Experimental Gonococcal Urethritis and Reinfection with Homologous Gonococci in Male Volunteers

Schmidt, Katherine A.; Schneider, Herman; Lindstrom, Jill; Boslego, John W.; Warren, Richard; Verg, Lillian Van De; Deal, Carolyn D.; McClain, J. Bruce; Griffiss, J. McLeod

doi:10.1097/00007435-200110000-00001

Cited by 70 publications

(66 citation statements)

References 46 publications

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“…In general, gonococcal infection is characterized as a localized and mild disease, and gonococcal infection rarely induces protective immunity against future infection, as evidenced by repetitive infections of individuals with the same strain (20,21). We recently demonstrated that immunosuppression, or immune tolerance, elicited by gonococci was associated with the selective inhibition of Th1 and Th2 cells through the induction of TGF-b along with the enhancement of Th17 cell development in response to TLR4 signaling by LOS (22).…”

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confidence: 99%

Induction of Endotoxin Tolerance by Pathogenic Neisseria Is Correlated with the Inflammatory Potential of Lipooligosaccharides and Regulated by MicroRNA-146a

John

Jarvis

2014

The Journal of Immunology

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In this article, we report that retreatment of human monocytic THP-1 cells and primary monocytes with pathogenic Neisseria or with purified lipooligosaccharides (LOS) after previous exposure to LOS induced immune tolerance, as evidenced by reduced TNF-α and IL-1β cytokine expression. LOS that we have previously shown to vary in their potential to activate TLR4 signaling, which was correlated with differences in levels of lipid A phosphorylation, had similarly variable ability to induce tolerance. Efficacy for induction of tolerance was proportional to the level of lipid A phosphorylation, as LOS from meningococcal strain 89I with the highest degree of phosphorylation was the most tolerogenic following retreatment with LOS or whole bacteria, compared with LOS from gonococcal strains 1291 and GC56 with reduced levels of phosphorylation. Hydrogen fluoride treatment of 89I LOS to remove phosphates rendered the LOS nontolerogenic. Tolerance induced by the more highly inflammatory meningococcal LOS was correlated with significantly greater downregulation of p38 activation, greater induction of the expression of A20 and of microRNA-146a, and greater reductions in IL-1R–associated kinase 1 and TRAF6 levels following LOS retreatment of cells. The role of miR-146a in regulation of induction of TNF-α was confirmed by transfecting cells with an inhibitor and a mimic of miR-146a. Our results provide a mechanistic framework for understanding the variable pathophysiology of meningococcal and gonococcal infections given that after an initial exposure, greater upregulation of microRNA-146a by more highly inflammatory LOS conversely leads to the suppression of immune responses, which would be expected to facilitate bacterial survival and dissemination.

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confidence: 99%

Induction of Endotoxin Tolerance by Pathogenic Neisseria Is Correlated with the Inflammatory Potential of Lipooligosaccharides and Regulated by MicroRNA-146a

John

Jarvis

2014

The Journal of Immunology

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“…For N. gonorrhoeae and N. meningitidis Tfp, such concerns are complicated by the extensive antigenic variability of the PilE pilin subunit that arises due to gene conversion-like events between a single expression locus and multiple, variable partial gene copies (9). The high degree of PilE antigenic variation likely contributes to both the failure of gonococcal infection to engender protective immunity (10) and the lack of efficacy associated with N. gonorrhoeae Tfp-based vaccines (11).…”

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confidence: 99%

Neisseria gonorrhoeae Type IV Pili Undergo Multisite, Hierarchical Modifications with Phosphoethanolamine and Phosphocholine Requiring an Enzyme Structurally Related to Lipopolysaccharide Phosphoethanolamine Transferases

Aas

Egge-Jacobsen

Winther‐Larsen

et al. 2006

Journal of Biological Chemistry

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The zwitterionic phospho-forms phosphoethanolamine and phosphocholine are recognized as influential and important substituents of pathogen cell surfaces. PilE, the major pilin subunit protein of the type IV pilus (Tfp) colonization factor of Neisseria gonorrhoeae undergoes unique, post-translational modifications with these moieties. These phospho-form modifications have been shown to be O-linked alternately to a specific, conserved serine residue of PilE. However, the enzymes and precursors involved in their addition are unknown, and the full spectrum of PilE posttranslational modifications has yet to be defined. Here, an intact protein-based mass spectrometric approach was integrated with bioinformatics and reverse genetics to address these matters. Specifically we show that a protein limited in its distribution to pathogenic Neisseria species and structurally related to enzymes implicated in phosphoethanolamine modification of lipopolysaccharide is necessary for PilE covalent modification with phosphoethanolamine and phosphocholine. These findings strongly suggest that protein phospho-form modification is mechanistically similar to processes underlying analogous modifications of prokaryotic saccharolipid glycans. We also show that PilE undergoes multisite and hierarchical phospho-form modifications and that the stoichiometries of site occupancy can be influenced by PilE primary structure and the abundance of the pilin-like protein PilV. Together, these findings have important implications for the structure and antigenicity of PilE.Covalent post-translational modifications of surface proteins in microbial pathogens are now a well established phenomenon. By modifying structure and potentially function, such post-translational modifications are likely to play an important role in the parasite-host interaction. Moreover, post-translational modifications provide effective means to augment the information content of compact genomes, to generate diversity, and to influence antigenicity. By way of example, covalent protein modifications with N-and O-linked carbohydrate appear more and more as common features of proteins of bacterial pathogens (1). Studies have revealed a surprisingly high degree of conservation and relatedness in a number of these systems, and in some instances glycosylation-defective mutants have been shown to be attenuated in virulence-associated properties (2, 3) and colonization (4 -7). Nonetheless, the full significance of protein glycosylation has yet to be precisely defined in any prokaryotic system. Type IV pili (Tfp) 4 are proteinaceous polymeric filaments that serve critical roles in disease pathogenesis and prokaryotic cell biology in many Gram-negative species. Important human pathogens expressing Tfp include Neisseria gonorrhoeae, Neisseria meningitidis, Vibrio cholerae, Pseudomonas aeruginosa, and enteropathogenic strains of Escherichia coli (8). Tfp contribute to colonization by virtue of promoting binding to epithelial cells, motility-generating capacity, and the ability to aggregate ...

