UTMB Department of Pathology

Directory lookup

Yersinia pestis Pathogenesis and Evolution

Currently, my major research interest is the pathogenesis of Yersinia pestis, the etiological agent of plague. Although plague is not a public heath problem in most parts of the world, its potential for contagion, the lack of an effective vaccine, and the recent emergence of multiple antibiotic resistance strains place this organism squarely at the top of the United States’ select agent list as a potential candidate for bioterrorism use. The long-term goal of my research is to elucidate the molecular mechanisms that underlie the nature of the acute bacterial infectious process caused by Y. pestis. The identification of the environmental signals that the bacteria encounter in the host cells and the potential virulence genes regulated by those signals will lead to a better understanding of the process of cross-talk between pathogen and its host during the infection. The unraveling of the Y. pestis virulence network will allow us to determine novel targets for therapeutics beyond antibiotics, to generate new vaccines and develop robust diagnostic assays.

Y. pestis has evolved within the last ~10,000 years from Yersinia pseudotuberculosis, known to cause chronic enteropathogenic disease. Despite their close resemblance, plague bacilli have lost many genes involved in regulatory and metabolic pathways and even virulence, but acquired unique genes by lateral transfer. Y. pestis gained two additional plasmids. A large plasmid pMT1 (~100 kb) encodes for capsule formation and a function essential for multiplication in the plague flea vector. This plasmid has a minimal impact on Y. pestis virulence, at least when tested using a murine animal model of plague. In contact, a small plasmid pPCP1 (9.6 kb) appears to be more important for virulence, because this plasmid contains plague plasminogen activator (Pla). Pla expression is associated with the marked ability of Y. pestis to spread from the peripheral site of the flea bite to the lymph node, followed by multiplication and further invasion of the circulation. The importance of Pla for the dissemination of Y. pestis in host tissues has been verified for the reference strains KIM and CO92; the pla mutants of these strains showed a significantly reduced virulence upon administration via the subcutaneous route of infection. Although the contribution of Pla in plague pathogenesis may vary for the different Y. pestis isolates, we believe that this surface-located protease could be an excellent target for the anti-plague vaccines and therapeutics.

Nevertheless, the presence of additional plasmids by themselves cannot account for the remarkable increase in virulence observed in Y. pestis. The central hypothesis of our study is that both gain and loss of the chromosomal genetic content re-programmed the entire virulence network in Y. pestis, making this microorganism one of the most lethal pathogens known to mankind. The details of such a multifunctional “optimization" of the virulent properties are the subject of our research, and we would like to define the corresponding changes in lethality using the molecular terms. The approach recently used by us to address the regulation of Y. pestis transcriptosome was the study of temporal global changes in gene expression during temperature transition. DNA microarray experiments revealed that ~12% of Y. pestis genome is thermoregulated, reflecting the adaptation of the pathogen to alternative temperatures within the flea vector and in the mammalian host. Differential transcription during the temperature shift also identified a useful list of putative virulence-associated genes to target as novel candidates for future research on the control of this pathogen.

