The role of the mevalonate pathway in the patho-physiology of Borrelia burgdorferi

Lyme disease is the most common arthropod-borne infection in the United States and is caused by the spirochetal pathogen Borrelia burgdorferi (Bb). The genome of Bb is very limited and thus Bb is dependent on its arthropod vector and vertebrate hosts to provide many essential metabolic compounds. Therefore, any complete metabolic pathways in Bb serve as interesting targets for study as they must be providing the bacterium with a metabolite it cannot acquire from its hosts. One such intact pathway in Bb is the mevalonate pathway, leading to the synthesis of a molecule called isopentyl pyrophosphate (IPP). In prokaryotes, IPP is a precursor molecule for peptidoglycan and post-translational modification of proteins. The rate limiting step of the mevalonate pathway, HMG-CoA reductase (HMGR), is the target for statins, providing a novel opportunity for study in Bb. Through qRT-PCR analysis, we found that Bb encodes a transcriptionally active mevalonate pathway. We have shown that Bb possesses a functional HMGR which can be inhibited by statins. Statins have an inhibitory effect on Bb grown under in vitro conditions, and the overexpression of HMGR can partially overcome that inhibition in the bacterium. We then tested the effect of two different statins on the susceptible C3H/HeN mouse model of Lyme disease. Statins significantly reduced bacterial burden in distal tissues and led to an increased T_H2 response. There was a difference in the levels of inflammation in statin-treated mice when compared to vehicle-treated controls. Finally, as Mg2+ is a co-factor for MurC, MraY, and UppS, three proteins essential for peptidoglycan biosynthesis, and IPP is a necessary precursor for peptidoglycan we have analyzed the contributions of a magnesium transporter (MgtE) and protein kinase C 1 inhibitor (PKC1I) to the growth and patho-physiology of Bb. Therfore, both the mevalonate pathway and magnesium transport provide novel targets for reducing transmission and incidence of Lyme disease.