Hpt, a bacterial homolog of the microsomal glucose- 6-phosphate translocase, mediates rapid intracellular proliferation inListeria

Abstract

Efficient replication in vivo is essential for a microparasite to colonize its host and the understanding of the molecular mechanisms by which microbial pathogens grow within host tissues can lead to the discovery of novel therapies to treat infection. Here we present evidence that the foodborne bacterial pathogen Listeria monocytogenes, a facultative intracellular parasite, exploits hexose phosphates (HP) from the host cell as a source of carbon and energy to fuel fast intracellular growth. HP uptake is mediated by Hpt, a bacterial homolog of the mammalian translocase that transports glucose-6-phosphate from the cytosol into the endoplasmic reticulum in the final step of gluconeogenesis and glycogenolysis. Expression of the Hpt permease is tightly controlled by the central virulence regulator PrfA, which upon entry into host cells induces a set of virulence factors required for listerial intracellular parasitism. Loss of Hpt resulted in impaired listerial intracytosolic proliferation and attenuated virulence in mice. Hpt is the first virulence factor to be identified as specifically involved in the replication phase of a facultative intracellular pathogen. It is also a clear example of how adaptation to intracellular parasitism by microbial pathogens involves mimicry of physiological mechanisms of their eukaryotic host cells.

The AlternativeTranslational Profile That Underlies the Immune-Evasive State of Persistence in Chlamydiaceae Exploits Differential Tryptophan Contents of the Protein Repertoire

“…These permeases belong to the organophosphate:inorganic phosphate antiporter family of the major facilitator superfamily of permeases (114). It has been shown that the permeases from Chlamydiaceae are closer to the mammalian permeases on a protein tree than they are to other bacterial hexose-P permeases (26), and lateral gene transfer (LGT) in one direction or the other was suggested. Since that time, the genome of "Ca.…”

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

“…This metabolic process depends on the synthesis of Hpt, a hexose phosphate transporter protein that enables bacterial intracellular multiplication and is necessary for proliferation in mouse organs. 145,146 The lipoate ligase LplA1 is among other bacterial proteins required for growth in host cells. This enzyme is essential to perform a critical lipoyl modification in the E2 subunit of pyruvate dehydrogenase, in the presence of limiting concentrations of available host lipoyl substrates, which suggests that abortive growth is due to loss of pyruvate dehydrogenase function.…”

Listeria monocytogenes phosphatidylinositol-specific phospholipase C has evolved for virulence by greatly reduced activity on GPI anchors

“…Listeriolysin O (LLO), a secreted pore-forming cytolysin, has specifically evolved for activity in a phagosome by having a low pH optimum (5). Two other virulence factors, a hexose phosphate transporter and a lipoate protein ligase, are specific adaptations for intracellular replication and survival (6,7). Here, we report that Listeria monocytogenes phosphatidylinositol-specific phospholipase C (LmPI-PLC) has also evolved for intracellular growth and virulence by a specific structural modification that leads to greatly reduced activity on glycosylphosphatidylinositol (GPI)-anchored proteins.…”