A putative xanthine dehydrogenase protects Borrelia burgdorferi from reactive oxygen species and promotes virulence

Abstract

Borrelia burgdorferi is a pathogenic bacterium and the causative agent of Lyme Disease. It is exposed to reactive oxygen species (ROS) in both the vertebrate and tick hosts. While some mechanisms by which B. burgdorferi ameliorates the effects of ROS exposure have been studied, there are likely many other unknown mechanisms of ROS neutralization that contribute to virulence. Here, we follow up on a three gene cluster of unknown function, BB_0554, BB_0555, and BB_0556, that our prior unbiased transposon insertional sequencing studies implicated in both ROS survival and survival in Ixodes scapularis. We confirmed these findings through genetic knockout and provide evidence that these genes are co-transcribed as an operon to produce a xanthine dehydrogenase. In agreement with these results, we found that B. burgdorferi exposure to either uric acid (a downstream product of xanthine dehydrogenase) or allopurinol (an inhibitor of xanthine dehydrogenase) could modulate sensitivity to ROS in a BB_0554-BB_0556 dependent manner. Together, this study identifies a previously uncharacterized three gene operon in B. burgdorferi as a putative xanthine dehydrogenase critical for virulence. ImportanceBorrelia burgdorferi, the causative agent of Lyme disease, is highly successful at evading host immune defenses such as reactive oxygen species, despite minimal identified defenses against oxidative stress. We identified a putative xanthine dehydrogenase that is important in survival of the organism when exposed to oxidative stress and in both its tick and murine hosts. The mechanism appears based on a previously unrecognized role of uric acid in neutralizing reactive oxygen species and highlights how B. burgdorferi can utilize its very limited metabolic capabilities in unique ways.