Lyme disease (LD), caused by the spirochete Borrelia burgdorferi (Bb), is the most common arthropod-borne infection in the United States. Bb is maintained in nature via an enzootic cycle that typically involves rodents and Ixodes ticks. To sustain this complex life cycle, Bb must continuously alter its transcriptome, proteome, and metabolome in response to arthropod- and mammalian host-derived signals. Our long term objective has been to characterize the environmental cues, regulatory pathways, and genes critical for these adaptive changes. In our previously funded application, we hypothesized that the alternative sigma factor RpoS acts as a """"""""gatekeeper"""""""" that (i) transcribes genes required for tick transmission as well as the establishment of mammalian infection and (ii) represses tick-phase genes during mammalian host-adaptation. Our validation of this hypothesis has yielded powerful new insights into the mechanisms that perpetuate the bacterium in nature and maintain Lyme disease as a global threat to human health. A number of our recent findings relate to the transmission of spirochetes during nymphal feeding, the seminal event for infection of humans as well as mice. Using methodologies developed for tracking and imaging live spirochetes within ticks, we discovered that dissemination of Bb in feeding nymphs involves an initial non-motile phase (termed """"""""adherence-mediated migration"""""""") followed by a transition to motility that enables individual organisms to penetrate the midgut. These studies have helped elucidate the range of adaptations, physiological as well as structural, that spirochetes must undergo in order to negotiate the formidable barriers they encounter en route to the mammal. They also have definitively demonstrated that RpoS-regulated genes are required for transmission of Bb (see Progress Report). Our collective results give rise to our primary hypothesis, to be assessed in Aims 1 and 2, that RpoS-upregulated genes (a) promote the biphasic dissemination of spirochetes and (b) collectively comprise a 'Go'signal for tick-to-mammal transmission. Additionally, we and others have identified a global regulatory network controlled by the Hk1/Rrp1 two-component system, which we conceptualize as imparting a tick-adaptive 'Stay'signal via the small nucleotide messenger cyclic di-GMP, a molecule known to promote sessile developmental states in bacteria. Our finding that the Hk1/Rrp1 regulon includes tick-phase genes repressed by RpoS within the mammal, coupled with our live-imaging studies, leads to our secondary hypothesis, to be assessed in Aim 3, that the degree of interplay between RpoS and the Hk1/Rrp1 pathway is a major determinant of spirochete behavior and gene expression during the blood meals. Our studies are based on the premise that improved understanding of the molecular mechanisms whereby Bb is transmitted by the arthropod vector will lead to new strategies for prevention and control of LD.

Public Health Relevance

Borrelia burgdorferi (Bb), the causative agent of Lyme disease, is maintained in nature by an enzootic life cycle that involves an Ixodes tick vector and a mammalian host, typically wild rodents. We have shown that genes transcribed by the alternative sigma factor RpoS are critical for transmission of Bb by ticks as well as infection of mice and, therefore, humans. The experiments in our proposal will define more precisely how and where RpoS-dependent genes function during the transmission process and how they are regulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029735-23
Application #
8611891
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Breen, Joseph J
Project Start
1990-04-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Caimano, Melissa J (2018) Generation of Mammalian Host-Adapted Borrelia burgdorferi by Cultivation in Peritoneal Dialysis Membrane Chamber Implantation in Rats. Methods Mol Biol 1690:35-45
Nally, Jarlath E; Grassmann, Andre A; Planchon, S├ębastien et al. (2017) Pathogenic Leptospires Modulate Protein Expression and Post-translational Modifications in Response to Mammalian Host Signals. Front Cell Infect Microbiol 7:362
Hawley, Kelly L; Cruz, Adriana R; Benjamin, Sarah J et al. (2017) IFN? Enhances CD64-Potentiated Phagocytosis of Treponema pallidum Opsonized with Human Syphilitic Serum by Human Macrophages. Front Immunol 8:1227
Grove, Arianna P; Liveris, Dionysios; Iyer, Radha et al. (2017) Two Distinct Mechanisms Govern RpoS-Mediated Repression of Tick-Phase Genes during Mammalian Host Adaptation by Borrelia burgdorferi, the Lyme Disease Spirochete. MBio 8:
Puthenveetil, Robbins; Kumar, Sanjiv; Caimano, Melissa J et al. (2017) The major outer sheath protein forms distinct conformers and multimeric complexes in the outer membrane and periplasm of Treponema denticola. Sci Rep 7:13260
Groshong, Ashley M; Dey, Abhishek; Bezsonova, Irina et al. (2017) Peptide Uptake Is Essential for Borrelia burgdorferi Viability and Involves Structural and Regulatory Complexity of its Oligopeptide Transporter. MBio 8:
Miller, Daniel P; Oliver Jr, Lee D; Tegels, Brittney K et al. (2016) The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin. Infect Immun 84:2051-2058
Caimano, Melissa J; Drecktrah, Dan; Kung, Faith et al. (2016) Interaction of the Lyme disease spirochete with its tick vector. Cell Microbiol 18:919-27
Kenedy, Melisha R; Scott 2nd, Edgar J; Shrestha, Binu et al. (2016) Consensus computational network analysis for identifying candidate outer membrane proteins from Borrelia spirochetes. BMC Microbiol 16:141
Gulia-Nuss, Monika; Nuss, Andrew B; Meyer, Jason M et al. (2016) Genomic insights into the Ixodes scapularis tick vector of Lyme disease. Nat Commun 7:10507

Showing the most recent 10 out of 98 publications