Metabolic regulation of the carbonyl stress pathway and methylglyoxal in Lyme disease and relapsing fever spirochetes

The carbonyl stress pathway in bacteria is mediated by the enigmatic metabolite methylglyoxal and is thought to be activated in response to cellular carbohydrate and phosphate imbalance. Methylglyoxal, produced from dihydroxyacetone phosphate by methylglyoxal synthase, covalently modifies nucleophilic groups of amino acid residues, such as lysine, arginine and cysteine, to yield advanced glycation end products. In this work, we have identified several environmental signals, including glycerol and peptides, which activate carbonyl stress in the Lyme disease spirochete Borrelia ( Borreliella ) burgdorferi . We establish that methylglyoxal production and protein glycation is dependent on the mgsA gene ( bb0364 ) product and show that this pathway is active in Lyme disease spirochetes, but not relapsing fever Borrelia or in B. mayonii . Furthermore, we have investigated the role of carbonyl stress in the tick-mouse model of Lyme disease and provide evidence that production of methylglyoxal and glycation of proteins is not necessarily lethal, as previously believed, at least in Lyme disease spirochetes. Finally, we show that expression of the B. burgdorferi mgsA and carbonyl stress pathway in the relapsing fever spirochete B. hermsii significantly reduces the peak level of spirochetemia during the relapse phase of murine infection. Together, our results identify a new post-translation modification system in Lyme disease spirochetes that appears to be important in governing the lifestyle of this pathogen and seems to be selected against in spirochetes that reach high numbers in the blood.