. The technique of pulsed field gel electrophoresis has been used as a tool to aid in this characterization. The aims of this study were to standardize the PFGE technique, determine the molecular profiles of reference strains used at the National Reference Laboratory for Leptospirosis/World Health Organization Collaborating Center for Leptospirosis and create a database with these profiles. METHODS: Nineteen strains were analyzed by means of PFGE, using the restriction enzyme NotI. RESULTS: Each strain presented a unique profile that could be considered to be a specific genomic identity, with the exception of the serovars Icterohaemorrhagiae and Copenhageni, whose profiles were indistinguishable. CONCLUSIONS: It was possible to create a database of molecular profiles, which are being used in the Laboratory for comparing and identifying strains isolated from clinical cases