Lactate Stimulation of Gonococcal Metabolism in Media Containing Glucose: Mechanism, Impact on Pathogenicity, and Wider Implications for Other Pathogens

Abstract

Over the past decade, studies of Neisseria gonorrhoeae have shown that in media containing glucose, lactate stimulates metabolism, and this could affect pathogenicity (7,19). Recently, the probable mechanism of this stimulation has been identified as one that could apply to other pathogens (68). Earlier studies implicated lactate metabolism in the serum resistance of Haemophilus influenzae (30), and during the past year, the use of signature-tagged mutagenesis and an infant rat model identified a putative (i.e., homologous with the gene in Escherichia coli) lactate permease-deficient mutant of Neisseria meningitidis with diminished virulence (62; C. M. Tang, personal communication). There may be a common role for lactate in the pathogenicity of these and other pathogens. Lactate and glucose are present together in most sites where infection occurs in vivo. This review summarizes the present position on gonococci and its implications regarding other pathogens. Throughout, the phrase "stimulation of metabolism by lactate" refers to this event occurring in a medium containing glucose. ENERGY SOURCES OF GONOCOCCIThe nutritional requirements for growth of gonococci include amino acids, purines, pyrimidines, vitamins, and an energy source (8). The last is restricted; only glucose, pyruvate, and lactate are used efficiently (39). The mechanism for lactate stimulation of gonococcal metabolism depends on interaction between it and glucose. The literature records information on the metabolism of one or the other alone but not in combination; it is summarized below.Glucose is metabolized at pH 7.2 and 8.0 primarily (ca. 80%) via the Entner-Doudoroff pathway, with some contribution (ca. 20%) from the pentose phosphate pathway (40). At a pH above 7, most of the pyruvate and acetyl coenzyme A (CoA) generated from glucose accumulates as acetate, with only small amounts being oxidized by the tricarboxylic acid (TCA) cycle (40). However, at pH 6, the contribution of the pentose pathway increases to about 50% and more acetyl-CoA is metabolized via the TCA cycle (40).Lactate provides energy for growth by being a substrate for electron transport when it is oxidized to pyruvate (3, 4). Gonococci contain at least three lactic dehydrogenase (LDH) enzymes. The most important are two electron transport-linked LDHs that are associated with the cytoplasmic membrane and independent of NAD ϩ (13, 67). Isoenzyme LDH-I utilizes lactate exclusively as its substrate and with a preference for the D-isomer, while isoenzyme LDH-II has broad substrate specificity (lactate, phenyl-lactate, and 4-hydroxy-phenyl-lactate), but it is steriospecific for L-isomers. The third LDH is a cytoplasmic, soluble NAD ϩ -dependent LDH (25). Pyruvate produced from lactate is catabolized by the TCA cycle (24). STIMULATION OF METABOLISM BY LACTATEEvidence for the stimulation of metabolism by lactate comes from several sources.Interaction of gonococci with neutrophils. Cohen and his colleagues showed that when gonococci were phagocytosed by neutrophils, their metabolic...

Production of outer membrane vesicles (OMV) in batch cultivation of Neisseria meningitidis serogroup B

“…According to this study, the lactate degradation is accomplished by way of an intact tricarboxylic acid cycle (TCA), as well as pentose-phosphate and Entner-Doudoroff pathways. Probably the lactatedehydrogenase key enzymes can develop the two-way function of lactate generation (glycolysis) or lactate absorption (gluconeogenesis) in these pathways (15,22).…”

Necessity of Meningococcal γ-Glutamyl Aminopeptidase for Neisseria meningitidis Growth in Rat Cerebrospinal Fluid (CSF) and CSF-Like Medium

“…The composition was based on that of the defined agar medium for N. meningitidis (4) except that the concentrations of five amino acids (L-glutamine, 500 M; L-glutamate, 8 M; L-glycine, 7 M; L-arginine, 18 M; and L-cysteine, 1 M) and three ␥-glutamyl peptides (␥-glutamyl-glutamate, 30 M; ␥-glutamyl-cysteine, 2 M; and GSH, 1 M) were almost equal to those in human CSF or rat brain (7,17). Moreover, in this study, 0.5% glucose and 0.1% lactate were added to CMM as carbon sources at concentrations that were 10 times higher than the actual concentrations in human CSF (20) to avoid the effects of carbon starvation. In CMM, H44/76 could grow well but HT1089 could not (Fig.…”

Effect of Host Lactate on Gonococci and Meningococci: New Concepts on the Role of Metabolites in Pathogenicity

“…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.…”

“…This first indication that lactate metabolism might be important in the pathogenicity of N. gonorrhoeae has been amply confirmed during the past decade (17,61,77), and now lactate has been shown to have important effects on Neisseria meningitidis (15,16). This review uses the work on gonococci as background to describe recent research on the meningococcus, which in turn provided the key to proving the influence of lactate on gonococcal pathogenicity in vivo.…”

“…Some differences between meningococci and gonococci in their responses to lactate are discussed, and new concepts of the role of metabolites in pathogenicity arising from the work are summarized. Throughout this review, it should be kept in mind that lactate is present in urogenital and respiratory secretions, blood, phagocytes, and cerebrospinal fluid (CSF), together with glucose and pyruvate (61), two other energy sources used effectively by gonococci and meningococci (37,42,43). Hence, in vivo, gonococci and meningococci grow on a mixture of carbon sources.…”