Whole genome sequencing of human Borrelia burgdorferi isolates reveals linked blocks of accessory genome elements located on plasmids and associated with human dissemination.

Lyme disease is the most common vector-borne disease in North America and Europe. The clinical manifestations of Lyme disease vary based on the genospecies of the infecting Borrelia burgdorferi spirochete, but the microbial genetic elements underlying these associations are not known. Here, we report the whole genome sequence (WGS) and analysis of 299 B. burgdorferi (Bb) isolates derived from patients in the Eastern and Midwestern US and Central Europe. We develop a WGS-based classification of Bb isolates, confirm and extend the findings of previous single- and multi-locus typing systems, define the plasmid profiles of human-infectious Bb isolates, annotate the core and strain-variable surface lipoproteome, and identify loci associated with disseminated infection. A core genome consisting of ~900 open reading frames and a core set of plasmids consisting of lp17, lp25, lp36, lp28-3, lp28-4, lp54, and cp26 are found in nearly all isolates. Strain-variable (accessory) plasmids and genes correlate strongly with phylogeny. Using genetic association study methods, we identify an accessory genome signature associated with dissemination in humans and define the individual plasmids and genes that make up this signature. Strains within the RST1/WGS A subgroup, particularly a subset marked by the OspC type A genotype, have increased rates of dissemination in humans. OspC type A strains possess a unique set of strongly linked genetic elements including the presence of lp56 and lp28-1 plasmids and a cluster of genes that may contribute to their enhanced virulence compared to other genotypes. These features of OspC type A strains reflect a broader paradigm across Bb isolates, in which near-clonal genotypes are defined by strain-specific clusters of linked genetic elements, particularly those encoding surface-exposed lipoproteins. These clusters of genes are maintained by strain-specific patterns of plasmid occupancy and are associated with the probability of invasive infection.

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Copyright: © 2023 Lemieux et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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P.C.S. is a co-founder of, shareholder in, and consultant to Sherlock Biosciences and Delve Bio, as well as a board member of and shareholder in Danaher Corporation. K.S. served as a consultant for T2 Biosystems, Roche, BioMerieux, and NYS Biodefense Fund, for the development of a diagnostic assay in Lyme borreliosis, and is currently employed at Takeda. F.S. served on the scientific advisory board for Roche on Lyme disease serological diagnostics and on the scientific advisory board for Pfizer on Lyme disease vaccine, and is an unpaid member of the steering committee of the ESCMID Study Group on Lyme Borreliosis/ESGBOR. J.A.B. has received research funding from Analog Devices Inc., Zeus Scientific, Immunetics, Pfizer, DiaSorin and bioMerieux, and has been a paid consultant to T2 Biosystems, DiaSorin, and Roche Diagnostics. G.P.W. reports receiving research grants from Institute for Systems Biology, Biopeptides, Corp., and Pfizer, Inc. He has been an expert witness in malpractice cases involving Lyme disease and babesiosis; and is an unpaid board member of the non-profit American Lyme Disease Foundation. J.E.L previously served as a consultant to Sherlock Biosciences.