Friday, April 18, 2025
4/18/2025
Global virulence regulatory network in the Lyme disease pathogen - Abstract Borrelia burgdorferi (Bb), the etiological agent of Lyme disease, maintains itself in nature via a complex life cycle involving an arthropod (tick) vector and small mammals. During its cycle between ticks and mammals, Bb undergoes dramatic adaptive changes in order to interact with and adapt to these two disparate niches. Previously, we discovered that BosR, a Fur/PerR homologue, plays a central role in regulating virulence gene expression and Bb pathogenicity. Our data showed that BosR is required for Bb's tick-mammal transmission as well as the establishment of mammalian infection. Moreover, we found that BosR regulates expression of rpoS. In addition, our preliminary findings revealed that (i) BosR has much broader biological relevance to Bb’s infectious cycle other than regulating rpoS expression; (ii) there is a unique mechanism(s) involved in the regulation of bosR expression in Bb; and (iii) distinct from other Fur family members, BosR employs a novel mechanism for DNA-binding and gene regulation. These combined data give rise to our hypothesis that BosR acts as an atypical Fur family member to modulate expression of Bb virulence determinants. This hypothesis will be addressed in three Specific Aims. In Aim 1 of this proposal, we will define the BosR regulon and characterize the contributions of BosR-regulated genes to Bb's infectious cycle. In Aim 2, we shall examine the biological roles of the cis-regulatory elements upstream of bosR. Through promoter deletion, reporter assay, and tick- animal infectious studies, we will decipher the roles of the cis-elements in in vivo gene expression and Bb's behavior in ticks and animals. In Aim 3, we shall determine the structure of BosR to elucidate the molecular bases underlying BosR's unconventional activities such as metal coordination and DNA interaction. These combined studies will (i) provide a transformative understanding of the in vivo importance of the BosR regulon; (ii) define the unique aspects of BosR; (iii) clarify the novel mechanism by which BosR controls Bb's virulence; and (iv) reveal new paradigms in bacterial gene and virulence regulation. Resultant findings could lead to the development of new strategies to prevent and/or treat Lyme disease.
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