Abstract
ABSTRACTBorrelia burgdorferi is an extreme amino acid (AA) auxotroph whose genome encodes few free AA transporters and an elaborate oligopeptide transport system (B. burgdorferi Opp [BbOpp]). BbOpp consists of five oligopeptide-binding proteins (OBPs), two heterodimeric permeases, and a heterodimeric nucleotide-binding domain (NBD). Homology modeling based on the crystal structure of liganded BbOppA4 revealed that each OBP likely binds a distinct range of peptides. Transcriptional analyses demonstrated that the OBPs are differentially and independently regulated whereas the permeases and NBDs are constitutively expressed. A conditional NBD mutant failed to divide in the absence of inducer and replicated in an IPTG (isopropyl-β-d-thiogalactopyranoside) concentration-dependent manner. NBD mutants grown without IPTG exhibited an elongated morphotype lacking division septa, often with flattening at the cell center due to the absence of flagellar filaments. Following cultivation in dialysis membrane chambers, NBD mutants recovered from rats not receiving IPTG also displayed an elongated morphotype. The NBD mutant was avirulent by needle inoculation, but infectivity was partially restored by oral administration of IPTG to infected mice. We conclude that peptides are a major source of AAs for B. burgdorferi both in vitro and in vivo and that peptide uptake is essential for regulation of morphogenesis, cell division, and virulence.
Highlights
IMPORTANCE Borrelia burgdorferi, the causative agent of Lyme disease, is an extreme amino acid (AA) auxotroph with a limited repertoire of annotated single-Amino acids (AAs) transporters
By mutagenizing the ATP-hydrolyzing nucleotide-binding domain (NBD) domain to incapacitate the entire BbOpp system, we demonstrated that peptides are essential for spirochete growth in vitro, as well as within the mammalian host, a milieu in which free AAs should be available [34]
The components of the Opp system of B. burgdorferi sensu lato are distributed among chromosome and plasmids (Fig. 1A and S1), mirroring the Lyme disease spirochete’s unusual, fragmented genome [35]
Summary
IMPORTANCE Borrelia burgdorferi, the causative agent of Lyme disease, is an extreme amino acid (AA) auxotroph with a limited repertoire of annotated single-AA transporters. Some OBP homologues contain subtle structural modifications that allow binding of highly specific ligands (e.g., pheromones and muropeptides), which function as cues for the activation of signal transduction, cell competence, and gene regulation pathways [7]. The spirochete Treponema denticola has a complicated Opp system involving multiple OBPs, permeases, and NBD proteins arranged in noncanonical order [13]. This oral commensal has limited AA biosynthetic capacity and instead uses an array of proteases to create a peptide-rich microenvironment in gingival tissues and energy generation via fermentation [14]. Glutamate symporter Cysteine transporter Met, Tyr, or Lys transporter Met, Tyr, or Lys transporter Arginine/ornithine symporter
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