A Mutant Form of the
            <i>Neisseria gonorrhoeae</i>
            Pilus Secretin Protein PilQ Allows Increased Entry of Heme and Antimicrobial Compounds

Chen, Ching Ju; Tobiason, Deborah M.; Thomas, C.; Shafer, William M.; Seifert, H. Steven; Sparling, P. Frederick

doi:10.1128/jb.186.3.730-739.2004

Cited by 53 publications

(53 citation statements)

References 53 publications

(70 reference statements)

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“…As mentioned previously, two classes of mutants have been isolated in Neisseria gonorrhoeae that were more susceptible to both heme and PPIX. In addition to these porphyrin sensitivities, both classes of mutants were hypersensitive to other HAs as well (3). Subsequently, tests similar to those carried out by Chen et al (3) demonstrated that ght mutants are also hypersensitive to HAs such as Triton X-100 and rifampin in addition to heme and PPIX.…”

Section: Discussionmentioning

confidence: 59%

“…Efforts to transfer the nonpolar ght::Kan r construct from the meningococci to the gonococci to better understand HA hypersensitivity and ght's effects on piliation proved unsuccessful (data not presented), suggesting that ght may be an essential gene in the gonococci. Moreover, a meningococcal strain harboring mutations in HpuB and HmbR is not able to grow in the presence of hemoglobin as a sole iron source under the same conditions described by Chen et al for their gonococcal mutants (3).…”

Section: Discussionmentioning

confidence: 97%

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Resistance ofNeisseria meningitidisto the Toxic Effects of Heme Iron and Other Hydrophobic Agents Requires Expression ofght

et al. 2005

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Several genetic systems that allow the use of iron-protoporphyrin IX (heme) have been described for the pathogenic bacterium Neisseria meningitidis. However, many questions about the process of heme acquisition and utilization remain to be answered. To isolate and analyze unidentified genes that play a role in heme iron uptake and utilization, a Himar1 transposon mutant library was screened in N. meningitidis serogroup A strain IR4162. One locus identified by transposon mutagenesis conferred protection against heme toxicity. A mutant with a deletion in a gene termed ght (gene of hydrophobic agent tolerance) within this locus was susceptible to heme and other hydrophobic agents compared to the parental strain. Transcriptional analysis indicated that ght is cotranscribed with an upstream open reading frame NMA2149. Uncharacterized orthologues of ght were identified in many other gram-negative bacteria. We present genetic evidence for the importance of ght in resistance to hydrophobic agents and its potential role in interaction with other hydrophobic agent resistance mechanisms within N. meningitidis.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 97%

Resistance ofNeisseria meningitidisto the Toxic Effects of Heme Iron and Other Hydrophobic Agents Requires Expression ofght

et al. 2005

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“…The channel function of neisserial secretins has been assessed to some extent (Chen et al, 2004;Zhao et al, 2005). Meningococcal PilQ can behave as a gated channel and regulator of transmembrane flux control.…”

Section: Discussionmentioning

confidence: 99%

Topology of the outer-membrane secretin PilQ from Neisseria meningitidis

et al. 2006

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Neisseria meningitidis is the causative agent of epidemic meningococcal meningitis and septicaemia. Type IV pili are surface organelles that mediate a variety of functions, including adhesion, twitching motility, and competence for DNA binding and uptake in transformation. The secretin PilQ is required for type IV pilus expression at the cell surface, and forms a dodecameric cage-like macromolecular complex in the meningococcal outer membrane. PilQ-null mutants are devoid of surface pili, and prevailing evidence suggests that the PilQ complex facilitates extrusion and retraction of type IV pili across the outer membrane. Defining the orientation of the meningococcal PilQ complex in the membrane is a prerequisite for understanding the structure-function relationships of this important protein in pilus biology. In order to begin to define the topology of the PilQ complex in the outer membrane, polyhistidine insertions in N-and C-terminal regions of PilQ were constructed, and their subcellular locations examined. Notably, the insertion epitopes at residues 205 and 678 were located within the periplasm, whereas residue 656 was exposed at the outer surface of the outer membrane. Using electron microscopy with Ni-NTA gold labelling, it was demonstrated that the insertion at residue 205 within the N-terminus mapped to a site on the arm-like features of the 3D structure of the PilQ multimer. Interestingly, mutation of the same region gave rise to an increase in vancomycin permeability through the PilQ complex. The results yield novel information on the PilQ N-terminal location and function in the periplasm, and reveal a complex organization of the membrane-spanning secretin in vivo.

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“…HpuA and HpuB form a functional complex, and both are required for the utilization of hemoglobin and hemoglobin-haptoglobin as nutrient iron sources (59,61). Coincidentally, a spontaneous point mutation in Neisseria gonorrhoeae pilQ (pilQ1) suppresses the mutant hpuAB phenotype (16). PilQ forms a channel in the outer membrane and is required for pilus biogenesis, but its mutant form allows the entry of heme and various antimicrobial compounds with a TonB-independent, PilT-dependent mechanism (16).…”

Section: Heme Sources Exploited By Bacterial Pathogensmentioning

confidence: 99%

Overcoming the Heme Paradox: Heme Toxicity and Tolerance in Bacterial Pathogens

2010

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Virtually all bacterial pathogens require iron to infect vertebrates. The most abundant source of iron within vertebrates is in the form of heme as a cofactor of hemoproteins. Many bacterial pathogens have elegant systems dedicated to the acquisition of heme from host hemoproteins. Once internalized, heme is either degraded to release free iron or used intact as a cofactor in catalases, cytochromes, and other bacterial hemoproteins. Paradoxically, the high redox potential of heme makes it a liability, as heme is toxic at high concentrations. Although a variety of mechanisms have been proposed to explain heme toxicity, the mechanisms by which heme kills bacteria are not well understood. Nonetheless, bacteria employ various strategies to protect against and eliminate heme toxicity. Factors involved in heme acquisition and detoxification have been found to contribute to virulence, underscoring the physiological relevance of heme stress during pathogenesis. Herein we describe the current understanding of the mechanisms of heme toxicity and how bacterial pathogens overcome the heme paradox during infection.

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A Mutant Form of the Neisseria gonorrhoeae Pilus Secretin Protein PilQ Allows Increased Entry of Heme and Antimicrobial Compounds

Cited by 53 publications

References 53 publications

Resistance ofNeisseria meningitidisto the Toxic Effects of Heme Iron and Other Hydrophobic Agents Requires Expression ofght

Resistance ofNeisseria meningitidisto the Toxic Effects of Heme Iron and Other Hydrophobic Agents Requires Expression ofght

Topology of the outer-membrane secretin PilQ from Neisseria meningitidis

Overcoming the Heme Paradox: Heme Toxicity and Tolerance in Bacterial Pathogens

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