RNA-mediated gene regulation in the Lyme disease pathogen

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

The spirochete Borrelia burgdorferi is the causative agent of Lyme disease, the most prevalent vector-borne illness in the United States, where children 5 – 9 years old are most commonly affected. Given that B. burgdorferi inhabits tick and mammalian hosts, environments with very different temperatures, immune responses and sources of metabolites, the bacterium must harbor robust gene regulatory mechanisms in order to survive. Yet, fundamental aspects of gene expression have not been studied extensively in B. burgdorferi. Ongoing work in our lab has been focused on the regulation of spirochete motility (1). Flagella propel pathogens through their environments yet are expensive to synthesize and are immunogenic. Thus, complex hierarchical regulatory networks control flagellar gene expression. Spirochetes are highly motile bacteria, but peculiarly in the Lyme spirochete Borrelia burgdorferi, the archetypal flagellar regulator σ28 is absent. We rediscovered gene bb0268 in B. burgdorferi as flgV, a broadly-conserved gene in the flagellar superoperon alongside σ28 in many Spirochaeta, Firmicutes and other phyla, with distant homologs in Epsilonproteobacteria. We found that B. burgdorferi FlgV is localized within flagellar basal bodies. B. burgdorferi lacking flgV construct fewer and shorter flagellar filaments and are defective in cell division and motility. During the enzootic cycle, B. burgdorferi lacking flgV survive and replicate in Ixodes ticks but are attenuated for dissemination and infection in mice. Our work defines infection timepoints when spirochete motility is most crucial and implicates FlgV as a broadly distributed structural flagellar component that modulates flagellar assembly.