Vaccines for Gonorrhea: Can We Rise to the Challenge?

Zhu, Wanling; Chen, Ching Ju; Thomas, C.; Anderson, John M.; Jerse, Ann E.; Sparling, P. Frederick

doi:10.3389/fmicb.2011.00124

Cited by 84 publications

(102 citation statements)

References 113 publications

(149 reference statements)

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confidence: 99%

“…Furthermore, natural gonococcal infection confers no protective immunity; as such, previously infected individuals remain susceptible to future infections (8). The ability of the gonococcus to phase and antigenically vary its surface structures is thought to contribute to its evasion of the host adaptive immune response (8,9). Recent studies have also demonstrated that the gonococcus proactively skews the host response away from humoral immunity and toward innate immunity, which is to the pathogen's advantage (9).…”

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Neisseria gonorrhoeae Evades Calprotectin-Mediated Nutritional Immunity and Survives Neutrophil Extracellular Traps by Production of TdfH

et al. 2016

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c Neisseria gonorrhoeae successfully overcomes host strategies to limit essential nutrients, termed nutritional immunity, by production of TonB-dependent transporters (TdTs)-outer membrane proteins that facilitate nutrient transport in an energy-dependent manner. Four gonococcal TdTs facilitate utilization of iron or iron chelates from host-derived proteins, including transferrin (TbpA), lactoferrin (LbpA), and hemoglobin (HpuB), in addition to xenosiderophores from other bacteria (FetA). The roles of the remaining four uncharacterized TdTs (TdfF, TdfG, TdfH, and TdfJ) remain elusive. Regulatory data demonstrating that production of gonococcal TdfH and TdfJ are unresponsive to or upregulated under iron-replete conditions led us to evaluate the role of these TdTs in the acquisition of nutrients other than iron. In this study, we found that production of gonococcal TdfH is both Zn and Zur repressed. We also found that TdfH confers resistance to calprotectin, an immune effector protein highly produced in neutrophils that has antimicrobial activity due to its ability to sequester Zn and Mn. We found that TdfH directly binds calprotectin, which enables gonococcal Zn accumulation in a TdfH-dependent manner and enhances bacterial survival after exposure to neutrophil extracellular traps (NETs). These studies highlight Zn sequestration by calprotectin as a key functional arm of NET-mediated killing of gonococci. We demonstrate for the first time that N. gonorrhoeae exploits this host strategy in a novel defense mechanism, in which TdfH production hijacks and directly utilizes the host protein calprotectin as a zinc source and thereby evades nutritional immunity.

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Neisseria gonorrhoeae Evades Calprotectin-Mediated Nutritional Immunity and Survives Neutrophil Extracellular Traps by Production of TdfH

et al. 2016

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“…Treatment failures with the last viable class of antibiotics, third-generation cephalosporins, have been encountered in several countries (7,8). The development of a protective vaccine(s) is of paramount importance (9)(10)(11)(12)(13)). An exciting development in vaccine research has been the recent success of an experimental vaccine composed of membrane vesicles derived from N. gonorrhoeae FA1090 (14) coadministered with interleukin-12.…”

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Deciphering the Function of New Gonococcal Vaccine Antigens Using Phenotypic Microarrays

