Biology subjects

Wormser, G. P.

Publications and source records attributed to Wormser, G. P..

4 recordsLinked to original sources

bioRxiv2025

Complex exchanges among plasmids and clonal expansion of lineages shape the population structure and virulence of Borrelia burgdorferi

The many plasmids (commonly >20 per strain) of Borrelia burgdorferi (Bb) pose challenges for studies of Lyme disease. The genetic content of most plasmids cannot be resolved using short-read sequencing. We generated long-read assemblies (LRA) of 183 isolates of human-derived Bb and analyzed patterns of genome variation in the Lyme spirochete. LRAs confirm that populations consist of strongly-structured genotypes with nearly-clonal structure and tight-knit blocks of accessory genome elements. Notably, these patterns of linkage were statistical but not physical, with linkage blocks distributed across multiple plasmids. A consequence of this structure is that plasmid name and/or plasmid subtype does not capture strain-specific genetic content. We used network methods to characterize patterns of genetic linkage. We demonstrate that co-occurring gene networks, here termed genetic modules, are the fundamental unit of genome variation in Bb and designate genetic modules consisting of co-occurring genes. We linked genetic modules to Bb phenotype by identifying modules that influence dissemination in humans. This modular decomposition clarifies previously observed associations between strain and virulence. For example, virulent RST1/OspC type A strains are distinguished by the presence of virulence-associated modules containing gene content from lp28-1, lp56, and the chromosome along with the absence of gene content on lp28-1 and lp28-4 associated with localized disease. LRAs also demonstrate that the well-established statistical linkage between physical unlinked genetic markers (e.g. RST and OspC) is a general pattern among accessory genome elements. In summary, genetic modules containing genes linked across multiple replicons, rather than strain-defining plasmids, organize the Bb accessory genome and the strain-specific variation responsible for differences in human virulence.

microbiology↗

bioRxiv2024

Peromyscus leucopus, Mus musculus, and humans have distinct transcriptomic responses to larval Ixodes scapularis bites

Ixodes scapularis ticks are an important vector for at least six tick-borne human pathogens, including the predominant North American Lyme disease spirochete Borrelia burgdorferi. The ability for these ticks to survive in nature is credited, in part, to their ability to feed on a variety of hosts without excessive activation of the proinflammatory branch of the vertebrate immune system. While the ability for nymphal ticks to feed on a variety of hosts has been well-documented, the host-parasite interactions between larval I. scapularis and different vertebrate hosts is relatively unexplored. Here we report on the changes in the vertebrate transcriptome present at the larval tick bite site using the natural I. scapularis host Peromyscus leucopus deermouse, a non-natural rodent host Mus musculus (BALB/c), and humans. We note substantially less evidence of activation of canonical proinflammatory pathways in P. leucopus compared to BALB/c mice and pronounced evidence of inflammation in humans. Pathway enrichment analyses revealed a particularly strong signature of interferon gamma, tumor necrosis factor, and interleukin 1 signaling at the BALB/c and human tick bite site. We also note that bite sites on BALB/c mice and humans, but not deermice, show activation of wound-healing pathways. These data provide molecular evidence of the coevolution between larval I. scapularis and P. leucopus as well as expand our overall understanding of I. scapularis feeding. SignificanceIxodes scapularis tick bites expose humans to numerous diseases in North America. While larval tick feeding enables pathogens to enter the tick population and eventually spread to humans, how larval ticks interact with mammals has been understudied compared to other tick stages. Here we examined the transcriptomic response of a natural I. scapularis rodent host (Peromyscus leucopus), a non-native I. scapularis rodent host (Mus musculus), and an incidental host (humans). We find that there are differences in how all three species respond to larval I. scapularis, with the natural host producing the smallest transcriptomic signature of a canonical proinflammatory immune response and the incidental human host producing the most robust signature of inflammation in response to the larval tick. These data expand our understanding of the pressures on ticks in the wild and inform our ability to model these interactions in laboratory settings.

immunology↗

bioRxiv2023

Whole genome sequencing of Borrelia burgdorferi isolates reveals linked clusters of plasmid-borne accessory genome elements associated with virulence.

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 patient-derived B. burgdorferi sensu stricto (Bbss) isolates from patients in the Eastern and Midwestern US and Central Europe. We develop a WGS-based classification of Bbss isolates, confirm and extend the findings of previous single- and multi-locus typing systems, define the plasmid profiles of human-infectious Bbss isolates, annotate the core and strain-variable surface lipoproteome, and identify loci associated with disseminated infection. A core genome consisting of [~]800 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 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, are associated with increased rates of dissemination. OspC type A strains possess a unique constellation of strongly linked genetic changes 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. The patterns of OspC type A strains typify a broader paradigm across Bbss isolates, in which genetic structure is defined by correlated groups of strain-variable genes located predominantly on plasmids, particularly for expression of surface-exposed lipoproteins. These clusters of genes are inherited in blocks through strain-specific patterns of plasmid occupancy and are associated with the probability of invasive infection.

microbiology↗

bioRxiv2019

Measurement of organ-specific and acute-phase blood protein levels in early Lyme disease

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that 1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or 2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2 and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.

systems biology↗