![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Previous Article | Next Article 
Infection and Immunity, September 2007, p. 4190-4198, Vol. 75, No. 9
0019-9567/07/$08.00+0 doi:10.1128/IAI.00117-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
| MINIREVIEW |
Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,1 Centre for Molecular Microbiology and Infection, Department of Infectious Diseases, Flowers Building, Imperial College London, Armstrong Road, London SW7 2AZ, United Kingdom2
 |
INTRODUCTION |
|---|
 Top INTRODUCTION REFERENCES |
|---|
|
STIMULATION OF GONOCOCCAL METABOLISM BY LACTATE: THE MECHANISM INVOLVED AND RELATION TO PATHOGENICITY |
|---|
The mechanisms of metabolic stimulation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of gonococci radiolabeled with either lactate or glucose during growth on single or mixed carbon sources showed that the production of specific proteins was not induced by lactate. Instead, lactate carbon was incorporated preferentially into the fatty acids of membrane lipids and LPS (77). The fate of the lactate carbon was followed by nuclear magnetic resonance analysis of membrane lipids and LPS purified from gonococci grown in a defined medium with labeled glucose alone, with labeled lactate and unlabeled glucose, and with labeled glucose and unlabeled lactate (77, 78). With glucose alone, the label was found in the fatty acids and the ethanolamine/glycerol moieties of the membrane lipids, and also in the fatty acids and sugar moieties of LPS. However, with labeled lactate in the presence of glucose, the label was not present in the ethanolamine/glycerol moieties of the membrane lipids or in the sugar moieties of LPS. With labeled glucose in the presence of lactate, the patterns were similar to those for growth in glucose alone. However, the addition of lactate resulted in detectable differences in the fatty acids of membrane lipids and the carbohydrate moieties of LPS. The cardinal result was that in the presence of glucose, lactate carbon was incorporated into fatty acid moieties and not into the ethanolamine/glycerol of membrane lipids or the carbohydrate of LPS. This revealed the underlying mechanism of metabolic stimulation.
When lactate is used alone by gonococci, it is oxidized to pyruvate and then fulfils two functions: (i) gluconeogenesis to produce sugar, glycerol, and ethanolamine moieties of gonococcal constituents and (ii) formation of acetyl-coenzyme A (CoA), the precursor of fatty acid synthesis, and constituents of the tricarboxylic acid (TCA) cycle (Fig. 1). Energy (via NADH and ATP) comes from the initial oxidation of lactate to pyruvate and acetyl-CoA and from the TCA cycle. Also, some acetyl-CoA is converted to acetate via acetyl phosphate, providing further energy (37). When glucose is present, gluconeogenesis from lactate does not take place, indicated by the absence of lactate carbon in ethanolamine, glycerol, or sugar moieties of membrane lipids and LPS. Instead, lactate is used solely as a source of additional energy, explaining the stimulation of metabolism in the presence of glucose (Fig. 1).
|
There are other effects of lactate that might benefit gonococci during the primary colonization period. Rapid growth promoted by lactate would provide an advantage to gonococci exposed to host defenses. The increased oxygen consumption caused by lactate might impair oxygen-dependent killing mechanisms of phagocytes (4) when gonococci survive and grow within human PMNs (6, 58, 67). Also, there is an increase in the production of protein virulence determinants, such as type IV pili (for adherence) and Opa proteins (for cell entry) (69), sialylated LPS (21), and porin 1B, an inhibitor of PMN action (2). Turning to inflammation, the main harmful effect of gonorrhea, enhanced LPS production due to lactate could increase the induction of inflammatory cytokines (50) and promote GroEl production, which might have the same effect (8, 47).
Clearly, lactate metabolism could increase gonococcal pathogenicity in vivo. Final proof would require the demonstration that a mutant unable to use lactate is attenuated in a relevant animal model, as has recently been shown for the relevance of LPS sialylation to pathogenicity (76). However, similar evidence was lacking for the influence of lactate until a solution emerged from studies on meningococci.
|
THE EFFECT OF LACTATE METABOLISM ON MENINGOCOCCAL PATHOGENICITY |
|---|
Early metabolic studies on N. meningitidis, like those on N. gonorrhoeae, involved either glucose or lactate, but not mixtures of the two. Lactate dehydrogenases (LDHs) (13) were recognized, together with pyruvate dehydrogenase (30) and all the TCA cycle enzymes (33). Later, analysis of available genome sequences (48, 65) indicated the presence of enzymes needed for gluconeogenesis and energy production by lactate and, like gonococci, for deriving energy from glucose by the Entner-Doudoroff pathway. A metabolic effect of lactate on meningococci similar to that on gonococci was therefore possible.
A lactate permease-deficient mutant of N. meningitidis. Signature-tagged mutagenesis using the infant rat model identified a putative lactate permease-deficient mutant of a serogroup B N. meningitidis strain (63). The mutation affected an open reading frame (NMB0543) (http://www.tigr.org) with a predicted product that shared 21% amino acid identity with a characterized lactate permease from Escherichia coli (10). Uptake of lactate by an NMB0543 mutant was insignificant compared with the rapid uptake by the wild-type strain (16), and unlike the latter, the mutant could not grow with lactate as the sole carbon source. Polar effects were excluded when growth on lactate alone was restored by complementation with a single copy of the gene (16). Hence, the gene product was designated a lactate permease (LctP).
As for the gonococcus, when millimolar quantities of lactate were added to N. meningitidis growing in a medium containing glucose, more rapid emergence from lag phase occurred, together with a higher rate of growth in early log phase, while the lctP mutant failed to respond to added lactate (16).
