Focused Examination of the Intestinal lamina Propria Yields Greater Molecular Insight into Mechanisms Underlying SIV Induced Immune DysfunctionReportar como inadecuado




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Background

The Gastrointestinal GI tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4+ T cell destruction. Consequently GI disease, a major complication of HIV-SIV infection can facilitate translocation of lumenal bacterial products causing localized-systemic immune activation leading to AIDS progression.

Methodology-Principal Findings

To better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection PI. More importantly we maximized information gathering by examining distinct mucosal components intraepithelial lymphocytes, lamina propria leukocytes LPL, epithelium and fibrovascular stroma separately. The use of sequential intestinal resections combined with focused examination of distinct mucosal compartments represents novel approaches not previously attempted. Here we report data pertaining to the LPL. A significant increase ±1.7-fold in immune defense-inflammation, cell adhesion-migration, cell signaling, transcription and cell division-differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway IL21, IL12R, STAT5A, IL10, SOCS1 and T-cell activation NFATc1, CDK6, Gelsolin, Moesin were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D-IL27 and IL28B-IFNγ3 anti-HIV-viral, activation induced cytidine deaminase B-cell function and approximately 57 genes regulating oxidative phosphorylation, a critical metabolic shift associated with T-cell activation. The 90d transcriptome revealed further augmentation of inflammation CXCL11, chitinase-1, JNK3, immune activation CD38, semaphorin7A, CD109, B-cell dysfunction CD70, intestinal microbial translocation Lipopolysaccharide binding protein and mitochondrial antiviral signaling NLRX1 genes. Reduced expression of CD28, CD4, CD86, CD93, NFATc1 T-cells, TLR8, IL8, CCL18, DECTIN1 macrophages, HLA-DOA and GPR183 B-cells at 90d PI suggests further deterioration of overall immune function.

Conclusions-Significance

The reported transcriptional signatures provide significant new details on the molecular pathology of HIV-SIV induced GI disease and provide new opportunity for future investigation.



Autor: Mahesh Mohan, Deepak Kaushal, Pyone P. Aye, Xavier Alvarez, Ronald S. Veazey, Andrew A. Lackner

Fuente: http://plos.srce.hr/



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