Darrin Akins, PhD
Associate Dean for Research, Professor of Microbiology and Immunology
Ph.D.: 1995, University of Texas Southwestern Medical Ctr, Dallas
Pre-OUHSC: University of Texas Southwestern Medical Ctr, Dallas
Research Interests: Pathogenic spirochetes, Lyme disease pathogenesis, host-parasite relationships.
Teaching: Molecular Microbiology, Microbial Pathogenesis
Lyme disease (Lyme borreliosis), a multisystem disorder characterized by dermatologic, cardiac, neurologic, and rheumatologic manifestations, is the most common tick-borne infection in the United States. The spirochetal agent of Lyme disease, Borrelia burgdorferi, is maintained in nature through a complex enzootic cycle which typically involves wild rodents and ticks of the genus Ixodes.
To maintain this cycle in nature, B. burgdorferi physiologically adapts to two dramatically different environments. Interestingly, recent studies have indicated that several borrelial antigens are expressed specifically in either the tick or mammalian host environment. Furthermore, there is now a substantial body of evidence indicating that B. burgdorferi dramatically alters its antigenic composition during tick-feeding and subsequent to host transmission.
In fact, the term "host-adapted" has been coined to describe the phenotype of this spirochete as it appears in the mammalian host during a natural infection. The antigenic changes which occur during mammalian infection are thought to play a key role in this organisms ability to persist for long periods of time in an infected host despite the robust humoral and cellular immune responses it elicits. Therefore, a major focus of our laboratory is to identify antigens expressed exclusively in the mammalian host environment and determine their potential role in immunoevasion and host-parasite interactions during infection.
B. burgdorferi has a rather unusual genetic organization for a prokaryotic organism. It contains a linear chromosome and numerous circular and linear plasmids. Interestingly, almost all of the differentially expressed borrelial antigens identified to date have been localized to plasmid elements. Given that B. burgdorferi virulence has been correlated with its plasmid content, we are investigating the role of plasmid-encoded proteins in Lyme disease pathogenesis.
Presently, we are focusing these research efforts on a group of previously identified circular plasmid-encoded proteins which are differentially expressed in either the tick or mammalian environment. A unique phylogenetic trait of these proteins is that although they comprise three unrelated groups, they all share an almost identical export signal with each other and with other borrelial outer surface proteins. It appears that all three families are the result of gene fusion events which brought together distinct proteins with a single export signal.
We are presently investigating the implications of this evolutionarily unstable group of proteins and are using them as a model system to better understand differential gene expression and host-adaptation in B. burgdorferi. At the same time, we also are determining the potential utility of these proteins as novel serodiagnostic tools and vaccine candidates for Lyme disease.
Lastly, a recently developed animal model now allows us to generate large numbers of mammalian host-adapted spirochetes for further molecular studies. We are utilizing this novel animal model in conjunction with several differentially expressed, plasmid-encoded proteins to help elucidate the signal(s) that result in B. burgdorferi "switching" to the host-adapted phenotype. The overall goal of this research is to gain a better understanding of the dynamics of the host-adaptation process which appears to be an important part of the parasitic strategy of the Lyme disease spirochete.
Changes in the polypeptide profile of
"mammalian host-adapted" B. burgdorferi
|Comparison of the polypeptide profiles of B. burgdorferi grown in vitro at 23° C, 34° C, or temperature-shifted to 37° C, and host-adapted (HA)B. burgdorferi cultivated in rat peritoneal chambers. Asterisks indicate polypeptides which are downregulated or "turned off" when compared with the HA polypeptide profile. Arrows in the HA lane indicate newly expressed or upregulated polypeptides seen only in "mammalian host-adapted" B. burgdorferi.
Current Laboratory Personnel:
Henna Iqbal, Graduate Student
Melisha Kenedy, Ph.D., Assistant Professor of Research
Cecilia Nguyen, Research Assistant
Binu Shrestha, Graduate Student
Akins, D. R., K. W. Bourell, M. J. Caimano, M. V. Norgard and J. D. Radolf. 1998. A new animal model for studying Lyme disease spirochetes in mammalian host-adapted state. Journal of Clinical Investigation. 101:2240-2250.