Lactate metabolism induces resistance to complement-mediated serum killing: the multifactorial mechanisms involved. The main innate host defenses against the meningococcus are complement-mediated extracellular lysis and probably ingestion and killing by phagocytes. We deal here with resistance to the first of these defenses. Notably, after growth for 2 h in a medium containing lactate, glucose, and CMP-NANA, the survival of the lctP mutant was only 16% of that of the wild type in the presence of normal human serum (16). Consistent with this greater sensitivity to serum, the mutant bound more complement component C3 than the wild-type strain.
Clearly, lactate metabolism enhances meningococcal resistance to killing by complement. What mechanisms are involved? For gonococci, the enhanced resistance is due to lactate increasing the amount of sialylated LPS. Meningococci also contain sialylated LPS, but in contrast to gonococci, serogroup B and C meningococci synthesize their own CMP-NANA (40). Strains can also utilize exogenous CMP-NANA to increase LPS sialylation (14). In the LPSs of both meningococci and gonococci, the sialic acid is linked to the terminal galactose residue of the carbohydrate side chain lacto-N-neotetraose epitope (60, 62).
Observations of the lactate permease-deficient N. meningitidis demonstrated that lactate increases sialylation of meningococcal LPS. When bacteria were grown with lactate, glucose, and CMP-NANA, immunoblotting of whole-cell extracts showed that the LPS from the LctP-deficient mutant was less sialylated, while the complemented mutant had levels of sialylation similar to those of the wild-type strain (16). Thus, the increase in meningococcal serum resistance induced by lactate could be due to the enhanced LPS sialylation. However, the situation is not as clear as for gonococci due to the expression of a polysialic acid capsule by seroroup B and C N. meningitidis, which also mediates resistance to complement-mediated killing (23, 34, 39, 73).
The relative importance of capsular polysialic acid and sialylated LPS in overall resistance remains a matter of debate. Estabrook et al. (14) examined serogroup C meningococci from healthy carriers and found that endogenous and exogenous LPS sialylation are associated with serum resistance. Kahler et al. (34) looked at mutants of an invasive serogroup B meningococcus with altered capsule, LPS, and sialylation; they stated that capsulation is essential for serum resistance but that LPS structures and sialylation also contribute. Vogel et al. (70, 71) studied isogenic 
2-3 sialyltransferase (lst) mutants of three encapsulated clinical isolates. The mutants were more serum sensitive than the wild types, but only at high serum concentrations. They concluded that LPS sialylation was of minor importance for serum resistance. Sialylation of meningococcal LPS does not increase binding of factor H, as happens for gonococci (56), so the mechanism of its role is unknown. In reviewing the situation, Vogel and Frosch (72) cautioned that factors other than capsulation and LPS sialylation could influence serum resistance and that their relative importance could vary from strain to strain. For instance, glycosylation of pili affects the serum resistance of some strains (28), and Opa proteins may reduce serum resistance mediated by LPS sialylation by being an additional target for C4 (A. Prasad, U. Vogel, J. Ngampasutadol, S. Gulati, S. Getzlaff, P. A. Rice, and S. Ram, presented at the 14th International Pathogenic Neisseria Conference, Milwaukee, WI, 5 to 10 September 2004).
There are several mechanisms by which lactate could affect production of sialylated LPS and capsular polysialic acid. General stimulation of metabolism would produce more of both in a shorter time. Lactate may be the predominant carbon source for the biosynthesis of capsular and LPS sialic acid, which is formed from phosphoenol pyruvate (PEP) and N-acetyl mannosamine (20). The PEP can be derived from glucose via pyruvate and glycerol-3-phosphate formed by the Entner-Doudoroff pathway, but this involves four and eight metabolic steps, respectively (Fig. 2). Production of PEP from lactate is more direct, involving only two steps (Fig. 2). Finally, lactate might induce changes in the LPS structure that affect killing by complement, either directly by changing LPS moieties that interact with complement components (e.g., phosphoethanolamine residues [51]) or indirectly by affecting the degree of sialylation.
|
|
During the first stage of colonization, initial attachment to nasopharyngeal epithelial cells is determined by type IV pili for encapsulated strains and by Opa and Opc proteins for nonencapsulated strains (1, 45, 69). The next step is multiplication in the underlying tissue; meningococci are seen in the nasopharynx internal to the epithelial layer (57). To investigate the role of lactate during colonization, infection of human nasopharyngeal mucosa explants from resected adenoids was used (15). The explants contain lactate and glucose at levels similar to those in serum (0.6 to 2.4 mM and 3.9 to 5.8 mM for lactate and glucose, respectively). At 4 h after inoculation, the populations of the wild-type and lactate permease-deficient strains were the same as those at 0 h, but from 4 to 18 h, the numbers of wild-type bacteria increased 10-fold whereas levels of the mutant were static. Possible explanations for the colonization defect of the lctP mutant are reduced adherence to epithelial cells, susceptibility to host defenses, and growth retardation due to inability to use lactate. There was no detectable change in type IV pili, Opa, and Opc, and the mutant adhered to Chang epithelial cells better than the wild type, probably because of its lower degree of LPS sialylation (9). As for resistance to host defenses, there is little inflammation during meningococcal colonization of the nasopharynx (5) and complement levels are negligible in healthy individuals (36). Furthermore, the mutant and wild-type strains survived equally during the first 4 h in the explants, indicating that there was no significant role for resistance to host defenses. Hence, lactate stimulation of the growth is the most likely explanation for the enhanced colonization of the wild-type strain, showing that lactate has an important role in the first stage of pathogenesis (15).