1. Chain, P.S.G., E. Carniel, F. W. Larimer, J. Lamerdin, P. O. Stoutland, W. M Regala, A. M. Georgescu, L. M. Vergez, M. L. Land, V. L. Motin, R. R. Brubaker, J. Fowler, J. Hinnebusch, M. Marceau, C. Medigue, M. Simonet, V. Chenal-Francisque, B. Souza, D. Dacheux, J. M. Elliott, A. Derbise, L. J. Hauser, and E. Garcia. Insights into the evolution of Yersinia pestis through whole genome comparison with Yersinia pseudotuberculosis. Proc. Natl. Acad. Sci. USA. 101:13826-13831; 2004
2. Motin, V.L., A. M. Georgescu, J. P. Fitch, P. P. Gu, D. O. Nelson, S. L. Mabery, J. B. Garnham, B. A. Sokhansanj, L. L. Ott, M. A. Coleman, J. M. Elliott, L. M. Kegelmeyer, A. J. Wyrobeck, T. R. Slezak, R. R. Brubaker, and E. Garcia. Temporal Global Changes in Gene Expression during Temperature Transition in Yersinia pestis. J. Bacteriol.186:6398-6305; 2004
3. Slepenkin, A., V. Motin, L.M. de la Maza, and E.M. Peterson. Temporal expression of type III secretion genes of Chlamydia pneumonia. Infect. Immun. 71:2555-2562; 2003
4. Motin, V.L., A.M. Georgescu, J.M. Elliott, P. Hu, P.L. Worsham, L.L. Ott, T.R. Slezak, B.A. Sokhansanj, W.M. Regala, R.R. Brubaker, and E. Garcia. Genetic variability of Yersinia pestis isolates as predicted by PCR-based IS100 genotyping and analysis of structural genes encoding glycerol-3-phosphate dehydrogenase (glpD). J. Bacteriol. 184:1019-1027; 2002
5. Thulasiraman, V., S.L. McCutchen-Maloney, V.L. Motin, and E. Garcia. Detection and identification of virulence factors in Yersinia pestis using SELDI ProteinChip system. BioTechniques 30:428-432; 2001
6. Motin, V.L., L.M. de la Maza, and E.M. Peterson. Immunization with a peptide corresponding to chlamydial heat shock protein 60 increases the humoral immune response in C3H mice to a peptide representing variable domain 4 of the major outer membrane protein of Chlamydia trachomatis. Clin. Diagn. Lab. Immunol. 6:356-363; 1999
7. Kutyrev, V., R.J. Mehigh, V.L. Motin, M.S. Pokrovskaya, G.B. Smirnov, and R.R. Brubaker. Expression of the plague plasminogen activator in Yersinia pseudotuberculosis and Escherichia coli. Infect. Immun. 67:1359-1367; 1999
8. Garcia, E., Yu.A. Nedialkov, J. Elliott, V.L. Motin, and R.R. Brubaker. Molecular characterization of KatY (Antigen 5), a thermoregulated chromosomally encoded catalase-peroxidase of Yersinia pestis. J. Bacteriol. 181:3114-3122; 1999
9. Peterson, E.M., J. You, V.L. Motin, and L.M. de la Maza. Protection of mice from an intravaginal challenge with Chlamydia trachomatis, serovar E, by intranasal immunization with serovar E. Vaccine 17:2901-2907; 1999.
10. Motin, V.L., K.F. Jones., L.M. de la Maza, V.A. Fischetti, and E.M. Peterson. Display of the Variable Domain 4 (VD4) of Chlamydia trachomatis MOMP on the surface of Streptococcus gordonii. In “Chlamydial Infections” Proceedings 9th International Symposium on Human Chlamydial Infection. Napa, p. 547-550; 1998
11. Motin, V.L., Yu.A. Nedialkov, and R.R. Brubaker. Immunity to plague provided by anti-inflammatory fusion proteins of V antigen. In “Vaccines 97”. Cold Spring Harbor, p.185-190; 1997
12. Nedialkov, Yu.A., V.L. Motin, and R.R. Brubaker. Resistanse to lipopolysaccharide mediated by the Yersinia pestis V antigen-polyhistidine fusion peptide: amplification of Interleukin-10. Infect. Immun. 65:1196-1203; 1997
13. Motin, V.L., S.M. Kutas, and R.R. Brubaker. Suppression of mouse skin allograft rejection by protein A-yersinia V antigen fusion peptide. Transplantation 63:1040-1042; 1997
14. Peterson, E.M., X. Cheng, V.L. Motin, and L.M. de la Maza. Effect of immunoglobulin G isotype on the infectivity of Chlamydia trachomatis in a mouse model of intravaginal infection. Infect. Immun. 65:2693-2699; 1997
15. Motin, V.L., Yu.A. Nedialkov, and R.R. Brubaker. V antigen-polyhistidine fusion peptide: specific binding to LcrH and active immunity against plague. Infect. Immun. 64:4313-4318; 1996
16. Filippov, A.A., P.N. Oleinikov, V.L. Motin, O.A. Protsenko, and G.B. Smirnov. Sequencing of two Y. pestis IS elements, IS285 and IS100. Contr. Microbiol. Immunol. 13:306-309; 1995
