Rickettsial diseases caused by the Anaplasmataceae family pathogens of the genera Ehrlichia and Anaplasma remain a growing public health concern for over three decades and are also the second leading cause of tick- borne human infections in the USA and many parts of the world. Despite the complex cellular environments of arthropods and vertebrates having sophisticated systems of defense, the Anaplasmataceae pathogens evolved strategies to evade host clearance. Our prior studies demonstrated that the differential expression in vertebrate and tick cells alters host responses leading to variations in vertebrate host clearance/persistence. The central hypothesis of our competing renewal application remains that E. chaffeensis differentially regulates its gene expression in response to host cell environmental signals and that the host cell-specific gene expression is essential for pathogen?s continued survival in vertebrate and tick cell environments. We have made substantial progress in addressing the three specific aims of the previous funded project. The progress from the prior funded cycle included numerous peer-reviewed publications, which paved the way for additional exciting new directions for this proposed competing renewal application. Goals set for the three new specific aims of this renewal application have a strong premise, as supported with published research results and with additional unpublished preliminary data. The extensive novel data generated with the previous R01 grant support formed a strong foundation for the following proposed three specific aims of this renewal application. 1) Characterize sequence-specific DNA binding proteins (DBPs) in E. chaffeensis impacting RNA polymerase function in support of understanding the pathogen?s host- specific differential gene expression. 2) Characterize the functional significance of genes identified as essential for E. chaffeensis in vivo growth. 3) Mutagenesis and in vivo screening in defining genomic regions critical for the bacterial pathogenesis in vertebrate and tick hosts. The proposed specific aims are a logical extension of the substantial progress we have made during the previous funding cycle. The project goals have a strong scientific premise, as they are supported with the research data reported in many peer-reviewed publications and with the inclusion of additional preliminary data.

Public Health Relevance

The results from this study will provide important information for understanding Ehrlichia chaffeensis pathogenesis, gene regulation and how the tick-transmitted pathogen escapes host response in vertebrates and how the loss of gene expression may impact its survival in ticks and vertebrates. This study will also allow us to determine how the tick transmitted pathogen continues to survive in ticks and animals, thus will aid in identifying targets for controlling the bacterial infections in people in the near future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI070908-10
Application #
9831547
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perdue, Samuel S
Project Start
2007-12-15
Project End
2024-06-30
Budget Start
2019-07-10
Budget End
2020-06-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Kansas State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
929773554
City
Manhattan
State
KS
Country
United States
Zip Code
66506
Eedunuri, Vijay K; Zhang, Yuntao; Cheng, Chuanmin et al. (2018) Protein and DNA synthesis demonstrated in cell-free Ehrlichia chaffeensis organisms in axenic medium. Sci Rep 8:9293
McGill, Jodi L; Wang, Ying; Ganta, Chanran K et al. (2018) Antigen-Specific CD4+CD8+ Double-Positive T Cells Are Increased in the Blood and Spleen During Ehrlichia chaffeensis Infection in the Canine Host. Front Immunol 9:1585
Wilkerson, Melinda J; Black, Kelley E; Lanza-Perea, Marta et al. (2017) Initial development and preliminary evaluation of a multiplex bead assay to detect antibodies to Ehrlichia canis, Anaplasma platys, and Ehrlichia chaffeensis outer membrane peptides in naturally infected dogs from Grenada, West Indies. J Vet Diagn Invest 29:109-114
Kuczynska-Wisnik, Dorota; Cheng, Chuanmin; Ganta, Roman R et al. (2017) Protein aggregation in Ehrlichia chaffeensis during infection of mammalian cells. FEMS Microbiol Lett 364:
Jaworski, Deborah C; Cheng, Chuanmin; Nair, Arathy D S et al. (2017) Amblyomma americanum ticks infected with in vitro cultured wild-type and mutants of Ehrlichia chaffeensis are competent to produce infection in naïve deer and dogs. Ticks Tick Borne Dis 8:60-64
Wang, Ying; Wei, Lanjing; Liu, Huitao et al. (2017) A genetic system for targeted mutations to disrupt and restore genes in the obligate bacterium, Ehrlichia chaffeensis. Sci Rep 7:15801
Raghavan, Ram K; Goodin, Douglas G; Neises, Daniel et al. (2016) Hierarchical Bayesian Spatio-Temporal Analysis of Climatic and Socio-Economic Determinants of Rocky Mountain Spotted Fever. PLoS One 11:e0150180
McGill, Jodi L; Nair, Arathy D S; Cheng, Chuanmin et al. (2016) Vaccination with an Attenuated Mutant of Ehrlichia chaffeensis Induces Pathogen-Specific CD4+ T Cell Immunity and Protection from Tick-Transmitted Wild-Type Challenge in the Canine Host. PLoS One 11:e0148229
Liu, Huitao; Jakkula, Laxmi U M R; Von Ohlen, Tonia et al. (2016) Sequence determinants spanning -35 motif and AT-rich spacer region impacting Ehrlichia chaffeensis Sigma 70-dependent promoter activity of two differentially expressed p28 outer membrane protein genes. DNA Res :
Nair, Arathy D S; Cheng, Chuanmin; Ganta, Chanran K et al. (2016) Comparative Experimental Infection Study in Dogs with Ehrlichia canis, E. chaffeensis, Anaplasma platys and A. phagocytophilum. PLoS One 11:e0148239

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