Genome sequencing

New tricks of tick-borne pathogen

Lyme disease is the most common vector-borne disease in Europe, the United States and parts of Asia1,2. In North America, the infection is transmitted by deer ticks between small mammals or, inadvertently, to people (Fig. 1). Like HIV and other emerging infections of the late twentieth century, the aetiologic agent — Borrelia burgdorferi — was unknown to the last generation of microbiologists and physicians. Now, before we are even close to understanding the pathogenesis of Lyme disease, Fraser et al.3 report the near-complete sequence of the B. burgdorferi genome on page 580of this issue. These findings are a first in several respects: this is the first genome from the eubacterial phylum of spirochaetes, with their peculiar morphology, physiology and behaviour; it is the first genome of a parasite that infects both invertebrates and vertebrates; and it is the first genome of a prokaryote with several genetic elements, most of which are linear.

Figure 1: Life cycle of Ixodes tick vectors of Borrelia burgdorferi, the spirochaete agent of Lyme disease that has now been sequenced by Fraser et al.3.
figure1

Small rodents, such as mice, are reservoirs for B. burgdorferi. The tick becomes infected from feeding on a mouse and remains infected as it changes to nymph and then adult. The spirochaetes are transmitted by infected nymphs to other mice and to humans, which are inadvertent hosts. Deer are important hosts for adult ticks, but are not effective reservoirs for B. burgdorferi.

But those who were expecting to find in B. burgdorferi a rich vein of gold in which to mine virulence determinants have to be disappointed. The sequence is as notable for what it does not contain as for what it does. Instead of finding many orthologues4 of toxin and invasion genes, global regulatory systems, two-component signal-transduction pathways and bacteriophages of other pathogenic bacteria, the authors found an almost bewildering array of duplicated lipoprotein genes, unique to Borrelia spp. and of unknown function. These genes are located on extrachromosomal stretches of DNA called plasmids. One of the lipoproteins, OspA, has already been crystallized and structurally characterized5, and it is undergoing human field trials as a vaccine against Lyme disease, although no one yet knows what it does.

Discovery of the linear chromosome in Borrelia6,7 challenged ideas of what a bacterial chromosome is. The findings of Fraser et al.3 now provide further evidence that the distinction between a plasmid and chromosome is primarily a matter of size. The linear and circular plasmids of Borrelia spp. are equimolar with chromosomes8,9, they contain genes that are usually found on chromosomes (for example, guaA and tRNAGly), and they have apparently undergone recombination with the chromosome. These elements could equally be examples of minichromosomes as of plasmids, and they seem to provide an opportunity and place for the organism to duplicate genes and rearrange them without much cost or damage. Moreover, by possessing several copies of highly similar genes on the same (and different) elements, there is the potential for diverse antigenic variation — and this has been observed in relapsing fever Borrelia spp.10.

Determination of the B. burgdorferi genome has opened doors for investigation and closed just as many. By understanding the biosynthetic and transport limitations of B. burgdorferi, we may be able to develop a medium in which to grow as-yet uncultivable Borrelia spp. The results encourage study of a more metabolically competent spirochaete, such as the free-living Spirochaeta aurantia, for a better understanding of how this ancient group of bacteria evolved, and to identify catalytic molecules of industrial importance. But the sequence does not explain the persistence of the disease in some people yet not in others; the differential expression of surface proteins in the tick and in the mammal; or migration of the spirochaetes from the midgut to the salivary gland of the tick, or from the skin to the brain of the mammal. These explanations will require taking the hints (and primers) from the genome and returning to animal models and the clinics.

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Barbour, A., Zückert, W. New tricks of tick-borne pathogen. Nature 390, 553–554 (1997). https://doi.org/10.1038/37475

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