Abstract
To prevent damage by reactive oxygen species, many bacteria have evolved rapid detection and response systems, including the OxyR regulon. The OxyR system detects reactive oxygen and coordinates the expression of numerous defensive antioxidants. In many bacterial species the coordinated OxyR-regulated response is crucial for in vivo survival. Regulation of the OxyR regulon of Haemophilus influenzae was examined in vitro, and significant variation in the regulated genes of the OxyR regulon among strains of H. influenzae was observed. Quantitative PCR studies demonstrated a role for the OxyR-regulated peroxiredoxin/glutaredoxin as a mediator of the OxyR response, and also indicated OxyR self-regulation through a negative feedback loop. Analysis of transcript levels in H. influenzae samples derived from an animal model of otitis media demonstrated that the members of the OxyR regulon were actively upregulated within the chinchilla middle ear. H. influenzae mutants lacking the oxyR gene exhibited increased sensitivity to challenge with various peroxides. The impact of mutations in oxyR was assessed in various animal models of H. influenzae disease. In paired comparisons with the corresponding wild-type strains, the oxyR mutants were unaffected in both the chinchilla model of otitis media and an infant model of bacteremia. However, in weanling rats the oxyR mutant was significantly impaired compared to the wild-type strain. In contrast, in all three animal models when infected with a mixture of equal numbers of both wild-type and mutant strains the mutant strain was significantly out competed by the wild-type strain. These findings clearly establish a crucial role for OxyR in bacterial fitness.
Highlights
For many microbes, resistance to oxidative stress is a prerequisite for survival
Each strain remained viable over the time course of the experiment. To confirm that this kinetic profile was not restricted to hktE, profiles were examined for the peroxiredoxin/glutaredoxin gene pgdX
Growing within the human host, H. influenzae is assaulted by oxidative agents, and must detect and detoxify these potentially lethal oxidants if it is to survive and proliferate
Summary
Resistance to oxidative stress is a prerequisite for survival This is especially so for bacteria which colonize mammals, since the host species fight infection via generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In order to acquire heme and iron directly from human heme-containing and/or iron-containing proteins, H. influenzae has evolved a complex array of mechanisms [3,4,5,6,7,8,9,10]. Many of these H. influenzae iron and heme acquisition mechanisms are tightly regulated in response to iron/heme levels [11,12]. This tight regulation may be necessary since intracellular iron levels need to be balanced so that the redox potential of the cell is not perturbed and so that free radicals are not generated via the Fenton reaction as a consequence of excess iron in an oxidative environment [13]
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