et al. 2017

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The function and extracellular location of cell envelope proteins make them attractive candidates for developing vaccines against bacterial diseases, including challenging drug-resistant pathogens, such as Neisseria gonorrhoeae. A proteomicsdriven reverse vaccinology approach has delivered multiple gonorrhea vaccine candidates; however, the biological functions of many of them remain to be elucidated. Herein, the functions of six gonorrhea vaccine candidates-NGO2121, NGO1985, NGO2054, NGO2111, NGO1205, and NGO1344 -in cell envelope homeostasis were probed using phenotype microarrays under 1,056 conditions and a ΔbamE mutant (Δngo1780) as a reference of perturbed outer membrane integrity. Optimal growth conditions for an N. gonorrhoeae phenotype microarray assay in defined liquid medium were developed, which can be useful in other applications, including rapid and thorough antimicrobial susceptibility assessment. Our studies revealed 91 conditions having uniquely positive or negative effects on one of the examined mutants. A cluster analysis of 37 and 57 commonly beneficial and detrimental compounds, respectively, revealed three separate phenotype groups: NGO2121 and NGO1985; NGO1344 and BamE; and the trio of NGO1205, NGO2111, and NGO2054, with the last protein forming an independent branch of this cluster. Similar phenotypes were associated with loss of these vaccine candidates in the highly antibiotic-resistant WHO X strain. Based on their extensive sensitivity phenomes, NGO1985 and NGO2121 appear to be the most promising vaccine candidates. This study establishes the principle that phenotype microarrays can be successfully applied to a fastidious bacterial organism, such as N. gonorrhoeae. IMPORTANCE Innovative approaches are required to develop vaccines against prevalent and neglected sexually transmitted infections, such as gonorrhea. Herein, we have utilized phenotype microarrays in the first such investigation into Neisseria gonorrhoeae to probe the function of proteome-derived vaccine candidates in cell envelope homeostasis. Information gained from this screening can feed the vaccine candidate decision tree by providing insights into the roles these proteins play in membrane permeability, integrity, and overall N. gonorrhoeae physiology. The optimized screening protocol can be applied in investigations into the function of other hypothetical proteins of N. gonorrhoeae discovered in the expanding number of whole-genome sequences, in addition to revealing phenotypic differences between clinical and laboratory strains.KEYWORDS Neisseria gonorrhoeae, vaccine antigens, cell envelope, phenotypic microarrays, antibiotics, Biolog I n Gram-negative bacteria, the cell envelope is composed of the outer membrane, the cell wall, and the cytoplasmic or inner membrane, each of which can be further broken down into its constituents (1). The outer membrane is a bilayer composed of a lipopolysaccharide (LPS) or lipooligosaccharide (LOS) outer leaflet facing the extracel-

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“…Gonorrhea remains a major public health concern due to increasing Gc resistance to antibiotics, lack of protective immunity from prior infection, and no protective vaccine (2,3). The inflammatory response associated with gonorrhea leads to serious complications such as pelvic inflammatory disease and infertility (4).…”

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Assembly of NADPH Oxidase in Human Neutrophils Is Modulated by the Opacity-Associated Protein Expression State of Neisseria gonorrhoeae

2014

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Neisseria gonorrhoeae (the gonococcus, Gc) triggers a potent inflammatory response and recruitment of neutrophils to the site of infection. Gc survives exposure to neutrophils despite these cells' antimicrobial products, such as reactive oxygen species (ROS). ROS production in neutrophils is initiated by NADPH oxidase, which converts oxygen into superoxide. The subunits of NADPH oxidase are spatially separated between granules (gp91 phox /p22 phox ) and the cytoplasm (p47 phox , p67 phox , and p40 phox ). Activation of neutrophils promotes the coassembly of NADPH oxidase subunits at phagosome and/or plasma membranes. While Gc-expressing opacity-associated (Opa) proteins can induce neutrophils to produce ROS, Opa-negative (Opa ؊ ) Gc does not stimulate neutrophil ROS production. Using constitutively Opa ؊ and OpaD-positive (OpaD ؉ ) Gc bacteria in strain FA1090, we now show that the difference in ROS production levels in primary human neutrophils between these backgrounds can be attributed to differential assembly of NADPH oxidase. Neutrophils infected with Opa ؊ Gc showed limited translocation of NADPH oxidase cytoplasmic subunits to cellular membranes, including the bacterial phagosome. In contrast, these subunits rapidly translocated to neutrophil membranes following infection with OpaD ؉ Gc. gp91 phox and p22 phox were recruited to Gc phagosomes regardless of bacterial Opa expression. These results suggest that Opa ؊ Gc interferes with the recruitment of neutrophil NADPH oxidase cytoplasmic subunits to membranes, in particular, the p47 phox "organizing" subunit, to prevent assembly of the holoenzyme, resulting in an absence of the oxidative burst.

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Vaccines for Gonorrhea: Can We Rise to the Challenge?

Cited by 84 publications

References 113 publications

Neisseria gonorrhoeae Evades Calprotectin-Mediated Nutritional Immunity and Survives Neutrophil Extracellular Traps by Production of TdfH

Neisseria gonorrhoeae Evades Calprotectin-Mediated Nutritional Immunity and Survives Neutrophil Extracellular Traps by Production of TdfH

Deciphering the Function of New Gonococcal Vaccine Antigens Using Phenotypic Microarrays

Assembly of NADPH Oxidase in Human Neutrophils Is Modulated by the Opacity-Associated Protein Expression State of Neisseria gonorrhoeae

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