A relevant model of bloodstream infection in humans by meningococci is systemic infection of infant rats, and both sialylated LPS and the polysialic acid capsule are virulence determinants in this model (73). In the model, the lctP mutant was significantly attenuated compared directly with wild-type bacteria in competitive infections (16). The competitive index (CI, the ratio of the numbers of mutant and wild type recovered from the animals divided by the ratio in the inoculum) was 0.108 for the lactate permease-deficient mutant (a CI of 1 indicates no attenuation). This could have resulted either from a lower growth rate or a decrease in resistance to killing by complement and/or by phagocytes. Experiments using complement-deficient rats were not possible, so a murine model was used. The CI of the mutant in systemic infection of mice (0.15) was similar to that in rats. However, in congenic C3-negative mice, the CI was 0.8, i.e., the virulence of the lctP mutant was restored in mice lacking intact complement. Thus, during systemic spread, lactate influences the virulence of the meningococcus by preventing complement-mediated killing and possibly increasing complement-dependent opsonophagocytosis, not by stimulating growth.
Turning to the influence of lactate on the final stage of meningococcal infection, wild-type bacteria grew faster than the lctP mutant in human CSF and reached a higher final population (16). Nuclear magnetic resonance analysis showed that N. meningitidis utilized glucose and lactate simultaneously but that lactate was used more rapidly. This result is similar to that when gonococci grow in guinea pig chamber fluid (25). Clearly, lactate stimulation of meningococcal growth in CSF may be relevant to the development of meningitis, particularly as CSF lactate levels rise during meningitis while glucose concentrations fall (11).
Differences between meningococci and gonococci in response to lactate. Lactate stimulates metabolism and growth of both gonococci and meningococci in media containing glucose, and the mechanism of growth stimulation for gonococci probably applies to meningococci. However, the species differ in the fact that unlike gonococci, some meningococci can synthesize their own sialic acid and CMP-NANA. This difference between the species affects the mechanism of increase in sialylated LPS and serum resistance induced by lactate. For gonococci, general stimulation of metabolism by lactate, producing more LPS and sialyltransferase, is predominant (22). For meningococci, the major role of lactate appears to be in promoting sialic acid production for LPS sialylation and incorporation in capsular polysaccharide.
The meningococcal lactate permease is an immunogen. Bacterial permeases are located on inner bacterial membranes and therefore are unlikely to have immunizing activity. The following observations (64) were therefore surprising. Recombinant LctP produced in an E. coli vector was purified and used to immunize mice by the subcutaneous route on two occasions. A week later, the animals were challenged with live bacteria. In two experiments, mice receiving LctP were partially protected against live challenge, in contrast to nonimmunized animals. This significant but incomplete protection was comparable to that produced by meningococcal PorA. Although it is not predicted to be on the outer membrane, LctP was detected on intact N. meningitidis by fluorescence-activated cell sorter analysis and enzyme-linked immunosorbent assay (64). This is similar to some periplasmic proteins of meningococci that elicit high levels of serum bactericidal antibodies (26). The mechanism of protection induced by LctP is unknown, as it evoked only low levels of serum bactericidal antibodies (64). Antibody neutralization of lactate permease activity may lead to a lower growth rate or lower resistance to killing by serum or opsonophagocytosis.
|
PROOF THAT LACTATE METABOLISM IS RELEVANT TO THE PATHOGENICITY OF GONOCOCCI IN VIVO |
|---|
Searches of the N. gonorrhoeae genome sequence with the deduced amino acid sequence of the meningococcal LctP revealed an identical sequence (NGO1449), except that Val167 in the meningococcal sequence is an Ala in the gonococcus. The sequence is predicted to encode a protein with 14 transmembrane domains, consistent with an inner membrane permease. A deletion mutant of NGO1449 was constructed and shown to be defective for uptake of exogenous lactate and growth in defined media with lactate as the sole carbon source; complementation of the mutant reverted these phenotypes to the wild type (17). Therefore, NGO1499 was assigned as the gonococcal LctP.
In vitro studies related to pathogenicity of the lactate permease-deficient gonococcal mutant. Since emergence from lag phase and rapid initial growth could benefit gonococci in the initial phases of infection, the growth of the mutant was examined in a defined medium with physiological concentrations of glucose and lactate (10 and 2 mM, respectively). The growth of the mutant was significantly less than that of the wild type and the complemented mutant under these conditions (17). Furthermore, the lctP mutant was more sensitive than the wild type to complement-mediated killing by human serum; fluorescence-activated cell sorter studies showed that the mutant was less sialylated than the wild type, whereas the results for the complemented mutant were similar to those for the wild type (17). This decrease in LPS sialylation probably accounts for the enhanced sensitivity of the mutant to complement-mediated killing by serum. However, changes other than LPS sialylation may have a role. Indeed, the addition of lactate to gonococcal cultures containing physiological concentrations of glucose is associated with changes in the fatty acid and carbohydrate composition of LPS (77, 78). Alterations of both lipid and carbohydrate components of LPS have been associated with changes in serum resistance of pathogenic neisseria (72, 73).
In vivo studies on the pathogenicity of the lactate permease mutant. The ability of the lctP mutant to colonize the murine vagina was compared with that of the wild-type strain. In this model of gonorrhea (31, 32), 4- to 6-week-old BALB/c mice are treated with 17-ß estradiol and streptomycin to promote gonococcal infection of the vagina. The antibiotic reduces the commensal flora that can inhibit the gonococcal infection, and lactate and glucose concentrations in the mouse vaginal fluid were similar to those reported in human vaginal secretions (17). The lctP mutant demonstrated a dramatic disadvantage in this model compared with the parent strain. On days 4, 6, and 8 after inoculation, the CI of the mutant fell to 0.2, 0.04, and 0.02, respectively. In contrast, the complemented strain did not display a colonization defect throughout the course of infection.
