Neisseria gonorrhoeae modulates iron-limiting innate immune defenses in macrophages.
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.
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Susu M
SM
Zughaier
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Justin L
JL
Kandler
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America ; Laboratories of Microbial Pathogenesis, Department of Veterans Affairs Medical Center, Decatur, Georgia, United States of America.
William M
WM
Shafer
D015536:Down-Regulation; D006801:Humans; D006884:Hydroxybutyrate Dehydrogenase / Q000235:genetics; D007113:Immunity, Innate; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D009344:Neisseria gonorrhoeae / Q000276:immunology* / Q000378:metabolism; D014774:Virulence
D007501:Iron; C510607:BDH2 protein, human; D006884:Hydroxybutyrate Dehydrogenase