Borrelia burgdorferi (Bb), the Lyme disease (LD) spirochete, is maintained in nature via an enzootic cycle which typically involves wild rodents and Ixodes ticks. During the current funding interval, we have used an expanding armamentarium of model systems and genetic tools to define the physiological and virulence-related functions of Bb genes involved in mammalian host adaptation as well as the mechanisms that underlie the spirochete's transition from arthropod vector to mammalian host. Much of this work has centered about delineating the relative contributions of the RpoS-dependent and -independent transcriptional pathways to the processes which enable spirochetes to transit from tick to mammal. Microarray-based transcriptional profiling of wild-type and rpoS mutant spirochetes grown in dialysis membrane chambers (DMCs) has enabled us to define the in vivo RpoS regulon, the cohort of genes that the alternate sigma factor RpoS controls, both positively and negatively, in response to mammalian host-derived signals. By extrapolating from these and related findings to the scenario of the infected nymphal tick, we have formulated our central hypothesis: beginning with the taking of the blood meal, RpoS acts as a """"""""gatekeeper"""""""" that coordinates the reciprocal upregulation and repression of a subset of differentially expressed borrelial genes required to establish mammalian infection. As a corollary to this hypothesis, we propose that the """"""""RpoS off' state represents an alternate developmental program required by the spirochete to establish the tick-phase of the enzootic life cycle. The principal long-term objective of our Research Plan is to integrate the search for novel Bb virulence determinants that function within the tick or the mouse with efforts to decipher the mechanisms that underlie differential gene expression by the LD spirochete. To accomplish this objective, we have formulated three Specific Aims: (i) to further characterize genes within the in vivo RpoS regulon which we hypothesize are induced by the blood meal and promote infection of the mammalian host; (ii) to further characterize genes which require RpoS for repression in vivo and which we hypothesize are required for the tick- phase of the spirochete's life cycle; and (iii) to develop a broader understanding of the RpoS regulon by delineating its """"""""on"""""""" and """"""""off"""""""" states during the enzootic cycle and examining selected facets of RpoS function. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029735-18
Application #
7393855
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Breen, Joseph J
Project Start
1990-04-01
Project End
2012-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
18
Fiscal Year
2008
Total Cost
$528,612
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
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, Sébastien 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

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