This result means there is no doubt that lactate aids gonococcal infection of the mouse vagina. However, the underlying reasons for this are not clear. Lactate enhancement of LPS sialylation (thereby increasing factor H deposition) may be the reason for the greater resistance of the wild type to killing by human serum compared with the lctP mutants. However, this cannot apply to the murine results, because murine factor H does not bind to the gonococcus (46). Recent observations of a sialyltransferase-deficient mutant are pertinent (76). Wild-type bacteria passaged in the murine vagina for up to 9 days were highly resistant to killing by normal human serum, but not after incubation with neuraminidase or a single passage in vitro in the absence of CMP-NANA. In contrast, the lst-deficient mutant was sensitive to killing by human serum throughout the 9-day period. Thus, LPS sialylation occurs in the murine vagina and renders gonococci resistant to killing by human serum. The effect of LPS sialylation on resistance to murine serum cannot be tested, as it does not kill gonococci in vitro (76). Hence, the possibility of sialylation affecting killing by complement-mediated mechanisms was examined by competitive infection of the lst mutant in C5-deficient mice. The mutant was as attenuated in the C5-deficient mice as in normal mice (76), indicating that interference with complement-mediated lysis is not the explanation for the enhancement of vaginal infection by LPS sialylation. Thus, it is likely that lactate enhancement of vaginal infection is not due to changes in LPS sialylation.
There are two other mechanisms that might account for lactate promoting vaginal infection. First, the effect of lactate in a rapid emergence from lag phase and early growth may be crucial in the early stages of infection. Second, increased LPS sialylation induced by lactate may increase resistance to killing by PMNs (24). The latter explanation is supported by recent findings with the lst-deficient mutant (76). LPS sialylation not only rendered bacteria more resistant to killing in vitro by mouse PMNs, it also promoted less association of the bacteria with PMNs and a weaker respiratory burst. Thus, LPS sialylation enhances the pathogenicity of the gonococcus in the murine model by increasing resistance to killing by PMNs. This is consistent with the report (4) that lactate promotes excess oxygen usage by gonococci within phagocytes with a consequent reduction in oxygen-dependent killing mechanisms. Clearly, the lctP-deficient mutant could be investigated in similar experiments. The mouse model results have obvious implications for the role of lactate in human gonorrhea and warrant testing of the mutant in human volunteers.
|
NEW CONCEPTS OF THE ROLE OF METABOLITES IN PATHOGENICITY ARISING FROM STUDIES ON GONOCOCCI AND MENINGOCOCCI |
|---|
The effects of metabolites in combination must be considered, as pathogens grow on mixtures in vivo. Like the individual metabolites mentioned above, the role of lactate in gonococcal pathogenicity lies in stimulating overall metabolism and growth. However, its dramatic effect is dependent on the presence of glucose, as occurs in vivo. The mechanism of this stimulation has been elucidated, and it may apply to other pathogens that occupy sites in vivo containing lactate and glucose, because they have the enzymes needed for it to operate (61). Clearly, lactate stimulates the metabolism of N. meningitidis in media containing glucose. Similar studies on the influence of lactate on the pathogenicity of Haemophilus influenzae (35) have been supported recently by the identification of an attenuated putative lactate permease-deficient mutant (29).
Antigens involved in metabolism may contribute to vaccines. Until now, most vaccines have been based on virulence determinants, such as toxins, adhesins, and capsules. The surprise discovery that meningococcal LctP has immunizing ability shows that antigens connected with metabolism should also be considered. Obvious candidates are the products of genes with metabolic functions that have been revealed by in vivo expression technology, STM, or directed approaches to operate in vivo and affect virulence (43, 59).
Growth-stimulating metabolites can influence the production of specific virulence determinants. For meningococci, lactate not only stimulates growth, it is a more direct source than glucose for producing PEP needed for sialic acid biosynthesis and hence two virulence determinants, sialylated LPS and the polysialic capsule. Furthermore, these two effects can influence different stages in pathogenesis. For meningococci, growth stimulation promotes initial colonization and survival in cerebrospinal infection, while enhanced expression of virulence determinants and inhibition of host defenses contributes to spread in the bloodstream. The two roles of lactate might also operate for E. coli K-1 and group B streptococci, because like N. meningitidis, they also synthesize sialic acid (7, 68). We are not aware of any other metabolites, such as glutamate (41), that have this dual role either on their own or in combination with another metabolite, but the observations of meningococci may be relevant to research on other organisms.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
Published ahead of print on 11 June 2007.
