The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect

This is the final version. Available from American Society for Microbiology via the DOI in this record. Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a -1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated A. fumigatus growth inhibition, a phenomenon called the “caspofungin paradoxical effect” (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthaseencoding genes. Here, we demonstrate that the CPE is dependent on the cell wall integrity (CWI) mitogen-activated protein kinase MpkAMPK1 and its associated transcription factor (TF) RlmARLM1, which regulate chitin synthase gene expression in response to different concentrations of caspofungin. Furthermore, the calcium- and calcineurin-dependent TF CrzA binds to and regulates the expression of specific chitin synthase genes during the CPE. These results suggest that the regulation of cell wall biosynthetic genes occurs by several cellular signaling pathways. In addition, CrzA is also involved in cell wall organization in the absence of caspofungin. Differences in the CPE were also observed between two A. fumigatus clinical isolates, which led to the identification of a novel basic leucine zipper TF, termed ZipD. This TF functions in the calcium-calcineurin pathway and is involved in the regulation of cell wall biosynthesis genes. This study therefore unraveled additional mechanisms and novel factors governing the CPE response, which ultimately could aid in developing more effective antifungal therapies.CNPqFAPES

Vigilância do desenvolvimento neuropsicomotor de crianças de um programa DST/AIDS

A terapia anti-retroviral de alta potência (TARV) é uma forma eficaz de prevenção da transmissão do vírus HIV de mãe para filho. No entanto, os estudos ainda investigam os efeitos da exposição intraútero à TARV, dentre eles o atraso no desenvolvimento neuropsicomotor (DNPM). O presente estudo apresenta o relato de um projeto de extensão, cujos objetivos foram verificar o DNPM de crianças de um programa DST/AIDS, orientar as famílias considerando seu contexto socioeconômico e realizar encaminhamentos para serviços de saúde específicos. A vigilância do DNPM foi feita em três etapas: (1) avaliação em ambulatório; (2) avaliação e orientações em domicílio; (3) elaboração de relatórios aos gestores de saúde. Foram utilizados os testes DENVER II e o PEDI, além de um questionário socioeconômico. Participam do programa DST/AIDS 15 crianças, sendo 12 soro-revertidas, 1 soropositiva e 2 indefinidas. Doze crianças foram avaliadas, e os domínios mais comprometidos foram linguagem, pessoal-social e motor fino, respectivamente. Quanto ao nível econômico, 73,3% pertenciam ao nível E, e 58,3% das mães eram analfabetas ou cursaram apenas o primário. Crianças filhas de mães HIV positivo, além de fatores biológicos, geralmente estão expostas a fatores de risco ambientais que contribuem para alterações do DNPM. Desta forma, o acompanhamento por uma equipe de profissionais de saúde, em parceria com a família da criança, torna-se uma importante ferramenta para a identificação e intervenção precoce.Highly active antiretroviral therapy (HAART) is an effective way of preventing mother-to-child transmission of HIV. However, further studies investigate the effects of short and long term exposure to HAART in-utero and its consequence on child neuropsychomotor development (NPMD). The paper presents a report and discussion of results of an extension project whose objectives were to verify the NPMD of children participating of the STD/AIDS program, to orientate families according to their socioeconomic context and make referrals to specific health services. The NPMD surveillance was divided into three parts: (1) ambulatory evaluation; (2) home evaluation and orientations; (3) reporting health managers. DENVER II and PEDI tests were used and also a socioeconomic questionnaire. Fifteen children were on the program of which 12 uninfected, 1 HIV+ and 2 indeterminate. Twelve children were evaluated and the most impaired domain were language, personal-social and fine motor, respectively. Regarding to socioeconomic status, 73,3% were E level and 58,3% of mothers were analphabet or had primary school. Children born of infected mothers, besides the biological risks, usually are exposed to environment/social risks that can affect the NPMD. Thus, monitoring by a team of health professionals, in partnership with the child's family, becomes an important tool for identification and early intervention