Abstract
Neisseria meningitidis (Nm) and N. gonorrhoeae (Ng) are adapted to different environments within their human host. If the basis of this difference has not yet been fully understood, previous studies (including our own data) have reported that, unlike Ng, Nm tolerates high manganese concentrations. As transition metals are essential regulators of cell growth and host pathogen interactions, we aimed to address mechanisms of Nm Mn2+ tolerance and its pathogenic consequences. Using bioinformatics, gene deletion and heterologous expression we identified a conserved bacterial manganese resistance factor MntX (formerly YebN). The predicted structure suggests that MntX represents a new family of transporters exporting Mn. In the Neisseria genus, this exporter is present and functional in all Nm isolates but it is mutated in a majority of Ng strains and commonly absent in nonpathogenic species. In Nm, Mn2+ export via MntX regulates the intracellular Mn/Fe ratio and protects against manganese toxicity that is exacerbated in low iron conditions. MntX is also important for N. meningitidis to resist killing by human serum and for survival in mice blood during septicemia. The present work thus points to new clues about Mn homeostasis, its interplay with Fe metabolism and the influence on N. meningitidis physiology and pathogenicity.
Highlights
It is largely accepted that access to metals impacts on the equilibrium of host pathogen interface [1,2]
Neisseria meningitidis is an obligate resident of the human nasopharynx but can be responsible for septicemia and meningitis
During our efforts to understand the specific selective pressure underwent by N. meningitidis to survive in its human niche, we have brought to light a new family of bacterial manganese-exporters (MntX) strongly conserved in N. meningitidis but often inactivated or absent in other Neisseria species
Summary
It is largely accepted that access to metals impacts on the equilibrium of host pathogen interface [1,2]. Bacteria must acquire nutrients for survival from the host environment during the course of the interaction These nutrients comprise transition metals (such as Fe, Mn, Zn, Ni, Cu, Co and Mo) [3] which have the specific characteristic of an incompletely filled ‘‘d’’ orbital. Transition metals are essential for the survival of bacteria Their accumulation can be toxic if the quantity, state of oxidation or intracellular localization and regulation are inadequate [5]. OH-) that alter macromolecular structures such as proteins, membranes and DNA, leading to cell death [5] In bacteria, this duality has forced selection of strategies to orchestrate essential transition metals homeostasis by sensing, acquiring, storing or, when needed, exporting them properly. Prokaryote-eukaryote co-evolution has selected immune strategies aimed at controlling metals availability and restricting bacterial growth [3,6,7]
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