|
REFERENCES |
|---|
|
TopINTRODUCTIONREFERENCES |
|---|
| 1. | Aho, E. L., J. A. Dempsey, M. M. Hobbs, D. G. Klapper, and J. G. Cannon. 1991. Characterization of the opa (class 5) gene family of Neisseria meningitides. Mol. Microbiol. 5:1429-1437.[CrossRef][Medline] |
| 2. | Bjerknes, R., H. Guttormsen, C. O. Solberg, and L. M. Wetzler. 1995. Neisserial porins inhibit human neutrophil actin polymerization, degranulation, opsonin receptor expression, and phagocytosis but prime the neutrophils to increase their oxidative burst. Infect. Immun. 63:160-167.[Abstract] |
| 3. | Braude, A. I., and J. Siemienski. 1960. Role of bacterial urease in experimental pyelonephritis. J. Bacteriol. 80:171-179. |
| 4. | Britigan, B. E., D. Klapper, T. Svendsen, and M. S. Cohen. 1988. Phagocyte-derived lactate stimulates oxygen consumption by Neisseria gonorrhoeae. J. Clin. Investig. 81:318-324.[Medline] |
| 5. | Cartwright, K. A., J. M. Stuart, D. M. Jones, and N. D. Noah. 1987. The Stonehouse survey; nasopharyngeal carriage of meningococci and Neisseria lactamica. Epidemiol. Infect. 99:591-601.[Medline] |
| 6. | Casey, S. G., D. R. Veale, and H. Smith. 1979. Demonstration of intracellular growth of gonococci in human phagocytes using spectinomycin to kill extracellular organisms. J. Gen. Microbiol. 113:395-398.[Medline] |
| 7. | Chaffin, D. O., L. M. Mentele, and C. E. Rubens. 2005. Sialylation of group B streptococcal capsular polysaccharide is mediated by cpsK and is required for optimal capsule polymerization and expression. J. Bacteriol. 187:4615-4626. |
| 8. | Coates, A. R., and B. Henderson. 1998. Chaperonins in health and disease. Ann. N. Y. Acad. Sci. 851:48-53. |
| 9. | De Vries, F. P., A. van Der Ende, J. P. van Putten, and J. Dankert. 1996. Invasion of primary nasopharyngeal epithelial cells by Neisseria meningitidis is controlled by phase variation of multiple surface antigens. Infect. Immun. 64:2998-3006.[Abstract] |
| 10. | Dong, J. M., J. S. Taylor, D. J. Latour, S. Iuchi, and E. C. Lin. 1993. Three overlapping lctP genes involved in L-lactate utilization by Escherichia coli. J. Bacteriol. 175:6671-6678. |
| 11. | Dougherty, J. M., and R. M. Roth. 1986. Cerebral spinal fluid. Emerg. Med. Clin. N. Am. 4:281-297.[Medline] |
| 12. | Edwards, U., A. Muller, A. S. Hammerschmidt., R. Gerardy-Schahn, and M. Frosch. 1994. Molecular analysis of the biosynthesis pathway of the alpha-2,8 polysialic acid capsule by Neisseria meningitidis serogroup B. Mol. Microbiol. 14:141-149.[CrossRef][Medline] |
| 13. | Erwin, A. L., and E. M. Gotschlich. 1996. Cloning of a Neisseria meningitidis gene for L-lactate hydrogenase (L-LDH): evidence for a second meningococcal L-LDH with different regulation. J. Bacteriol. 178:4807-4813. |
| 14. | Estabrook, M. M., J. M. Griffiss, and G. A. Jarvis. 1997. Sialylation of Neisseria meningitidis lipooligosaccharide inhibits serum bactericidal activity by masking lacto-N-neotetraose. Infect. Immun. 65:4436-4444.[Abstract] |
| 15. | Exley, R. M., L. Goodwin, E. Mowe, J. Shaw, H. Smith, R. C. Read, and C. M. Tang. 2005a. The Neisseria meningitidis lactate permease is required for nasopharyngeal colonization. Infect. Immun. 73:5762-5766. |
| 16. | Exley, R. M., J. Shaw, E. Mowe, Y. Sun, N. P. West, M. Williamson, M. Boto, H. Smith, and C. M. Tang. 2005. Available carbon source influences the resistance of Neisseria meningitidis against complement. J. Exp. Med. 201:1637-1645. |
| 17. | Exley, R. M., H. Wu, J. Shaw, M. C. Schneider, H. Smith, A. E. Jerse, and C. M. Tang. 2007. Lactate acquisition promotes the successful colonisation of the murine genital tract by Neisseria gonorrhoeae. Infect. Immun. 75:1318-1324. |
| 18. | Fischer, R. S., G. C. Martin, P. Rao, and R. A. Jensen. 1994. Neisseria gonorrhoeae possesses two nicotinamide adenine dinucleotide-dependent lactate dehydrogenases. FEMS Microbiol. Lett. 115:39-44.[CrossRef][Medline] |
| 19. | Frangipane, J. V., and R. F. Rest. 1993. Anaerobic growth and cytidine 5'-monophospho-N-acetylneuraminic acid act synergically to induce high serum resistance in Neisseria gonorrhoeae. Infect. Immun. 61:1657-1666. |
| 20. | Ganguli, S., G. Zapata, T. Wallis, C. Reid, G. Boulnois, W. F. Vann, and I. S. Roberts. 1994. Molecular cloning and analysis of genes for sialic acid synthesis in Neisseria meningitidis group B and purification of the meningococcal CMP-NeuNAc synthetase enzyme. J. Bacteriol. 176:4583-4589. |
| 21. | Gao, L., L. Linden, N. J. Parsons, J. A. Cole, and H. Smith. 2000. Uptake of metabolites of gonococci grown with lactate in a medium containing glucose; evidence for a surface location of the sialyltransferase. Microb. Pathog. 28:257-266.[CrossRef][Medline] |
