Unknown,Transcriptomics,Genomics,Proteomics

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Type I IFN-signaling following Pneumocystis (PC)-infection and clearance in CD4 T cell-competent mice

ABSTRACT: Type I IFN-signaling suppresses an excessive IFN-{gamma} response and prevents lung damage and chronic inflammation following Pneumocystis (PC)-infection and clearance in CD4 T cell-competent mice. Type I IFN -signaling in pulmonary CD11c+ DCs and alveolar macrophages may prevent chronic inflammation following PC lung infection and clearance by suppressing an excessive IFN-g-response via the induction of SOCS1. IFNAR-/- and wildtype mice were both Pneumocystis infected via itratracheal instillation. Pulmonary CD11c+ cells were isolated from collagen digested lungs at day 7 and day 14 post infection from both wildtype and IFNAR-/- mice using a magnetic cell sorting technique from Miltenyi with CD11c microbeads. Cells from three individual animals per group were isolated and assessed. Comparison of 2 treatment types at 2 timepoints to determine whether type I IFN signaling is initiated in resident and early recruited pulmonary CD11c+ cells following Pneumocystis lung infection and whether this is relevant to the outcome of the inflammatory response during the initiation of clearance.

ORGANISM(S): Mus musculus

SUBMITTER: Kate McInnerney

PROVIDER: E-GEOD-18607 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Type-I IFN signaling suppresses an excessive IFN-gamma response and thus prevents lung damage and chronic inflammation during Pneumocystis (PC) clearance in CD4 T cell-competent mice.

Meissner Nicole N Swain Steve S McInnerney Kate K Han Soo S Harmsen Allen G AG

The American journal of pathology 20100415 6

Immune-reconstitution after highly active antiretroviral therapy (HAART) is often incomplete, and some HIV-infected individuals fail to regenerate type-I interferon (IFN)-producing pDCs. We recently demonstrated that during Pneumocystis (PC) infection in CD4 T cell-competent mice the absence of type-I IFN signaling results in chronic pulmonary inflammation and fibrosis despite clearance. Because the mechanisms involved are poorly understood, we further characterized the role of type-I IFN signal ...[more]

PMID: 20395428

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Project description:HIV-infected persons are at increased risk for developing pulmonary diseases including chronic obstructive pulmonary disease (COPD), and the fungal opportunistic pathogen, Pneumocystis jirovecii (Pc) has been implicated in the pathogenesis of HIV-related COPD. We previously developed a non-human primate model of HIV-related COPD using simian-human immunodeficiency virus (SHIV) and Pc co-infection in cynomolgus macaques. In the present study we examined gene expression profiles in lung tissue from SHIV/Pc co-infected monkeys with COPD and compared them to SHIV-infected monkeys infected with normal lung function. Microarray technology was used to develop gene profiles, and differential gene expression was determined by a comparative evaluation of competing normalization methods applied to our expression data set followed by validation using quantitative real-time polymerase chain reaction analysis for select genes. Of over 52,000 transcripts representing more than 20,000 genes analyzed, the SHIV/Pc infected macaques with COPD exhibited 243 differentially expressed (DE) genes compared to SHIV-infected monkeys with normal lung function. DE genes fell into a number of functional categories which may be important in COPD development including: inflammation (pulmonary surfactants A2, B, C, D, upregulated; alternative macrophage activation-associated CC chemokine, upregulated), protease/antiprotease balance (cathepsin H, upregulated; alpha-1-chymotrypsin and secretory leukocyte peptidase inhibitor, downregulated), redox balance (glutathione peroxidase 4 and mitochondrial aldehyde dehydrogenase 2, upregulated) and tissue homeostasis (connective tissue growth factor, downregulated; ornithine decarboxylase antizyme, upregulated). These results identify factors and pathways that may be involved in early development of Pneumocystis and SHIV-associated COPD and reveal several novel, potential therapeutic targets. There are totally 11 samples in the experiment. The sample breakdown is as follows: KN14(group 1) is a true control in that the monkey was not infected with simian-human immunodeficiency virus (SHIV) nor was it colonized with Pneumocystis. KN02, KN03, KN07 and KN08 (group 2) are also controls of a sort. They were infected with SHIV but they did not become colonized with Pneumocystis. The remainder (KN01, KN04, KN06, KN11, KN12, KN13) (group3) were both infected with SHIV and colonized with Pneumocystis. The primary interest is in comparing the two SHIV-infected groups (2 and 3)

Dataset Information

Type I IFN-signaling following Pneumocystis (PC)-infection and clearance in CD4 T cell-competent mice

Publications

Type-I IFN signaling suppresses an excessive IFN-gamma response and thus prevents lung damage and chronic inflammation during Pneumocystis (PC) clearance in CD4 T cell-competent mice.

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