Akins, D. R., M. J. Caimano, X. Yang, F. Cerna, M. V. Norgard, and J. D. Radolf. 1999. Molecular and evolutionary analysis of Borrelia burgdorferi 297 plasmid-encoded lipoproteins with OspE- and OspF-like leader peptides.Infection and Immunity, 67:1526-1532.
Stevenson, B., W. R. Zückert, and D. R. Akins. 2000. Repetition, conservation, and variation: the multiple cp32 plasmids of Borrelia species. Journal of Molecular Microbiology and Biotechnology. 2:411-422.
Hefty, P. S., S. E. Jolliff, M. J. Caimano, S. K. Wikel, J. D. Radolf, and D. R. Akins. 2001. Regulation of the OspE-related, OspF-related, and Elp lipoproteins of Borrelia burgdorferi strain 297 by mammalian host-specific signals. Infection and Immunity. 69:3618-3627.
Elias, A. F., P. E. Stewart, D. Grimm, M. J. Caimano, C. H. Eggers, K. Tilly, J. L. Bono, D. R. Akins, J. D. Radolf, T. G. Schwan, and P. Rosa. 2002. Clonal Polymorphism in Borrelia burgdorferi strain B31 MI: implications for mutagenesis in an infectious strain background. Infection and Immunity. 70:2139-2150.
Hefty, P. S., S. E. Jolliff, M. J. Caimano, S. K. Wikel, and D. R. Akins. 2002. Changes in the temporal and spatial patterns of outer surface lipoprotein expression generates population heterogeneity and antigenic diversity in Borrelia burgdorferi, the Lyme disease spirochete.Infection and Immunity. 70:3468-3478.
Alitalo, A., T. Meri, H. Lankinen, I. Seppala, P. Lahdenne, P. S. Hefty, D. Akins, and S. Meri. 2002. Complement factor H binding in Lyme disease spirochetes is mediated by inducible expression of multiple plasmid-encoded OspE paralogs.Journal of Immunology. 169:3847-3853.
Hefty, P. S., C. S. Brooks, A. M. Jett, G. L. White, S. K. Wikel, R. C. Kennedy, and D. R. Akins. 2002. The OspE-related, OspF-related and Elp lipoproteins are immunogenic in baboons experimentally infected with Borrelia burgdorferi and in human Lyme disease patients. Journal of Clinical Microbiology. 40:4256-4265.
Ojaima, C., C. Brooks, D. Akins, S. Casjens, P. Rosa, A. Elias, A. Barbour, A. Jasinskas, J. Benach, L. Katona, J. Radolf, M. Caimano, J. Skare, K. Swingle, S. Sims, and I. Schwartz. 2002. Borrelia burgdorferi gene expression profiling with membrane-based arrays. Methods in Enzymology. 358:165-177.
Ojaimi, C., C. Brooks, S. Casjens, P. Rosa, A. Elias, A.. Barbour, A. Jasinskas, J. Benach, L. Katona, J. Radolf, M. Caimano, J. Skare, K. Swingle, D. Akins*, and I. Schwartz*. 2003. Profiling temperature-induced changes in Borrelia burgdorferi gene expression using whole genome arrays. Infection and Immunity. (In press). *co-senior authors
Brooks, C. S., P. S. Hefty, S. E. Jolliff, and D. R. Akins. 2003. Global analysis of Borrelia burgdorferi genes regulated by mammalian host-specific signals. Infection and Immunity. 71:3371-3383. Gilmore, K. S., P. Srinivas, D. R. Akins, K. L. Hatter, and M. S. Gilmore. 2003. Growth, development and gene expression in a persistent Streptococcus gordonii biofilm. Infection and Immunity. 71:4759-4766.
Anderton, J. M., R. Tokarz, C. D. Thill, C. J. Kuhlow, C. S. Brooks, D. R. Akins, L. I. Katona, and J. L. Benach. 2004. Whole genome DNA array analysis of the response of Borrelia burgdorferi to a bactericidal monoclonal antibody. Infection and Immunity. 72:2035-2044.