| 22. | Gao, L., N. J. Parsons, A. Curry, J. A. Cole, and H. Smith. 1998. Lactate causes changes in gonococci including increased lipopolysaccharide synthesis during short-term incubation in media containing glucose. FEMS Microbiol. Lett. 169:309-316.[CrossRef][Medline] |
| 23. | Geoffroy, M. C., S. Floquet, A. Metais, X. Nassif, and V. Pelicic. 2003. Large-scale analysis of the meningococcal genome by gene disruption: resistance to complement-mediated lysis. Genome Res. 13:391-398. |
| 24. | Gill, M. J., D. P. McQuillen, J. P. van Putten, L. M. Wetzler, J. Bramley, H. Crooke, N. J. Parsons, J. A. Cole, and H. Smith. 1996. Functional characterization of a sialyltransferase deficient mutant of Neisseria gonorrhoeae. Infect. Immun. 64:3374-3378.[Abstract] |
| 25. | Goldner, M., C. W. Penn, S. C. Sanyal, D. R. Veale, and H. Smith. 1979. Phenotypically determined resistance of Neisseria gonorrhoeae to normal human serum; environmental factors in subcutaneous chambers in guinea pigs. J. Gen. Microbiol. 114:169-177.[Medline] |
| 26. | Grifantini, R., E. Bartolini, A. Muzzi, M. Draghi, E. Frigimelica, J. Berger, G. Ratti, R. Petracca, G Galli, M. Agnusdei, M. M. Guiliani, L. Santini, B. Brunelli, H. Tettelin, R. Rappuoli, F. Randazzo, and G. Grandi. 2002. Previously unrecognized vaccine candidates against group B meningococci identified by DNA microarrays. Nat. Biotechnol. 20:914-921.[CrossRef][Medline] |
| 27. | Gulati, S., A. Cox, L. A. Lewis, F. St. Michael, J. Li, R. Boden, S. Ram, and P. A. Rice. 2005. Enhanced factor H binding to sialylated gonococci is restricted to the sialylated lacto-N-neotetraose lipooligosaccharide species: implications for serum resistance and evidence for a bifunctional lipooligosaccharide sialyltransferase in gonococci. Infect. Immun. 73:7390-7397. |
| 28. | Hamadeh, R. M., M. M. Estabrook, P. Zhou, G. A. Jarvis, and J. M. Griffiss. 1995. Anti-Gal binds to pili of Neisseria meningitidis: the immunoglobulin A isotype blocks complement-mediated killing. Infect. Immun. 63:4900-4906.[Abstract] |
| 29. | Herbert, M. A., S. Hayes, M. E. Deadman, C. M. Tang, D. W. Hood, and E. R. Moxon. 2002. Signature tagged mutagenesis of Haemophilus influenzae identifies genes required for in vivo survival. Microb. Pathog. 33:211-223.[CrossRef][Medline] |
| 30. | Holten, E., and K. Jyssum. 1974. Activities of some enzymes concerning pyruvate metabolism in Neisseria. Acta Pathol. Microbiol. Scand. B 82:843-848. |
| 31. | Jerse, A. E. 1999. Experimental gonococcal genital tract infection and opacity protein expression in estradiol-treated mice. Infect. Immun. 67:5699-5708. |
| 32. | Jerse, A. E., E. T. Crow, A. N. Bordner, I. Rahman, C. N. Cornelissen, T. R. Moench, and K. Mehrazar. 2002. Growth of Neisseria gonorrhoeae in the female mouse genital tract does not require the gonococcal transferrin or hemoglobin receptors and may be enhanced by commensal lactobacilli. Infect. Immun. 70:2549-2558. |
| 33. | Jyssum, K. 1960. Intermediate reactions of the tricarboxylic acid cycle in meningococci. Acta Pathol. Microbiol. Scand. B 48:121-132. |
| 34. | Kahler, C. M., L. E. Martin, G. C. Shih, M. M. Rahman, R. W. Carlson, and D. S. Stephens. 1989. The (2-8)-linked polysialic acid capsule and lipooligosaccharide structure both contribute to the ability of serogroup B Neisseria meningitidis to resist the bactericidal activity of normal human serum. Infect. Immun. 66:5939-5947. |
| 35. | Kuratana, M., and P. Anderson. 1991. Host metabolites that phenotypically increase the resistance of Haemophilus influenzae type b to clearance mechanisms. J. Infect. Dis. 163:1073-1079.[Medline] |
| 36. | Lai a Fat, R. F., D. Suurmond, and R. van Furth. 1973. In vitro synthesis of immunoglobulins, secretory component and complement in normal and pathological skin and the adjacent mucous membranes. Clin. Exp. Immunol. 14:377-395.[Medline] |
| 37. | Leighton, M. P., D. J. Kelly, M. P. Williamson, and J. G. Shaw. 2001. An NMR and enzyme study of the carbon metabolism of Neisseria meningitidis. Microbiology 147:1473-1482. |
| 38. | MacLaren, D. M. 1968. The significance of urease in proteus pyelonephritis: a bacteriological study. J. Pathol. Bacteriol. 96:45-56.[CrossRef][Medline] |
| 39. | Mackinnon, F. G., R. Borrow, A. R. Gorringe, A. J. Fox, D. M. Jones, and A. Robinson. 1993. Demonstration of lipooligosaccharide immunotype and capsule as virulence factors for Neisseria meningitidis using an infant mouse intranasal infection model, Microb. Pathog. 15:359-366.[CrossRef] |
| 40. | Mandrel, R. E., J. J. Kim, C. M. John, B. W. Gibson, J. V. Sugi, M. A. Apicella, J. M. Griffiss, and R. Yamasaki. 1991. Endogenous sialylation of the lipooligosaccharide of Neisseria meningitidis. J. Bacteriol. 173:2823-2832. |
