Microbes Infect. 2016 Mar 16. pii: S1286-4579(16)00050-2. doi: 10.1016/j.micinf.2016.03.004. [Epub ahead of print]
Statins reduce spirochetal burden and modulate immune responses in the C3H/HeN mouse model of Lyme disease.
Van Laar TA1, Hole C1, Rajasekhar Karna SL1, Miller CL1, Reddick R2, Wormley FL1, Seshu J3.
1 South Texas Center for Emerging Infectious Diseases, Center for Excellence in Infection Genomics and Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA.
2 The Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78249, USA.
3 South Texas Center for Emerging Infectious Diseases, Center for Excellence in Infection Genomics and Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA.
Lyme disease (LD) is a systemic disorder caused by Borrelia burgdorferi. Lyme spirochetes encode for a functional 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR EC 188.8.131.52) serving as a rate limiting enzyme of the mevalonate pathway that contribute to components critical for cell wall biogenesis. Statins have been shown to inhibit B. burgdorferi in vitro. Using a mouse model of Lyme disease, we found that statins contribute to reducing bacterial burden and altering the murine immune response to favor clearance of spirochetes.
Copyright © 2016. Published by Elsevier Masson SAS.
Borrelia burgdorferi; Cell wall biogenesis; Lyme disease; Statins
PMID: 26993029 [PubMed - as supplied by publisher]
Edited to update to direct link to the Rel-Risk blog entry:
http://rel-risk.blogspot.com/2016/03/no ... et-al.html
Thursday, March 24, 2016
Van Laar TA, et al. Statins reduce spirochetal burden and modulate immune responses in the C3H/HeN mouse model of Lyme disease. Microbes Infect. 2016 Mar 15.
Sequence analysis of the borrelial genome indicates the presence of homologs of the mevalonate pathway (MP) leading to the synthesis of isopentenyl-5-pyrophosphate (IPP). IPP is an essential component of several isoprenoids and a precursor for peptidoglycan synthesis contributing to the structural integrity of several organisms.
Previous studies from our laboratory have shown that B. burgdorferi possesses a functional MP. The rate-limiting step of the MP is the reduction of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate by HMG-CoA reductase (HMGR). We also determined that B. burgdorferi has a functional HMGR and that enzyme activity could be inhibited using two commercially available HMGR inhibitors (statins). Though the mevalonate pathway is found in many genera of bacteria known to cause human disease, including Staphylococcus, Streptococcus, Listeria, and Borrelia, the potential antimicrobial use of statins has not been fully explored.
The inhibitory property of stains has several implications for interactions of B. burgdorferi with its hosts. As our in vitro data showed that statins were able to exert an inhibitory effect on B. burgdorferi, we wanted to test the effects of statins on a susceptible C3H/HeN [mouse] model of Lyme disease.
Though we have previously found that statins are able to inhibit survival of B. burgdorferi in vitro, the levels of statins in the blood of treated animals do not reach the concentrations necessary for complete bactericidal effects in vitro. However, the numbers of bacteria reaching distal tissues are significantly lower in statin-treated mice, providing evidence that even some bactericidal activity can have an impact on the course of a borrelial infection.
Statins have also been previously shown to negatively affect bacterial growth and survival, even in bacteria that do not encode an hmgr homolog due to their cholesterol lowering properties. Bacteria which require host cholesterol have defects in growth when cholesterol levels are lowered. As B. burgdorferi absolutely require cholesterol for their outer membranes, it is likely that the lowered levels of cholesterol would provide less cholesterol for B. burgdorferi to sequester, thus preventing B. burgdorferi from properly forming its membrane.
It appears that statin treatment contributes to decreased bacterial burden in infected mice, which could be due to either direct interference with spirochetal growth or by limiting available cholesterol to the bacteria. Moreover, it is also possible that alterations in the immune response to the spirochetes could lead to increased bacterial clearance. It is interesting to speculate that statins could potentially have a number of as yet uncharacterized primary or secondary anti-borrelial effects.
[Time to buy stock in statins before Lyme activists discover this paper. So do more people not taking statins contract overt LD than do people on a regular regimen of statins? Is that a beneficial side-effect for people living in LD endemic areas?]