Redox Regulation of DksA-dependent Borrelia burgdorferi infectivity

PROJECT SUMMARY
Borrelia burgdorferi, the etiologic agent of Lyme disease, is a major source of illness in the United States with
over 476,000 cases per year. Like other vector-borne pathogens, B. burgdorferi must overcome a wide variety
of environmental stresses during its infectious cycle in ticks of the genus Ixodes, and various mammalian hosts.
Among the challenges faced by B. burgdorferi are shifts in pH, temperature, osmolarity, nutrient availability,
reactive oxygen species (ROS) along with nitric oxide (NO) and its congeners [reactive nitrogen species (RNS)
(e.g., NO, NO2•, N2O3 and ONOO-)]. Of these, the roles of temperature and pH on B. burgdorferi virulence gene
expression and infectivity have been the best characterized. Previously published work from our laboratory and
others have demonstrated that B. burgdorferi encounters biologically significant amounts of ROS and RNS
during infection of its tick vector Ixodes scapularis and mammalian hosts. We have also shown that cysteine
thiols of proteins involved in gene regulation, antioxidant defenses, and central metabolism are targets of ROS
and RNS, although the impact of these modifications on B. burgdorferi infectivity have yet to be determined. Our
previously published work showed the DnaK suppressor protein (DksA) is a global regulator of gene expression
in B. burgdorferi and coordinates the stringent response during periods of nutrient limitation. We now have
preliminary data supporting a role for DksA in regulating virulence gene expression required for completion of its
infectious cycle in I. scapularis and mammalian hosts. Despite this, there are substantial gaps in our knowledge
about how DksA senses changes within its vector and mammalian hosts to direct B. burgdorferi gene expression.
In this application, we propose to test our central hypothesis that DksA senses tick-borne ROS/RNS to coordinate
the transcriptional responses of B. burgdorferi required for the completion of its infectious cycle. This proposal is
particularly innovative and will impact the field of tick-borne diseases by determining the mechanisms underlying
the ability of B. burgdorferi to sense changes in its environment to regulate gene expression. Since this area of
research is virtually uninvestigated for tick-borne diseases, our findings will undoubtedly provide insight to the
field and inform future strategies to prevent tick-borne infections.

Grant Number: 5R01AI167880-03
NIH Institute/Center: NIH
Principal Investigator: Travis Bourret