The Gonococcal Fur-Regulated tbpA and tbpB Genes Are Expressed during Natural Mucosal Gonococcal Infection

Department of Medicine, Boston University, Boston, Massachusetts, United States
Infection and Immunity (Impact Factor: 3.73). 08/2005; 73(7):4281-7. DOI: 10.1128/IAI.73.7.4281-4287.2005
Source: PubMed


Iron is limiting in the human host, and bacterial pathogens respond to this environment by regulating gene expression through
the ferric uptake regulator protein (Fur). In vitro studies have demonstrated that Neisseria gonorrhoeae controls the expression of several critical genes through an iron- and Fur-mediated mechanism. While most in vitro experiments
are designed to determine the response of N. gonorrhoeae to an exogenous iron concentration of zero, these organisms are unlikely to be exposed to such severe limitations of iron
in vivo. To determine if N. gonorrhoeae expresses iron- and Fur-regulated genes in vivo during uncomplicated gonococcal infection, we examined gene expression profiles
of specimens obtained from male subjects with urethral infections. RNA was isolated from urethral swab specimens and used
as a template to amplify, by reverse transcriptase PCR (RT-PCR), gonococcal genes known to be regulated by iron and Fur (tbpA, tbpB, and fur). The constitutively expressed gonococcal rmp gene was used as a positive control. RT-PCR analysis indicated that gonorrhea-positive specimens where rmp expression was seen were also 93% (51/55) fbpA positive, 87% (48/55) tbpA positive, and 86% (14 of 16 tested) tbpB positive. In addition, we detected a fur transcript in 79% (37 of 47 tested) of positive specimens. We also measured increases in levels of immunoglobulin G antibody
against TbpA (91%) and TbpB (73%) antigens in sera from infected male subjects compared to those in uninfected controls. A
positive trend between tbpA gene expression and TbpA antibody levels in sera indicated a relationship between levels of gene expression and immune response
in male subjects infected with gonorrhea for the first time. These results indicate that gonococcal iron- and Fur-regulated
tbpA and tbpB genes are expressed in gonococcal infection and that male subjects with mucosal gonococcal infections exhibit antibodies
to these proteins.

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    • "These antibody levels were well below those associated with a protective response, as was detected against tetanus toxoid. While the Tbps are clearly expressed in vivo (Agarwal et al., 2005), the mere presence of these proteins within the context of a natural infection is insufficient to initiate a high-titer, protective immune response (Price et al., 2004), consistent with the lack of immunity following natural infections. "
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    ABSTRACT: Neisseria gonorrhoeae causes the common sexually transmitted infection, gonorrhea. This microorganism is an obligate human pathogen, existing nowhere in nature except in association with humans. For growth and proliferation, N. gonorrhoeae requires iron and must acquire this nutrient from within its host. The gonococcus is well-adapted for growth in diverse niches within the human body because it expresses efficient transport systems enabling use of a diverse array of iron sources. Iron transport systems facilitating the use of transferrin, lactoferrin, and hemoglobin have two components: one TonB-dependent transporter and one lipoprotein. A single component TonB-dependent transporter also allows N. gonorrhoeae to avail itself of iron bound to heterologous siderophores produced by bacteria within the same ecological niche. Other TonB-dependent transporters are encoded by the gonococcus but have not been ascribed specific functions. The best characterized iron transport system expressed by N. gonorrhoeae enables the use of human transferrin as a sole iron source. This review summarizes the molecular mechanisms involved in gonococcal iron acquisition from human transferrin and also reviews what is currently known about the other TonB-dependent transport systems. No vaccine is available to prevent gonococcal infections and our options for treating this disease are compromised by the emergence of antibiotic resistance. Because iron transport systems are critical for the survival of the gonococcus in vivo, the surface-exposed components of these systems are attractive candidates for vaccine development or therapeutic intervention.
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    ABSTRACT: Gonorrhea is the second most commonly reported infectious disease in the USA, and incidence has been increasing in recent years. Antibiotic resistance among clinical isolates has reached a critical point at which the CDC currently recommends only a single class of antibiotic for treatment. These developments have hastened the search for a vaccine to protect against gonococcal infections. Vaccine efforts have been thwarted by the ability of the gonococcus to antigenically vary most surface structures. The transferrin-iron transport system is not subject to high-frequency phase or antigenic variation and is expressed by all pathogenic Neisseria. Vaccine formulations comprised of epitopes of the transferrin-binding proteins complexed with inactivated cholera toxin generated antibodies with potentially protective characteristics. These antigens, and others predicted from genome sequence data, could be developed into a vaccine that protects against neisserial infections.
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