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.
Highlights
Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted disease gonorrhea with more than 100 million cases estimated yearly world-wide [1]
We report that N. gonorrhoeae can survive intracellularly or in association with monocytes and macrophages, and that gonococcal infection of these cells upregulates expression of hepcidin, NGAL, and NRAMP1 and downregulates BDH2 and ferroportin expression
We found that N. gonorrhoeae survived killing by human THP-1 monocytes at 1, 2, and 5 hr post infection (Figure 1A)
Summary
Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted disease gonorrhea with more than 100 million cases estimated yearly world-wide [1] Gonococci can cause both symptomatic and asymptomatic infections in men and women, which is thought to be dictated by host and bacterial factors that determine the extent of stimulation of the pro-inflammatory response. Much less is known regarding how it acquires nutrients for growth, especially iron, during intracellular residence In this respect, most iron, whether in the extracellular or intracellular environments, is tightly complexed with iron-binding proteins and not readily available for microbes. The host increases production of hepcidin, the master ironregulating hormone, to limit the bioavailability of iron [7] This host defense strategy, called the iron-limiting innate immune defense [6], can influence iron availability and survival of intracellular bacteria in response to infection
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