17. Nakajima, R., V.L. Motin, and R.R. Brubaker. Suppression of cytokines in mice by protein A-V antigen fusion peptide and restoration of synthesis by active immunization. Infect. Immun. 63:3021-3029; 1995
18. Motin, V.L., R. Nakajima, G.B. Smirnov, and R.R. Brubaker. Passive immunity to Yersinia mediated by anti-recombinant V antigen and anti-protein A-V antigen fusion peptide. Infect. Immun. 62:4192-4201; 1994
19. Aniskovich, L.P., V.L. Motin, L.J. Lichoded, N.M. Balayeva, and G.B. Smirnov. Identification of Rickettsia prowazekii using the polymerase chain reaction. Eur. J. Epidemiol. 9:645-649 ; 1993
20. Domaradskaia, T.I., Iu.V. Ezepchuk, V.L. Motin, A.V. Mikul’kis, V.G. Korobko. Determination of thermostable and thermolabile enterotoxins in Escherichia coli strains by genetic, biological, and immunoserological methods. Mol. Gen. Microbiol. Virusol. 9-10:11-13; 1992
21. Kulakov, Yu.K., V.N. Gorelov, V.L. Motin, G.V. Brukhansky, and A.G. Skavronskaya. A highly sensitive non-isotopic system of DNA hybridization using amplification (PCR) for identifying and indicating presence of Brucella. Mol. Gen. Microbiol. Virusol. 7-8:23-27; 1992
22. Motin, V.L., M.S. Pokrovskaya, M.V. Telepnev, V.V. Kutyrev, N.A. Vidyaeva, A.A. Filippov, and G.B. Smirnov. The difference in the lcrV sequences between Y. pestis and Y. pseudotuberculosis and its application for characterization of Y. pseudotuberculosis strains. Microb. Pathogen. 12:165-175; 1992
23. Aniskovich, L.P., V.L. Motin, N.M. Balayeva, and G.B. Smirnov. Cloning and expression in Escherichia coli of the 37-kilodalton, 14-kilodalton, and/or 16-kilodalton antigens genes from Rickettsia prowazekii strain E. Acta. Virol. 36:90-102; 1992
24. Sever, I.S., T.S. Ilyina, V.L. Motin, and G.B. Smirnov. Phenotypic features of a strain of Y. pseudotuberculosis with the pVM82 plasmid, detected at pseudotuberculosis outbreak foci. Mol. Gen. Microbiol. Virusol. 10:10-14; 1991
25. Holzmayer, T.A., G.I. Karataev, M.N. Rozinov, I.L. Moskvina, Yu.L. Shumakov, V.L. Motin, S.M. Mebel, V.N. Gershanovich, I.A. Lapaeva. Bacteriophages of Bordetella sp.: features of lysogeny and conversion. Zentralbl. Bacteriol. Microbiol. Hyg. [A] 269:147-155; 1988
26. Motin, V.L., G.A. Shovadaeva, E.V. Nechaeva, G.I. Karataev, and G.B. Smirnov. Construction of a vector for insertion of vctB gene encoding for immunogenic B-subunit of cholera toxin into the Vibrio cholerae chromosome. In “Immunobiological preparations of new generation and methods of their control”, Gamaleya Institute for Epidemiology and Microbiology, Moscow, p.62-65; 1988
27. Gintsburg, A.L., N.Y. Yanishevsky, V.L. Motin, E.Y. Demme, G.I. Karataev, and G.B. Smirnov. The nature of RS1 sequences flanking the vct gene encoding the synthesis of cholera toxin in Vibrio cholerae El Tor. Mol. Gen. Microbiol. Virusol. 2:11-19; 1986
28. Smirnova, N.I., L.F. Livanova, I.A. Shaginian, and V.L. Motin. Genetic mapping of the regulatory gene determining the synthesis of enterotoxin in Vibrio cholerae. Genetika 22:339-405; 1986
29. Markov, A.P., E.V. Nechaeva, V.L. Motin, and G.B. Smirnov. Isolation of E.coli K-12 mutants deficient in precise excision of transposons. Mol. Gen. Microbiol. Virusol. 5:7-13; 1985
30. Krysteva, R.T., V.L. Motin, E.V. Nechaeva, and G.B. Smirnov. Study of the genetic control of plasmid RP4 inheritance in Salmonella typhimurium and Escherichia coli K-12. Mol. Gen. Microbiol. Virusol. 7:7-14 ; 1984
31. Gintsburg, A.L., N.V. Yanishevsky, V.L. Motin, I.A. Shaginyan, Yu.V. Vertiev, and G.B. Smirnov. Arrangement and cloning of Vibrio cholerae El Tor RV79 structure genes of enterotoxin. Mol. Gen. Microbiol. Virusol. 9:12-18; 1984
32. Gintsburg, A.L., M.S. Pokrovskaya, N.V. Yanishevsky, E. Titze, V.L. Motin, and G.B. Smirnov. Formation of plasmid by bacteriophage att80C1857 S7 (Tn9) after the infection of bacteria. Mol. Gen. Microbiol. Virusol. 4:15-20; 1983

Search PubMed database for Vladimir Motin