UMMS Affiliation

Program in Molecular Medicine; Program in Bioinformatics and Integrative Biology

Publication Date

2018-01-22

Document Type

Article

Disciplines

Bacterial Infections and Mycoses | Bioinformatics | Computational Biology | Genetics and Genomics | Immunity | Immunology of Infectious Disease

Abstract

To better understand the innate immune response to Vibrio cholerae infection, we tracked gene expression in the duodenal mucosa of 11 Bangladeshi adults with cholera, using biopsy specimens obtained immediately after rehydration and 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-kappaB, mitogen-activated protein kinase (MAPK), and Toll-like receptor (TLR)-mediated signaling pathways, which, unexpectedly, persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across the 11 participants. These genes included the endosomal Toll-like receptor gene TLR8, which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signaling in vivo, our pathway analysis found that interferon regulatory factor 7 and beta 1 and alpha 2 interferons were among the top upstream regulators activated during cholera. Among the innate immune effectors, we found that the gene for DUOX2, an NADPH oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases in DUOX2 and TLR8 expression were also modeled in vitro when Caco-2 or THP-1 cells, respectively, were stimulated with live V. cholerae but not with heat-killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response to V. cholerae extend our understanding of the mucosal immune signaling pathways and effectors activated in vivo following cholera.

Keywords

Vibrio cholerae, immune mechanisms, mucosal immunity

Rights and Permissions

Copyright © 2018, American Society for Microbiology. Publisher PDF posted as allowed by the publisher's copyright policy at https://journals.asm.org/content/copyright-transfer-and-supplemental-material-license-agreement-2017.

DOI of Published Version

10.1128/IAI.00594-17

Source

Infect Immun. 2018 Jan 22;86(2). pii: e00594-17. doi: 10.1128/IAI.00594-17. Print 2018 Feb. Link to article on publisher's site

Journal/Book/Conference Title

Infection and immunity

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

29133347

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