| 41. | Monaco, C., A. Talà, M. R. Spinosa, C. Progida, E. De Nitto, A. Gaballo, C. B. Bruni, C. Bucci, and P. Alifano. 2006. Identification of a meningococcal L-glutamate ABC transporter operon essential for growth in low-sodium environments. Infect. Immun. 74:1725-1740. |
| 42. | Morse, S. A., and L. Bartenstein. 1974. Factors affecting autolysis of Neisseria gonorrhoeae. Proc. Soc. Exp. Biol. Med. 145:1418-1421.[Medline] |
| 43. | Morse, S. A., and B. H. Hebeler. 1978. Effect of pH on the growth and glucose metabolism of Neisseria gonorrhoeae. Infect. Immun. 21:87-95. |
| 44. | Nassif, X. 2000. Gonococcal lipooligosaccharide: an adhesin for bacterial dissemination? Trends Microbiol. 8:539-541.[CrossRef][Medline] |
| 45. | Nassif, X., M. Marceau, C. Pujol., B. Bron, J. L Beretti, and M. K. Taha. 1997. Type-4 pili and meningococcal adhesiveness. Gene 192:149-153.[CrossRef][Medline] |
| 46. | Ngampasutadol, J. S. R., A. M. Blom, S. Gulati, and P. A. Rice. 2004. Serum resistance of Neisseria gonorrhoeae is restricted to humans; a possible explanation for the species specificity of gonococcal infection. Mol. Immunol. 41:285. |
| 47. | Pannekoek, Y., J. P. van Putten, and J. Dankert. 1992. Identification and molecular analysis of a 63-kilodalton stress protein from Neisseria gonorrhoeae. J. Bacteriol. 174:6928-6937. |
| 48. | Parkhill, J., M Achtman, K. D. James, S. D. Bentley, C. Churcher, S. R. Klee, G. Morelli, D. Basham, D. Brown, T. Chillingworth, R. M. Davies, P. Davis, K. Devlin, T. Feltwell, N. Hamlin, S. Holroyd, K. Jagels, S. Leather, S. Moule, K. Mungall, M. A. Quail, M. A. Rajandream, K. M. Rutherford, M. Simmonds, J. Skelton, S. Whitehead, B. G. Spratt, and B. G. Barrell. 2000. Complete DNA sequence of a serogroup A strain of Neisseria meningiditis Z2491. Nature 404:502-506.[CrossRef][Medline] |
| 49. | Parsons, N. J., G. J. Boons, P. R. Ashton, P. D. Redfern, P. Quirk, Y. Gao, C. Constantinidou, J. Patel, J. Bramley, J. A. Cole, and H. Smith. 1996. Lactic acid is the factor in blood cell extracts which enhances the ability of CMP-NANA to sialylate gonococcal lipopolysaccharide and induce serum resistance. Microb. Pathog. 20:87-100.[CrossRef][Medline] |
| 50. | Proctor, R. A., L. C. Denlinger, and P. J. Bertics. 1995. Lipopolysaccharide and bacterial virulence, p. 173-194. In J. A. Roth, C. A. Bolin, K. A. Brogden, F. C. Minion, and M. J Wannemuehler (ed.), Virulence mechanisms of bacterial pathogens. American Society for Microbiology, Washington, DC. |
| 51. | Ram, S., A. D. Cox, J. C. Wright, U. Vogel, S. Getzlaff, R. Boden, J. Li, J. S. Plested, S. Meri, S. Gulati, D. C. Stein, J. C. Richards, E. R. Moxon, and P. A. Rice. 2003. Neiserial lipooligosaccharide is a target for complement component C4b: inner core phosphoethanolamine residues define C4b linkage specificity. J. Biol. Chem. 278:50853-50862. |
| 52. | Ram, S., M. Cullinane, A. M. Blom, S. Gulati, D. P. McQuillen, B. G. Monks, C. O'Connell, R. Boden, C. Elkins, M. K. Pangburn, B. Dahlback, and P. A. Rice. 2001. Binding of C4b-binding protein to porin: a molecular mechanism of serum resistance of Neisseria gonorrhoeae. J. Exp. Med. 193:281-295. |
| 53. | Ram, S., D. P. McQuillen, S. Gulati, C. Elkins, M. K. Pangburn, and P. A. Rice. 1998. Binding of complement factor H to loop 5 of porin protein 1A: a molecular mechanism of serum resistance of non-sialylated Neisseria gonorrhoeae. J. Exp. Med. 188:671-680. |
| 54. | Ram, S., A. K. Sharma, S. D. Simpson, S. Gulati, D. P. McQuillen, M. K. Pangburn, and P. A. Rice. 1998. A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae. J. Exp. Med. 187:743-752. |
| 55. | Regan, T., A. Watts, H. Smith, and J. A. Cole. 1999. Regulation of the lipopolysaccharide-specific sialyltransferase activity of gonococci by growth state of the bacteria, but not by carbon source, catabolite repression or oxygen supply. Antonie Leeuwenhoek 75:369-379.[CrossRef][Medline] |
| 56. | Schneider, M. C., R. M. Exley, H. Chan, I. Feavers, Y. H. Kang, R. B. Sim, and C. M. Tang. 2006. Functional significance of factor H binding to Neisseria meningitidis. J. Immunol. 176:7566-7575. |
| 57. | Sim, R. J., M. M. Harrison, E. R. Moxon, and C. M. Tang. 2000. Underestimation of meningococci in tonsillar tissue by nasopharyngeal swabbing. Lancet 356:1653-1654.[CrossRef][Medline] |
| 58. | Simons, M. P., W. M. Nauseef, and M. A. Apicella. 2005. Interactions of Neisseria gonorrhoeae with adherent polymorphonuclear leukocytes. Infect. Immun. 73:1971-1977. |
| 59. | Smith, H. 2000. Questions about the behaviour of bacterial pathogens in vivo. Phil. Trans. R. Soc. Lond. B 355:551-564.[CrossRef][Medline] |
| 60. | Smith, H., N. J. Parsons, and J. A. Cole. 1995. Sialylation of neisserial lipopolysaccharide: a major influence on pathogenicity. Microb. Pathog. 19:365-377.[CrossRef][Medline] |
