The vector-borne spirochetes that cause relapsing fever are transmitted to humans by either soft ticks or human body lice. Despite identification of the etiological agents of relapsing fever over 100 years ago, very little information exists regarding their pathogenesis. Although relapsing fever is more common in developing countries, tick-borne relapsing fever (TBRF) occurs in areas of the U.S. where Ornithodoros species of soft ticks, the vectors for TBRF spirochetes, are endemic. During their natural enzootic cycle, vector-borne spirochetes exist in two distinct niches found within the arthropod vector and the vertebrate. It is well established that Lyme disease spirochetes must undergo significant changes in global gene expression to allow them to adapt to these two diverse environments, and a great deal of information exists regarding the regulatory networks that control this bacterial adaptive response. However, the correlate that occurs in TBRF spirochetes to facilitate vector-mediated transmission and mammalian infection remains undefined. Our overall goal is to expand our knowledge of the pathogenesis of TBRF spirochetes and to identify virulence determinants (e.g., virulence factors and regulatory components) required during mammalian infection. We hypothesize that TBRF spirochetes must sense environmental temperature and utilize this stimulus to control expression of genes essential for mammalian infection and vector transmission. In preliminary experiments, we first defined the global temperature-dependent gene response that occurs in Borrelia turicatae, one of the major Borrelia species responsible for TBRF in the U.S., and then used these data to establish a set of genes that will be characterized during the course of studies in this project.
Aim 1 seeks to identify cis- and trans-regulatory elements responsible for controlling the expression of temperature-responsive genes in B. turicatae.
In Aim 2, we will use targeted mutagenesis to inactivate individual temperature-responsive genes in B. turicatae and identify bacterial factors required for infection and pathogenesis.
These aims will provide critical knowledge regarding differential gene regulation occurring in TBRF spirochetes during transmission and infection, and identify virulence determinants required by the bacteria to cause disease. This research is aligned with the COBRE program's focus on microbial pathogenesis by defining molecular determinants of TBRF spirochetes that contribute to adaptation and interaction within the mammalian host. Regulators and virulence factors identified in this project represent potential targets against which future therapeutic interventions and/or diagnostics for TBRF could be developed. The further characterization of these virulence determinants will be the focus of future R01 grant proposals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
2P20GM103625-06
Application #
9150922
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Kennedy, J L; Denson, J L; Schwalm, K S et al. (2017) Complete Genome Sequence of a Novel WU Polyomavirus Isolate from Arkansas, USA, Associated with Acute Respiratory Infection. Genome Announc 5:
Lei, Mei G; Gupta, Ravi Kr; Lee, Chia Y (2017) Proteomics of Staphylococcus aureus biofilm matrix in a rat model of orthopedic implant-associated infection. PLoS One 12:e0187981
Koonce, Nathan A; Griffin, Robert J; Dings, Ruud P M (2017) Galectin-1 Inhibitor OTX008 Induces Tumor Vessel Normalization and Tumor Growth Inhibition in Human Head and Neck Squamous Cell Carcinoma Models. Int J Mol Sci 18:
Kieber-Emmons, Thomas; Monzavi-Karbassi, Behjatolah; Hutchins, Laura F et al. (2017) Harnessing benefit from targeting tumor associated carbohydrate antigens. Hum Vaccin Immunother 13:323-331
Kaldhone, Pravin R; Khajanchi, Bijay K; Han, Jing et al. (2017) Draft Genome Sequences of Salmonella enterica Isolates Containing Incompatibility Group I1 Plasmids from Swine, Poultry, and Human Sources. Genome Announc 5:
Hartman, Jessica H; Miller, Grover P; Caro, Andres A et al. (2017) 1,3-Butadiene-induced mitochondrial dysfunction is correlated with mitochondrial CYP2E1 activity in Collaborative Cross mice. Toxicology 378:114-124
Khajanchi, Bijay K; Hasan, Nur A; Choi, Seon Young et al. (2017) Comparative genomic analysis and characterization of incompatibility group FIB plasmid encoded virulence factors of Salmonella enterica isolated from food sources. BMC Genomics 18:570
Simon, Emily J; Howells, Morgan A; Stuart, Johnasha D et al. (2017) Serotype-Specific Killing of Large Cell Carcinoma Cells by Reovirus. Viruses 9:
Holthoff, Emily R; Byrum, Stephanie D; Mackintosh, Samuel G et al. (2017) Vulvar squamous cell carcinoma aggressiveness is associated with differential expression of collagen and STAT1. Clin Proteomics 14:40
Nounamo, Bernice; Li, Yibo; O'Byrne, Peter et al. (2017) An interaction domain in human SAMD9 is essential for myxoma virus host-range determinant M062 antagonism of host anti-viral function. Virology 503:94-102

Showing the most recent 10 out of 95 publications