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A role for lactate dehydrogenases in the survival of Neisseria gonorrhoeae in human polymorphonuclear leukocytes and cervical epithelial cells.

ABSTRACT: Lactate is an abundant metabolite, produced by host tissues and commensal organisms, and it represents an important potential carbon source for bacterial pathogens. In the case of Neisseria spp., the importance of the lactate permease in colonization of the host has been demonstrated, but there have been few studies of lactate metabolism in pathogenic Neisseria in the postgenomic era. We describe herein the characterization of genome-annotated, respiratory, and substrate-level lactate dehydrogenases (LDHs) from the obligate human pathogen Neisseria gonorrhoeae. Biochemical assays using N. gonorrhoeae 1291 wild type and isogenic mutant strains showed that cytoplasmic LdhA (NAD(+)-dependent D-lactate dehydrogenase) and the membrane-bound respiratory enzymes, LdhD (D-lactate dehydrogenase) and LldD (L-lactate dehydrogenase) are correctly annotated. Mutants lacking LdhA and LdhD showed greatly reduced survival in neutrophils compared with wild type cells, highlighting the importance of D-lactate metabolism in gonococcal survival. Furthermore, an assay of host colonization using the well-established human primary cervical epithelial cell model revealed that the two respiratory enzymes make a significant contribution to colonization of and survival within the microaerobic environment of the host. Taken together, these data suggest that host-derived lactate is critical for the growth and survival of N. gonorrhoeae in human cells.

SUBMITTER: Atack JM

PROVIDER: S-EPMC4215069 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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A role for lactate dehydrogenases in the survival of Neisseria gonorrhoeae in human polymorphonuclear leukocytes and cervical epithelial cells.

Atack John M JM Ibranovic Ines I Ong Cheryl-Lynn Y CL Djoko Karrera Y KY Chen Nathan H NH Vanden Hoven Rachel R Jennings Michael P MP Edwards Jennifer L JL McEwan Alastair G AG

The Journal of infectious diseases 20140415 8

Lactate is an abundant metabolite, produced by host tissues and commensal organisms, and it represents an important potential carbon source for bacterial pathogens. In the case of Neisseria spp., the importance of the lactate permease in colonization of the host has been demonstrated, but there have been few studies of lactate metabolism in pathogenic Neisseria in the postgenomic era. We describe herein the characterization of genome-annotated, respiratory, and substrate-level lactate dehydrogen ...[more]

PMID: 24737798

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Project description:Contact-dependent hemolysins are virulence factors in a number of human pathogens, including Helicobacter pylori, Rickettsia typhi, Bartonella bacilliformis, Mycobacterium tuberculosis, entero-invasive Escherichia coli, and Shigella. Here we demonstrate that Neisseria gonorrhoeae produces an outer membrane protein, phospholipase A, that exhibits contact-dependent lytic activity on host cell membranes. This enzyme can lyse human erythrocytes over a 3-day period, whereas a phospholipase A mutant cannot. We demonstrated phospholipase A activity in the parent strain but not in two, independent phospholipase A mutants. A gene for phospholipase A, pldA (hereafter referred to as pla to avoid confusion with the gene for phospholipase D, pld), is present in all sequenced gonococcal strains. Fluid phase, hemolytic activity assays showed that 25 of 29 gonococcal strains tested had hemolytic activity greater than 50% of the positive control. In support of PLA as a gonococcal outer membrane protein, supernatants from 24-, 48-, and 72-h cultures of N. gonorrhoeae strain 1291 did not contain hemolysin activity, and a monoclonal antibody specific for gonococcal phospholipase A failed to detect the enzyme in these supernatants. The organism must be viable for lysis to occur, and the inclusion of EDTA in the media removes all activity. Our studies have shown that a phospholipase A mutant has significantly reduced survival in human neutrophils and primary human cervical epithelial cells compared to the parent gonococcal strain after 3 h of incubation. Collectively, our data demonstrate that gonococcal PLA lyses host cell membranes, which is important for intracellular survival.ImportanceIntracellular survival is crucial to the success of Neisseria gonorrhoeae as a human pathogen. Multiple factors contribute to the intracellular survival of gonococci, including the ability to prohibit apoptosis of the epithelial cell the organism invades and mechanisms to evade host innate defense systems. The role of phospholipase A (PLA), an outer membrane protein, is important as it disrupts the host vacuolar and phagolysosomal membranes, preventing the effective delivery of innate immune factors that normally restrict organism growth within human cells. After cell entry, PLA disrupts the integrity of these host cell membranes, allowing the gonococcus to live free within disrupted vacuoles where it pilfers host cell nutrients that enable its survival and replication. A vaccine or drug that could neutralize PLA activity would disrupt the intracellular survival of the gonococcus.

Dataset Information

A role for lactate dehydrogenases in the survival of Neisseria gonorrhoeae in human polymorphonuclear leukocytes and cervical epithelial cells.

Publications

A role for lactate dehydrogenases in the survival of Neisseria gonorrhoeae in human polymorphonuclear leukocytes and cervical epithelial cells.

Similar Datasets

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