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Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity

BACKGROUND: Human filarial infection is characterized by downregulated parasite-antigen specific T cell responses but distinct differences exist between patients with longstanding infection (endemics) and those who acquired infection through temporary residency or visits to filarial-endemic regions...

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Autores principales: Steel, Cathy, Varma, Sudhir, Nutman, Thomas B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289604/
https://www.ncbi.nlm.nih.gov/pubmed/22389737
http://dx.doi.org/10.1371/journal.pntd.0001527
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author Steel, Cathy
Varma, Sudhir
Nutman, Thomas B.
author_facet Steel, Cathy
Varma, Sudhir
Nutman, Thomas B.
author_sort Steel, Cathy
collection PubMed
description BACKGROUND: Human filarial infection is characterized by downregulated parasite-antigen specific T cell responses but distinct differences exist between patients with longstanding infection (endemics) and those who acquired infection through temporary residency or visits to filarial-endemic regions (expatriates). METHODS AND FINDINGS: To characterize mechanisms underlying differences in T cells, analysis of global gene expression using human spotted microarrays was conducted on CD4(+) and CD8(+) T cells from microfilaremic Loa loa-infected endemic and expatriate patients. Assessment of unstimulated cells showed overexpression of genes linked to inflammation and caspase-associated cell death, particularly in endemics, and enrichment of the Th1/Th2 canonical pathway in endemic CD4(+) cells. However, pathways within CD8(+) unstimulated cells were most significantly enriched in both patient groups. Antigen (Ag)-driven gene expression was assessed to microfilarial Ag (MfAg) and to the nonparasite Ag streptolysin O (SLO). For MfAg-driven cells, the number of genes differing significantly from unstimulated cells was greater in endemics compared to expatriates (p<0.0001). Functional analysis showed a differential increase in genes associated with NFkB (both groups) and caspase activation (endemics). While the expatriate response to MfAg was primarily a CD4(+) pro-inflammatory one, the endemic response included CD4(+) and CD8(+) cells and was linked to insulin signaling, histone complexes, and ubiquitination. Unlike the enrichment of canonical pathways in CD8(+) unstimulated cells, both groups showed pathway enrichment in CD4(+) cells to MfAg. Contrasting with the divergent responses to MfAg seen between endemics and expatriates, the CD4(+) response to SLO was similar; however, CD8(+) cells differed strongly in the nature and numbers (156 [endemics] vs 36 [expatriates]) of genes with differential expression. CONCLUSIONS: These data suggest several important pathways are responsible for the different outcomes seen among filarial-infected patients with varying levels of chronicity and imply an important role for CD8(+) cells in some of the global changes seen with lifelong exposure.
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spelling pubmed-32896042012-03-02 Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity Steel, Cathy Varma, Sudhir Nutman, Thomas B. PLoS Negl Trop Dis Research Article BACKGROUND: Human filarial infection is characterized by downregulated parasite-antigen specific T cell responses but distinct differences exist between patients with longstanding infection (endemics) and those who acquired infection through temporary residency or visits to filarial-endemic regions (expatriates). METHODS AND FINDINGS: To characterize mechanisms underlying differences in T cells, analysis of global gene expression using human spotted microarrays was conducted on CD4(+) and CD8(+) T cells from microfilaremic Loa loa-infected endemic and expatriate patients. Assessment of unstimulated cells showed overexpression of genes linked to inflammation and caspase-associated cell death, particularly in endemics, and enrichment of the Th1/Th2 canonical pathway in endemic CD4(+) cells. However, pathways within CD8(+) unstimulated cells were most significantly enriched in both patient groups. Antigen (Ag)-driven gene expression was assessed to microfilarial Ag (MfAg) and to the nonparasite Ag streptolysin O (SLO). For MfAg-driven cells, the number of genes differing significantly from unstimulated cells was greater in endemics compared to expatriates (p<0.0001). Functional analysis showed a differential increase in genes associated with NFkB (both groups) and caspase activation (endemics). While the expatriate response to MfAg was primarily a CD4(+) pro-inflammatory one, the endemic response included CD4(+) and CD8(+) cells and was linked to insulin signaling, histone complexes, and ubiquitination. Unlike the enrichment of canonical pathways in CD8(+) unstimulated cells, both groups showed pathway enrichment in CD4(+) cells to MfAg. Contrasting with the divergent responses to MfAg seen between endemics and expatriates, the CD4(+) response to SLO was similar; however, CD8(+) cells differed strongly in the nature and numbers (156 [endemics] vs 36 [expatriates]) of genes with differential expression. CONCLUSIONS: These data suggest several important pathways are responsible for the different outcomes seen among filarial-infected patients with varying levels of chronicity and imply an important role for CD8(+) cells in some of the global changes seen with lifelong exposure. Public Library of Science 2012-02-28 /pmc/articles/PMC3289604/ /pubmed/22389737 http://dx.doi.org/10.1371/journal.pntd.0001527 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Steel, Cathy
Varma, Sudhir
Nutman, Thomas B.
Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity
title Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity
title_full Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity
title_fullStr Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity
title_full_unstemmed Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity
title_short Regulation of Global Gene Expression in Human Loa loa Infection Is a Function of Chronicity
title_sort regulation of global gene expression in human loa loa infection is a function of chronicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289604/
https://www.ncbi.nlm.nih.gov/pubmed/22389737
http://dx.doi.org/10.1371/journal.pntd.0001527
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