Evidence for cross-regulated cytokine response in human peripheral blood mononuclear cells exposed to whole gonococcal bacteria in vitro

Rarick, Matthew; McPheeters, Crystal; Bright, Sandra A.; Navis, Allison; Skefos, Jerry; Sebastiani, Paola; Montano, Monty

doi:10.1016/j.micpath.2006.02.003

Cited by 16 publications

(17 citation statements)

References 46 publications

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“…The rmp gene was used as a basis to compare the expression of N. gonorrhoeae Fur and iron regulated genes because: (i) in vitro broth-grown N. gonorrhoeae showed equivalent rmp gene expression under both iron-depleted and iron-replete conditions (1); (ii) endocervical cell-associated N. gonorrhoeae displayed equivalent levels of rmp transcripts throughout an 8-h growth period (see Results); and (iii) the antibody levels to TbpA in men who were infected for the first time with N. gonorrhoeae were correlated with tbpA gene expression when rmp gene expression was normalized, suggesting that rmp gene expression was constitutive (1). The rmp gene has also been used as a constitutive marker for N. gonorrhoeae during infection of human peripheral blood mononuclear cells (45). Furthermore, the Rmp protein is a conserved integral gonococcal outer membrane protein that possesses conserved antigenic properties and is expressed in clinical specimens (31,32,43).…”

Section: Vol 190 2008 Expression Of the Fur Regulon During Infectiomentioning

confidence: 88%

Expression of the Gonococcal Global Regulatory Protein Fur and Genes Encompassing the Fur and Iron Regulon during In Vitro and In Vivo Infection in Women

et al. 2008

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The ferric uptake regulatory protein, Fur, functions as a global regulatory protein of gene transcription in the mucosal pathogen Neisseria gonorrhoeae. We have shown previously that several N. gonorrhoeae Furrepressed genes are expressed in vivo during mucosal gonococcal infection in men, which suggests that this organism infects in an iron-limited environment and that Fur is expressed under these conditions. In this study we have demonstrated expression of the gonococcal fur gene in vitro, in human cervical epithelial cells, and in specimens from female subjects with uncomplicated gonococcal infection. In vitro studies confirmed that the expression of the gonococcal fur gene was repressed during growth under iron-replete growth conditions but that a basal level of the protein was maintained. Using GFP transcriptional fusions constructed from specific Fur binding sequences within the fur promoter/operator region, we determined that this operator region was functional during N. gonorrhoeae infection of cervical epithelial cells. Furthermore, reverse transcription-PCR analysis, as well as microarray analysis, using a custom Neisseria Fur and iron regulon microarray revealed that several Fur-and iron-regulated genes were expressed during N. gonorrhoeae infection of cervical epithelial cells. Microarray analysis of specimens obtained from female subjects with uncomplicated gonococcal infection corroborated our in vitro findings and point toward a key role of gonococcal Fur-and iron-regulated genes in gonococcal disease.Iron homeostasis is tightly regulated in almost all bacteria because of the toxicity that results from the formation of ironcatalyzed reactive oxygen species even though iron is essential for a number of physiological functions (53). The iron-responsive transcriptional regulator Fur (ferric uptake regulator) controls the transcription of many iron-regulated genes in several microorganisms (10,11,23,24,47,48). Homologs of Fur are widespread in gram-negative bacteria and are also found in some gram-positive organisms (6, 9, 37). The role of the Fur protein as a repressor has been well documented where Fur forms a dimer with ferrous iron and binds to a consensus sequence (Fur-box) that overlaps the promoters of iron-regulated genes, resulting in the inhibition of transcription. The regulation of gene transcription by Fur and iron has been defined by the construction of Fur mutants in a variety of organisms, including Bacillus subtilis (2), Campylobacter jejuni (29), Escherichia coli (38), Vibrio cholerae (40), Neisseria meningitidis (10, 47), and Helicobacter pylori (17). Fur also functions to control the expression of genes required for pathogenesis (33, 37, 44, 52) in addition to controlling the transcription of iron transport genes. The Fur protein plays a role in the acid shock response (26), detoxification of oxygen radicals (14, 28), production of toxins and other virulence factors (37, 51), quorum sensing (8), and the regulation of metabolic pathways (42, 48) in a number of organisms. Furthermore...

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Section: Vol 190 2008 Expression Of the Fur Regulon During Infectiomentioning

confidence: 88%

Expression of the Gonococcal Global Regulatory Protein Fur and Genes Encompassing the Fur and Iron Regulon during In Vitro and In Vivo Infection in Women

et al. 2008

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“…In studies on N. gonorrhoeae-T-cell interactions, it has been shown that Th1 and Th2 cytokines are upregulated by PBMC upon exposure to N. gonorrhoeae strain F62 (Opa Ϫ Pil ϩ ) (30). Additionally, the IgA1 protease of N. gonorrhoeae (MS11) induced T-cell proliferation, CD69 upregulation, and production of IFN-␥ and TNF-␣ (38).…”

