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Inflammation and degeneration of the olfactory epithelium in an immuno-deficient zebrafish

ABSTRACT: Vertebrates are protected from pathogens by an adaptive and an innate immune system. In mammals, loss of the adaptive immune system severely compromises viability. Zebrafish, in contrast, can survive for relatively long without adaptive immunity, as demonstrated by the immuno-deficient Rag1 mutant. Here, we examine whether the innate immune system is activated in the mutant, and ask whether this has any effect on the nervous system, given the finding that inflammation is linked to neurodegeneration in higher vertebrates. Using microarray analysis of the olfactory epithelium, we show that innate immune responses are upregulated. Neuronal genes are down-regulated, and immunofluorescence for the neural marker HuC shows a progressive loss of olfactory sensory neurons in mutants. Propodium iodide uptake indicates a corresponding increase in cell death. Rag1 mutant fish progressively lose their sensitivity to an olfactory cue, the alarm pheromone Schreckstoff, indicating that neuro-degeneration has a behavioral significance. Taken together, these data establish that immuno-deficiency in the zebrafish is accompanied by neuro-inflammation and loss of neurons. The microarray data document transcriptional changes associated with activation of innate immunity in the context of immunodeficiency and also identify novel genes that are potentially related to function of the olfactory system. Keywords: analysis of mutant

ORGANISM(S): Danio rerio

PROVIDER: GSE9260 | GEO | 2009/10/28

SECONDARY ACCESSION(S): PRJNA102885

REPOSITORIES: GEO

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Project description:<p>Approximately 550,000 babies born prematurely each year in the United States suffer from birth at a time in development when the respiratory tract and immune system would normally be protected and maintained in a naïve state. This project is a component of the NIH Prematurity and Respiratory Outcomes Program (PROP) whose goals are the identification of disease mechanisms and biomarkers to stratify premature infants, at the time of discharge, for their risk of subsequent pulmonary morbidity. This Clinical Research Center (CRC) project will investigate prematurity-dependent alterations in cellular innate and adaptive immune systems resulting in increased susceptibility to respiratory infections and environmental irritants, and leading to respiratory morbidity in the first year of life. Prior studies have established developmental (maturity) and disease-related changes in circulating and pulmonary lymphocyte populations, but a comprehensive assessment of their relationship to disease risk/outcome has not been undertaken. We hypothesize that cellular and molecular immuno-maturity is altered due to intrinsic and extrinsic factors presented by premature birth in such a way as to reduce resistance to viral infections and to promote cytotoxic damage to the lung. We will evaluate immunologic maturity by comprehensively phenotyping lymphocyte populations in peripheral blood sampled at premature delivery, at the time of discharge from the hospital and at twelve months corrected age. The lymphocytic phenotype will be analyzed particularly in the context of gestational age and maternal-fetal stressors capable of modulating oxidative stress (oxygen exposure, infection and environmental tobacco smoke exposure). Additionally, we will assess changes in the molecular phenotype of isolated CD8 lymphocytes, a cell type preferentially recruited to the lungs of premature infants and capable of contributing to disease pathogenesis, by genome-wide expression profiling, in order to uncover novel disease pathways and define a gene expression signature associated with disease risk. We propose to build a statistical model, using cellular and molecular phenotypes and additional clinical variables, for stratifying risk of lung morbidity within the first year of life. Finally, we will assess the development of the gut microbiome in the preterm subjects to correlate with the observation of development of the adaptive immune system.</p>

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Inflammation and degeneration of the olfactory epithelium in an immuno-deficient zebrafish

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