The arginine deaminase system plays distinct roles in Borrelia burgdorferi and Borrelia hermsii

Abstract

Borrelia species are amino acid auxotrophs that utilize di- and tri- peptides obtained through their oligopeptide transport system to supply amino acids for replicative growth during their enzootic cycles. However, Borrelia species from both the Lyme disease (LD) and relapsing fever (RF) groups harbor an amino acid transport and catabolism system, the Arginine Deiminase System (ADI), that could potentially augment intracellular L-arginine required for growth. RF spirochetes contain a “complete”, four gene ADI (arcA, B, D, and C) while LD spirochetes harbor arcA, B, and sometimes D but lack arcC (encoding carbamate kinase). In this study, we evaluated the role of the ADI system in bacterial survival and virulence and discovered important differences in RF and LD ADIs. Both in vitro and in a murine model of infection, B. hermsii cells significantly reduced extracellular L-arginine levels and that reduction was dependent on arginine deiminase expression. Conversely, B. burgdorferi did not reduce the concentration of L-arginine during in vitro growth experiments nor during infection of the mammalian host, suggesting a fundamental difference in the ability to directly utilize L-arginine compared to B. hermsii. Further experiments using a panel of mutants generated in both B. burgdorferi and B. hermsii, identified important differences in growth characteristics and ADI transcription and protein expression. We also found that the ADI system plays a key role in blood and spleen colonization in RF spirochetes. In this study we have identified divergent metabolic strategies in two closely related human pathogens, that ultimately impacts the host-pathogen interface during infection.

Metabolic modeling predicts unique drug targets in Borrelia burgdorferi

“…Acetyl-CoA initiates a partial mevalonate pathway (BB_0685) essential for the synthesis of peptidoglycan precursor undecaprenyl phosphate ( 48 ). The arginine deiminase system produces ornithine (BB_0842) ( 49 ), which is the peptidoglycan crosslinking diamino acid ( 50 , 51 ). Again, matching recent experimental data, two glycerol-3-phosphate dehydrogenases were predicted: one using NADH as a cofactor (BB_0368) ( 52 ) and one using FADH (BB_0243) ( 53 ).…”

“…For instance, the phospholipid synthases are predicted to be essential but could become nonessential due to passive uptake where the environment is abundant in phospholipids ( 55 ). The production of the cell wall diamino acid ornithine by arginine deiminase (BB_0841) is predicted essential here, but the enzyme has previously been inactivated both singly ( 49 ) and as part of a transposon library ( 57 ). Thus, the prediction of arginine deiminase essentiality is likely to reflect only the requirement for ornithine, which can be sourced either through the arginine deiminase system or by direct uptake from the environment.…”

Screening Marine Microbial Metabolites as Promising Inhibitors of Borrelia garinii: A Structural Docking Approach towards Developing Novel Lyme Disease Treatment

“…Richards et al have previously identified its role in Borrelia sp. growth, where it boosts intracellular L-arginine crucial for growth [ 79 ]. Inhibiting ADI has several advantages as a therapeutic strategy.…”

A simple non-invasive method to collect soft tick saliva reveals differences in Ornithodoros moubata saliva composition between ticks infected and uninfected with Borrelia duttonii spirochetes

“…Another important secondary source of energy in nutrient-poor environments (which is likely the case of salivary glands) could be the arginine dihydrolase (ADH) pathway, which occurs in many anaerobic bacteria, including spirochetes of the genus Treponema (Blakemore and Canale-Parola, 1976) and microaerophilic eukaryotes such as Giardia duodenalis (Brown et al, 1998). Interestingly, genes encoding all key components of the ADH pathway are present in RF Borrelia, whereas Lyme spirochetes possess only a truncated version of the pathway (Lescot et al, 2008;Lin et al, 2017;Richards et al, 2022), suggesting this could reflect the well-known differences in colonization strategies of the vector between these two groups of spirochetes (Schwan and Piesman, 2002). Albeit, the exact mechanisms behind such intertwined metabolism between the pathogen and its vector must be scrutinized in future studies.…”