Abstract
The bacterium responsible for Lyme disease, Borrelia burgdorferi, accumulates high levels of manganese without iron and possesses a polyploid genome, characteristics suggesting potential extreme resistance to radiation. Contrary to expectations, we report that wild-type B. burgdorferi B31 cells are radiosensitive, with a gamma-radiation survival limit for 106 wild-type cells of <1 kGy. Thus, we explored B. burgdorferi radiosensitivity through electron paramagnetic resonance (EPR) spectroscopy by quantitating the fraction of Mn2+ present as antioxidant Mn2+ metabolite complexes (H-Mn). The spirochetes displayed relatively low levels of H-Mn, in stark contrast to the extremely radiation-resistant Deinococcus radiodurans. The H-Mn content as revealed by EPR spectroscopy is sufficiently sensitive to detect small changes in radiosensitivity among B. burgdorferi strains. However, B. burgdorferi cells are significantly more sensitive than predicted by EPR, implicating their linear genome architecture as an additional explanation for radiosensitivity. We then explored the influence of the Mn2+-decapeptide-phosphate antioxidant complex MDP, known to shield proteins during irradiation, and showed that treatment with MDP preserves B. burgdorferi’s epitopes at 5 kGy irradiation, which crucially prevents cell proliferation. This finding defines some of the pivotal mechanisms that B. burgdorferi evolved to survive oxidative conditions experienced with tick and mammal immune responses. These observations also provide an opportunity for innovative vaccine development strategies employing ionizing radiation to disrupt the B. burgdorferi genome, while maintaining antigenic potency. These fresh insights extend our understanding of the unique biology of B. burgdorferi and open new avenues for considering novel whole-cell Lyme disease vaccines using MDP and irradiation-based inactivation.
| Original language | English (US) |
|---|---|
| Article number | e03131-24 |
| Journal | mBio |
| Volume | 16 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2025 |
Funding
We thank Dr. Aaron Thompson and Mr. Michael Woolbert (USUHS) for their assistance in irradiator maintenance and calibration. We also thank Sofia C. Echelmeyer (USUHS) for their graphical help. This study was largely supported by a CDMRP Tick-borne Disease Research Program grant (TB180110) to J.S.D. Additional funds were from the Defense Threat Reduction Agency (DTRA) grant HDTRA1620354 to M.J.D., NIH grant GM111097 to B.M.H., funds received from the USUHS Intramural Summer Program to J.S., and funding from the National Institute of Allergy and Infectious Diseases, award numbers R01AI080615 and P01AI138949 to U.P. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A.F.L., A.S., J.S., V.Y.M., E.K.G., R.P.V., M.J.D., B.M.H., U.P., and J.S.D. designed research; A.F.L., A.S., J.S., V.S.R., S.D.F., V.Y.M., E.K.G., and R.P.V. performed research; A.F.L., A.S., J.S., V.Y.M., E.K.G., R.P.V., M.J.D., B.M.H., U.P., and J.S.D. analyzed data; and M.J.D. and A.F.L. wrote the manuscript. M.J.D. and A.F.L wrote this report. Funder Grant(s) Author(s) DOD | USA | MEDCOM | Congressionally Directed Medical Research Programs (CDMRP) TB180110 J. Stephen Dumler DOD | Defense Threat Reduction Agency (DTRA) HDTRA1620354 Michael J. Daly HHS | NIH | National Institute of General Medical Sciences (NIGMS) GM111097 Brian M. Hoffman HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) R01AI080615,P01AI138949 Utpal Pal
Keywords
- Borrelia
- DNA repair
- Deinococcus
- EPR
- Lyme disease
- MDP
- Mn antioxidant
- MnSOD
- ROS
- gamma-radiation
- ionizing radiation
- irradiated vaccine
- polyploidy
ASJC Scopus subject areas
- Microbiology
- Virology