TonB-dependent transporters expressed by Neisseria gonorrhoeae

Review Article published: 27 May 2011 doi: 10.3389/fmicb.2011.00117 TonB-dependent transporters expressed by Neisseria gonorrhoeae Cynthia Nau Cornelissen* and Aimee Hollander Department of Microbiology, Virginia Commonwealth University Medical Center, Richmond, VA, USA Edited by: D. Scott Merrell, Uniformed Services University, USA Reviewed by: Susan K. Buchanan, National Institutes of Health, USA Shelley M. Payne, University of Texas, USA Jorge Crosa, Oregon Health and Science University, USA *Correspondence: Cynthia Nau Cornelissen, Department of Microbiology, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0678, USA. e-mail: 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. Keywords: iron, Neisseria gonorrhoeae, TonB, transferrin, xenosiderophores Introduction Neisseria gonorrhoeae and iron “piracy” Neisseria gonorrhoeae causes a very common, but often asymptomatic sexually transmitted infection (STI). The pathogen gains a foothold in the human host via the lower genital tract, but can ascend into the upper genital tract and beyond, disseminating through the bloodstream to the joints and skin. In rare cases, N. gonorrhoeae infections can even result in meningitis (Hook and Handsfield, 2008). Neonatal conjunctivitis, or ophthalmia neonatorum, results from transmission of the bacterium from an infected mother to her newborn during a vaginal delivery (Kohlhoff and Hammerschlag, 2008). These diverse manifestations require that the gonococcus thrive in a multitude of human environments, including in the blood, in semen, on mucosal surfaces, in joint fluid, and on the conjunctiva. In each niche, the pathogen must acquire all of the nutrients, including iron, that are necessary for multiplication. Unlike most bacteria, the Neisseria species do not produce siderophores in an effort to acquire iron from the environment (West and Sparling, 1985). As well-adapted human pathogens, these bacteria instead rely entirely on iron sources obtained within the human host. Iron sources utilized by N. gonorrhoeae include transferrin (Mickelsen and Sparling, 1981) and lactoferrin (Mickelsen et al., 1982), both of which are present in micromolar concentrations in semen, the normal transmission fluid for an STI pathogen (Anderson et al., 2003). Hemoglobin (Dyer et al., 1987) and heme can also be employed by the gonococcus as sole iron sources, both www.frontiersin.org of which are present periodically in the female genital tract during menses. Heterologous siderophores produced by other bacteria (xenosiderophores) are available to the gonococcus within the context of cervical or rectal infections. It is anticipated that bacteria co-inhabiting these niches produce siderophores under iron stressed conditions, and the gonococcus takes advantage of this iron-sequestering attempt by hijacking the ferric complexes en route to the producer. Aerobactin (West and Sparling, 1987) and enterobactin (Carson et al., 1999), both produced by enteric bacteria, have previously been demonstrated to support the growth of N. gonorrhoeae. Human transferrin is a glycoprotein responsible for binding to and transporting ferric iron throughout the human body. The protein is found at highest concentrations in the serum, cerebral spinal fluid, and joint fluid, but can also be detected on mucosal membranes, particularly in inflamed tissue. Lactoferrin is found in milk, secretions, and polymorpholeukocytes. Lactoferrin is believed to be primarily responsible for iron scavenging, rather than transport, and therefore is very poorly saturated with iron in vivo. By contrast, transferrin is approximately 30% saturated with iron in the serum (for a recent review, see Wally and Buchanan, 2007). Early studies of iron use by N. gonorrhoeae demonstrated that both human glycoproteins can be efficiently employed by the gonococcus as a sole source of iron. Low saturation levels did not hinder access to the bound iron. Moreover, these seminal studies demonstrated that iron is internalized, but the iron-binding protein remains intact outside of the cell. The process of iron May 2011 | Volume 2 | Article 117 | 1 Cornelissen and Hollander removal was shown to require metabolic energy and direct contact between the glycoprotein and the bacterial cell surface (McKenna et al., 1988). Two-component systems for iron transport from host proteins Transferrin–iron acquisition The mechanism of transferrin–iron acquisition by N. gonorrhoeae has been the subject of a great deal of study. The precise details of lactoferrin and hemoglobin utilization, while expected to be similar, are less well-developed. The initial steps in characterization of the gonococcal transferrin–iron acquisition system involved the identification of two membrane proteins that bound to human transferrin (Cornelissen et al., 1992). Expression of both proteins was decreased under iron-replete conditions, consistent with a role in iron internalization. The first transferrin binding protein (Tbp) to be identified and characterized in N. gonorrhoeae was TbpA (Cornelissen et al., 1992; Figures 1 and 2). The gene that encodes this protein was sequenced and found to be similar to those encoding a family of iron transport proteins in Gram-negative bacteria known as TonB-dependent transporters. These proteins share sequence similarity primarily at their N- and C-termini, con (...truncated)