Section: Discussionmentioning

confidence: 99%

Opa⁺and Opa⁻Isolates ofNeisseria meningitidisandNeisseria gonorrhoeaeInduce Sustained Proliferative Responses in Human CD4⁺T Cells

et al. 2009

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T cells may interact with a number of bacterial surface antigens, an encounter which has the potential to downmodulate host immune responses. Neisseria meningitidis, a human colonizer and an agent of septicemia and meningitis, expresses Opa proteins which interact with the CEACAM1 receptor expressed on activated T cells. Since CEACAM1 can act as an inhibitory receptor and T cells in subepithelial tissues may encounter whole bacteria, which often express Opa proteins in vivo, this study assessed primarily if Opa proteins expressed on meningococci affect T-cell functions. In addition, Opa-containing outer membrane vesicles (OMV) have been used as vaccine antigens, and therefore Opa ؉ and Opa ؊ OMV were also studied. While Opa ؉ bacteria adhered to CEACAM-expressing T cells, both the Opa ؉ and Opa ؊ phenotypes induced no to a small transient depression, followed by a prolonged increase in proliferation as well as cytokine production. Such responses were also observed with heat-killed bacteria or OMV. In addition, while anti-CEACAM antibodies alone inhibited proliferation, on coincubation of T cells with bacteria and the antibodies, bacterial effects predominated and were Opa independent. Thus, while Opa proteins of N. meningitidis can bind to T-cell-expressed CEACAM1, this is not sufficient to overcome the T-cell recognition of bacterial factors, which results in a proliferative and cytokine response, an observation consistent with the ability of the host to establish lasting immunity to Opa-expressing meningococci that it frequently encounters. The data also imply that Opa-proficient vaccine preparations may not necessarily inhibit T-cell functions via CEACAM1 binding.

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“…Signaling through cellular receptors on epithelial cells results in the activation and recruitment of phagocytic cells, including PMNs and macrophages. Primary macrophages and peripheral blood mononuclear cells also elicit a proinflammatory response when incubated with N. gonorrhoeae (30,34,39). These innate immune cells further contribute to the array of proinflammatory cytokines and antimicrobial factors.…”

mentioning

confidence: 99%

Mouse Strain-Dependent Differences in Susceptibility toNeisseria gonorrhoeaeInfection and Induction of Innate Immune Responses

Packiam

Veit

Anderson³

et al. 2010

Infect Immun

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Acute gonorrhea in women is characterized by a mucopurulent exudate that contains polymorphonuclear leukocytes (PMNs) with intracellular gonococci. Asymptomatic infections are also common. Information on the innate response to Neisseria gonorrhoeae in women is limited to studies with cultured cells, isolated immune cells, and analyses of cervicovaginal fluids. 17␤-Estradiol-treated BALB/c mice can be experimentally infected with N. gonorrhoeae, and a vaginal PMN influx occurs in 50 to 80% of mice. Here, we compared the colonization loads and proinflammatory responses of BALB/c, C57BL/6 and C3H/HeN mice to N. gonorrhoeae. BALB/c and C57BL/6 mice were colonized at similar levels following inoculation with 10 6 CFU of N. gonorrhoeae. BALB/c, but not C57BL/6, mice exhibited a marked vaginal PMN influx. Tumor necrosis factor alpha, interleukin-6, macrophage inflammatory protein 2 (MIP-2), and keratinocyte-derived chemokine were elevated in vaginal secretions from infected BALB/c mice, but not in those from C57BL/6 mice. MIP-2 levels positively correlated with a vaginal PMN influx. In contrast to BALB/c and C57BL/6 mice, C3H/HeN mice were resistant to infection, and there was no evidence of an inflammatory response. We conclude that N. gonorrhoeae causes a productive infection in BALB/c mice that is characterized by the induction of proinflammatory cytokines and chemokines and the recruitment of PMNs. Infection of C57BL/6 mice, in contrast, is more similar to asymptomatic infection. C3H/HeN mice are inherently resistant to N. gonorrhoeae infection, and this resistance is not due to an overwhelming inflammatory response to infection. Host genetic factors can therefore impact susceptibility and the immune response to N. gonorrhoeae.

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Evidence for cross-regulated cytokine response in human peripheral blood mononuclear cells exposed to whole gonococcal bacteria in vitro

Cited by 16 publications

References 46 publications

Expression of the Gonococcal Global Regulatory Protein Fur and Genes Encompassing the Fur and Iron Regulon during In Vitro and In Vivo Infection in Women

Expression of the Gonococcal Global Regulatory Protein Fur and Genes Encompassing the Fur and Iron Regulon during In Vitro and In Vivo Infection in Women

Opa⁺and Opa⁻Isolates ofNeisseria meningitidisandNeisseria gonorrhoeaeInduce Sustained Proliferative Responses in Human CD4⁺T Cells

Mouse Strain-Dependent Differences in Susceptibility toNeisseria gonorrhoeaeInfection and Induction of Innate Immune Responses

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Evidence for cross-regulated cytokine response in human peripheral blood mononuclear cells exposed to whole gonococcal bacteria in vitro

Cited by 16 publications

References 46 publications

Expression of the Gonococcal Global Regulatory Protein Fur and Genes Encompassing the Fur and Iron Regulon during In Vitro and In Vivo Infection in Women

Expression of the Gonococcal Global Regulatory Protein Fur and Genes Encompassing the Fur and Iron Regulon during In Vitro and In Vivo Infection in Women

Opa+and Opa−Isolates ofNeisseria meningitidisandNeisseria gonorrhoeaeInduce Sustained Proliferative Responses in Human CD4+T Cells

Mouse Strain-Dependent Differences in Susceptibility toNeisseria gonorrhoeaeInfection and Induction of Innate Immune Responses

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Opa⁺and Opa⁻Isolates ofNeisseria meningitidisandNeisseria gonorrhoeaeInduce Sustained Proliferative Responses in Human CD4⁺T Cells