Neisseria gonorrhoeae Modulates Iron-Limiting Innate Immune Defenses in Macrophages

• Type of Material: Article
• Authors: Susu M Zughaier, Emory University; Justin L. Kandler, Emory University; William M Shafer, Emory University
• Language: English
• Date: 2014
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Zughaier et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0087688
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 1
• Start Page: e87688
• End Page: e87688
• Grant/Funding Information: This study was supported by an Emory-Egleston Children's Research Center grant to S.M.Z., NIH grant U19 AI0131496 (P.F. Sparling, PI, University of North Carolina School of Medicine, W.M.S., Co-Investigator) and by a VA Merit Award grant to W.M.S. from the Medical Research Service of the Department of Veterans Affairs.
• Research Categories: Biology, Cell; Biology, Microbiology; Health Sciences, Immunology

Abstract

Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted infection termed gonorrhea. The gonococcus can survive extracellularly and intracellularly, but in both environments the bacteria must acquire iron from host proteins for survival. However, upon infection the host uses a defensive response by limiting the bioavailability of iron by a number of mechanisms including the enhanced expression of hepcidin, the master iron-regulating hormone, which reduces iron uptake from the gut and retains iron in macrophages. The host also secretes the antibacterial protein NGAL, which sequesters bacterial siderophores and therefore inhibits bacterial growth. To learn whether intracellular gonococci can subvert this defensive response, we examined expression of host genes that encode proteins involved in modulating levels of intracellular iron. We found that N. gonorrhoeae can survive in association (tightly adherent and intracellular) with monocytes and macrophages and upregulates a panel of its iron-responsive genes in this environment. We also found that gonococcal infection of human monocytes or murine macrophages resulted in the upregulation of hepcidin, NGAL, and NRAMP1 as well as downregulation of the expression of the gene encoding the short chain 3-hydroxybutyrate dehydrogenase (BDH2); BDH2 catalyzes the production of the mammalian siderophore 2,5-DHBA involved in chelating and detoxifying iron. Based on these findings, we propose that N. gonorrhoeae can subvert the iron-limiting innate immune defenses to facilitate iron acquisition and intracellular survival.