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“…After inoculation, some subjects may develop disease while others are asymptomatic or recover without treatment. Reinfection experiments usually have addressed whether experimental or natural infection with a pathogen affords protection against subsequent experimental challenge (5,14,17,24,33). Reinfection trials generally have not addressed the issue of differences in host susceptibility to disease.…”

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confidence: 99%

Differences in Host Susceptibility to Disease Progression in the Human Challenge Model ofHaemophilus ducreyiInfection

Spinola

Bong²,

Faber

et al. 2003

Infect Immun

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With human volunteers inoculated at two sites with Haemophilus ducreyi, outcomes for a subject were not independent. In a reinfection trial, 2 of 11 previous pustule formers and 6 of 10 previous resolvers resolved all sites of infection. There was no correlation between serum bactericidal or phagocytic activity and outcome in the trial. These data indicate that different hosts are differentially susceptible to disease progression versus resolution in the model.Human inoculation experiments with many infectious agents have contributed to our understanding of transmission, pathogenesis, natural history, treatment, and vaccine development (12,25,31). After inoculation, some subjects may develop disease while others are asymptomatic or recover without treatment. Reinfection experiments usually have addressed whether experimental or natural infection with a pathogen affords protection against subsequent experimental challenge (5, 14,17,24,33). Reinfection trials generally have not addressed the issue of differences in host susceptibility to disease.To study Haemophilus ducreyi pathogenesis in humans, we developed an experimental model of infection in human volunteers (40). In the model, subjects are inoculated at multiple sites with strain 35000HP (HP, human passaged) via puncture wounds made in the skin of the upper arm by an allergy-testing device (6, 39). Within 24 h of inoculation, papules develop. These spontaneously resolve or progress to pustules in resemblance to the initial stages of natural chancroid. Lesion outcomes for an individual subject inoculated at multiple sites with identical suspensions of 35000HP sometimes differ in that a pustule may develop at one site while another site resolves (6, 39). Due to the fact that outcomes at different sites are not always the same, we initially used site as the unit of measurement for the calculation of papule and pustule formation rates. These analyses show a significant effect of the estimated delivered dose (EDD) on papule and pustule formation rates (4, 10). Although there is no effect of gender on papule formation, men are twice as likely to form pustules as women (consistent with the high male-to-female ratio in natural disease) (10).Throughout experimental infection, H. ducreyi colocalizes with collagen and fibrin and professional phagocytes (7,8). Fibrin and collagen deposition occur as part of the normal process of wound repair and provide a matrix for the infiltrating polymorphonuclear leukocytes (PMNs) and macrophages (7). The presence of fibrin suggests that serum transudates into the wounds. Interestingly, an isogenic mutant that lacks DsrA, an outer membrane protein which has several functions (including serum resistance) (13, 15), forms papules that do not progress to pustule formation (11). In pustules, the parent 35000HP strain is surrounded but not taken up by PMNs or macrophages. Thus, serum resistance and evasion of phagocytosis are virulence determinants in the model.In the model, some subjects form at least one pustule and other subjects reso...

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Experimental Gonococcal Urethritis and Reinfection with Homologous Gonococci in Male Volunteers

Abstract: Although infection did not provide protection from reinfection under the conditions used, the results suggest that immunity to reinfection is more complex than anticipated by the experimental design.

Cited by 70 publications

References 46 publications

Induction of Endotoxin Tolerance by Pathogenic Neisseria Is Correlated with the Inflammatory Potential of Lipooligosaccharides and Regulated by MicroRNA-146a

Induction of Endotoxin Tolerance by Pathogenic Neisseria Is Correlated with the Inflammatory Potential of Lipooligosaccharides and Regulated by MicroRNA-146a

Neisseria gonorrhoeae Type IV Pili Undergo Multisite, Hierarchical Modifications with Phosphoethanolamine and Phosphocholine Requiring an Enzyme Structurally Related to Lipopolysaccharide Phosphoethanolamine Transferases

Differences in Host Susceptibility to Disease Progression in the Human Challenge Model ofHaemophilus ducreyiInfection

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