| 61. | Smith, H., E. A. Yates, J. A. Cole, and N. J. Parsons. 2001. Lactate stimulation of gonococcal metabolism in media containing glucose: mechanism, impact on pathogenicity and wider implications for other pathogens. Infect. Immun. 69:6565-6572. |
| 62. | Stephens, D. S., C. F. McAllister, D. Zhou, F. K. Lee, and M. A. Apicella. 1994. Tn916-generated lipooligosaccharide mutants of Neisseria meningitidis and Neisseria gonorrhoeae. Infect. Immun. 62:2947-2952. |
| 63. | Sun, Y., S. Bakshi, R. Chalmers, and C. M. Tang. 2000. Functional genomics of Neisseria meningiditis pathogenicity. Nat. Med. 6:1269-1273.[CrossRef][Medline] |
| 64. | Sun, Y., Y. Li, R. M. Exley, M. Winterbotham, C. Ison, H. Smith, and C. M. Tang. 2005. Identification of novel antigens that protect against systemic meningococcal infection. Vaccine 23:4136-4141.[CrossRef][Medline] |
| 65. | Tettelin, H., N. J. Saunders, J. Heidelberg, A. C. Jeffries, K. E. Nelson, J. A. Eisen, K. A. Ketchum, D. W. Hood, J. F. Peden, R. J. Dodson, W. C. Nelson, M. L. Gwinn, R. DeBoy, J. D. Peterson, E. K. Hickey, D. H. Haft, S. L. Salzberg, O. White, R. D. Fleischmann, B. A. Dougherty, T. Mason, A. Ciecko. D. S. Parksey, E. Blair, H. Cittone, E. B. Clark, M. D. Cotton, T. R. Utterback. H. Khouri, H. Qin, J. Vamathevan, J. Gill, V. Scarlato, V. Masignani, M. Pizza, G. Grandi, L. Sun, H. O. Smith, C. M. Fraser, E. R. Moxon, R. Rappuoli, and J. C. Venter. 2000. Complete genome sequence of Neisseria meningiditis serogroup B strain MC58. Science 287:1809-1815. |
| 66. | Van Deuren, M., P. Brandtzaeg, and J. W. van der Meer. 2000. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin. Microbiol. Rev. 13:144-166. |
| 67. | Veale. D. R., C. W. Penn, and H. Smith. 1978. Capacity of gonococci to survive and grow within human phagocytes. In G. F. Brooks, E. C. Gotschlich, K. K. Holmes, W. D. Sawyer, and F. E. Young (ed.), Immunobiology of Nieseria gonorrhoeae. American Society for Microbiology, Washington DC. |
| 68. | Vimr, E., and C. Lichtensteiger. 2002. To sialylate or not to sialylate: that is the question. Trends Microbiol. 10:254-257.[CrossRef][Medline] |
| 69. | Virji, M., K. Makepeace, D. J. Ferguson, M. Achtman, and E. R. Moxon. 1993. Meningococcal Opa and Opc proteins: their role in colonization and invasion of human epithelial and endothelial cells. Mol. Microbiol. 10:499-510.[Medline] |
| 70. | Vogel, U., H. Claus, G. Heinze, and M. Frosch. 1997. Functional characterization of an isogenic meningococcal -2,3-sialyltransferase mutant: the role of lipooligosaccharide sialylation for serum resistance in serogroup B meningococci. Med. Microbiol. Immunol. 186:159-166.[CrossRef][Medline] |
| 71. | Vogel, U., H. Claus, G. Heinze, and M. Frosch. 1999. Role of lipopolysaccharide sialylation in serum resistance of serogroup B and C meningococcal disease isolates. Infect. Immun. 67:954-957. |
| 72. | Vogel, U., and M. Frosch. 1999. Mechanisms of neisserial serum resistance. Mol. Microbiol. 32:1133-1139.[CrossRef][Medline] |
| 73. | Vogel, U., S. Hammerschmidt, and M. Frosch. 1996. Sialic acids of both the capsule and the sialylated lipooligosaccharide of Neisseria meningitidis serogroup B are prerequisites for virulence of meningococci in the infant rat. Med. Microbiol. Immunol. 185:81-87.[CrossRef][Medline] |
| 74. | Wandersman, C., and P. Delepelaire. 2004. Bacterial iron sources: from siderophores to hemophores. Annu. Rev. Microbiol. 58:611-647.[CrossRef][Medline] |
| 75. | Williams, A. E., J. Keppie, and H. Smith. 1964. The relation of erythritol usage to virulence in Brucellas. J. Gen. Microbiol. 37:285-292.[Medline] |
| 76. | Wu, H., and A. E. Jerse. 2006. Alpha-2,3-sialyltransferase enhances Neisseria gonorrhoeae survival during experimental murine genital tract infection. Infect. Immun. 74:4094-4103. |
| 77. | Yates, E., L. Gao, N. Woodcock, N. Parsons, J. Cole, and H. Smith. 2000. In a medium containing glucose, lactate carbon is incorporated by gonococci predominantly into fatty acids and glucose carbon incorporation is increased: implications regarding lactate stimulation of metabolism. Int. J. Med. Microbiol. 290:627-639.[Medline] |
| 78. | Yates, E. A., and H. Smith. 2003. Lactate carbon does not enter the sugars of lipopolysaccharide when gonococci are grown in a medium containing glucose and lactate: implications in vivo. FEMS Microbiol. Lett. 218:245-250.[CrossRef][Medline] |
| 79. | Yazdankhah, S. P., and D. A. Caugant. 2004. Neisseria meningitidis; an overview of the carriage state. J. Med. Microbiol. 53:821-832. |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| J. Bacteriol. | J. Virol. | Eukaryot. Cell |
|---|
| Microbiol. Mol. Biol. Rev. | Clin. Vaccine Immunol. | All ASM Journals |
|---|