Alitalo A., T. Meri, T. Chen, H. Lankinen, Z. Cheng, S. Jokiranta, I. Seppälä, P. Lahdenne, P. S. Hefty, D. R. Akins, and S. Meri. 2004. Lysine-dependent multipoint binding of the Borrelia burgdorferi virulence factor outer surface protein E to the C terminus of factor H. Journal of Immunology. 172:6195-6201.
Mashburn, L. M., A. M. Jett, D. R. Akins, and M. Whiteley. 2005. Staphylococcus aureus serves as an iron source for Pseudomonas aeruginosa during in vivo co-culture.Journal of Bacteriology. 187: 554-566.
Machado, L. J., H. Carabin, and D. R. Akins. 2005. Tularemia. p. 313-337. In: M. S. Bronze and R. A. Greenfield (eds.), Biodefense: Principles and Pathogens. Horizon Bioscience, Norfolk, England.
Brooks, C. S., S. R. Vuppula, A. M. Jett, A. Alitalo, S. Meri, D. R. Akins. 2005. Complement regulator-acquiring surface protein 1 imparts resistance to human serum in Borrelia burgdorferi.Journal of Immunology.
Alitalo, A., T. Meri, P. Comstedt, L. Jeffery, J. Tornberg, T. Strandin, H. Lankinen, S. Bergström, M. Cinco, S. R. Vuppala, D. R. Akins, and S. Meri. 2005. Expression of complement factor H binding immunoevasion proteins in Borrelia garinii isolated from patients with neuroborreliosis. European Journal of Immunology. 35: 3043-3053.
Brooks, C. S., S. R. Vuppala, A. M. Jett, and D. R. Akins. 2006. Identification ofBorrelia burgdorferi outer surface proteins. Infection and Immunity.74: 296-304.
Coleman, A. S., X. Yang, M. Kumar, X. Zhang, K. Promnares, D. Shroder, M. R. Kenedy, J. F. Anderson, D. R. Akins, and U. Pal. 2008. Borrelia burgdorfericomplement regulator-acquiring surface protein 2 does not contribute to complement resistance or host infectivity. PLoS ONE. 3: 3010e.
Kenedy, M. R., S. R. Vuppala, C. Siegel, P. Kraiczy and D. R. Akins. 2009. CspA-Mediated Binding of Human Factor H Inhibits Complement Deposition and Confers Serum Resistance in Borrelia burgdorferi. 77:(2773-2782).
Lenhart, T. R., and D. R. Akins. 2009. Borrelia burgdorferi locus BB0795 encodes a BamA ortholog required for growth and efficient localization of outer membrane proteins.(In revision, Molecular Microbiology).
Skare, J. T., J. A. Carroll, X. F. Yang, D. S. Samuels, and D. R. Akins 2010. Gene regulation, transcriptomics, and proteomics. In: D. S. Samuels and J. D. Radolf (eds.), Borrelia: Molecular Biology, Host Interaction and Pathogenesis. Caister Academic Press, Norfolk, England. p. 61-95.
Kenedy MR, Akins DR. 2011. The OspE-related proteins inhibit complement deposition and enhance serum resistance of Borrelia burgdorferi, the lyme disease spirochete. Inf Immun. 78(11):4477-87.
Caimano MJ, Kenedy MR, Kairu T, Desrosiers DC, Harman M, Dunham-Ems S, Akins DR, Pal U, Radolf JD. 2011. The hybrid histidine kinase Hk1 is part of a two-component system that is essential for survival of Borrelia burgdorferi in feeding Ixodes scapularis ticks. Infect Immun. 79(8):3117-30.
Lenhart TR, Kenedy MR, Yang X, Pal U, Akins DR. 2012.BB0324 and BB0028 are constituents of the Borrelia burgdorferi β-barrel assembly machine (BAM) complex. BMC Microbiol. 12:60
Kenedy MR, Lenhart TR, Akins DR. 2012. The role of Borrelia burgdorferi outer surface proteins.
FEMS Immunol Med Microbiol. 66(1):1-9.
Kenedy MR, Luthra A, Anand A, Dunn JP, Akins, DR. 2014. Structural modeling and physicochemical characterization provide evidence that P66 forms a β-barrel in the Borrelia burgdorferi outer membrane.
J. Bacteriology. 196(4):859-72