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Secretion of Hcp1 by Burkholderia pseudomallei Potentiates MNGCs Formation through E-selectin Upregulation

ABSTRACT: Multinucleated giant cells (MNGCs) facilitate pathogen dissemination, yet their formation mechanisms remain poorly understood. This study uncovered a novel pathogenic strategy by which Burkholderia pseudomallei exploited its type VI secretion system (T6SS) effector Hcp1 to drive MNGCs formation. Through integrative transcriptomic and mass spectrometry analyses, we demonstrated that Hcp1 specifically targeted arginine residues 78 and 86 of host Arginase-1 (ARG1), enhancing its enzymatic activity to reprogram arginine metabolism toward polyamine biosynthesis. This metabolic shifted triggered E-selectin transcriptional activation, a prerequisite for cell fusion and MNGCs assembly. Significantly, pharmacological inhibition of ARG1 or genetic ablation of E-selectin confered robust protection against B. pseudomallei infection in murine models, reducing pathogen burden by 65%-76%. Our findings established a mechanistic framework linking bacterial effector-mediated metabolic manipulation to MNGCs formation, while identifying ARG1/E-selectin signaling as a promising host-directed therapeutic axis against intracellular pathogens. This work advances the paradigm of pathogen-host metabolic interplay and provides translatable insights for combating antibiotic-resistant infections.

ORGANISM(S): Homo Sapiens

SUBMITTER: Qian Li

PROVIDER: PXD065553 | iProX | Fri Jun 27 00:00:00 GMT+01:00 2025

REPOSITORIES: iProX

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Project description:Protozoa of the genus Leishmania are the causative agents of leishmaniasis in humans. These parasites cycle between promastigotes in the sand fly mid-gut and amastigotes in phagolysosome of mammalian macrophages. During infection, host up-regulate nitric oxide synthase and parasite induce host arginase expression, both of which use arginine as a substrate. These elevated activities deplete macrophage arginine pools, a situation that invading Leishmania must overcome since it is an essential amino acid. Leishmania donovani imports exogenous arginine via a mono-specific amino acid transporter (AAP3) and utilizes it primarily through the polyamine pathway to provide precursors for trypanothione biosynthesis. Here we report the discovery of a pathway whereby promastigote and amastigote forms of the Leishmania sense the lack of environmental arginine and respond with rapid up-regulation in AAP3 expression and activity, as well as several other transporters. Significantly, this arginine deprivation response is also activated in parasites during macrophage infection. Phosphoproteomic analyses of L. donovani promastigotes have implicated a Mitogen-Activated Protein Kinase 2 (MPK2)-mediated signaling cascade in this response and L. mexicana mutants lacking MPK2 are unable to respond to arginine deprivation. In this study, we established that Leishmania cells sense the absence of arginine in their environment; both in culture (axenic promastigotes and amastigotes) and in macrophages during infection (amastigotes). This study describes the first amino acid deprivation sensing mechanism and the pathway that transduce this response, and reveals a novel host-pathogen metabolic interplay. Total RNA from Ten Leishmania donovani samples were analyzed using RNA-Seq. Cells from two life stages (promastigotes and amastigotes) were grown in axenic culture in the presence and absense of arginine. For each condition two biological replicates were grown and analyzed. In addition two macrophage grown amastigotes were analyzed.

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Secretion of Hcp1 by Burkholderia pseudomallei Potentiates MNGCs Formation through E-selectin Upregulation

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