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Timothy L. Yahr, PhD

Portrait
Professor of Microbiology and Immunology
Director of Graduate Studies

Contact Information

Primary Office
200A Eckstein Medical Research Building
431 Newton Rd
Iowa City, IA 52242
319-335-9688

Lab
200N Eckstein Medical Research Building
431 Newton Rd
Iowa City, IA 52242
319-335-8666

Education

BS, Biology, University of Wisconsin-Stevens Point
MS, Microbiology, Medical College of Wisconsin
PhD, Microbiology, Medical College of Wisconsin
Postdoctoral Fellow, Biochemistry, Dartmouth Medical School

Education/Training Program Affiliations

Biomedical Science Program, Department of Microbiology Graduate Program, Interdisciplinary Graduate Program in Translational Biomedicine, Medical Scientist Training Program

Center, Program and Institute Affiliations

Center for Biocatalysis and Bioprocessing, Center for Gene Therapy of Cystic Fibrosis and other Genetic Diseases

Research Summary

The Yahr laboratory studies virulence properties of the opportunistic pathogen Pseudomonas aeruginosa (Pa) with particular interest in the type III secretion system (T3SS). The T3SS functions like a molecular syringe to inject toxins into eukaryotic host cells. The type II secretion machinery consists of ~30 proteins which form a complex that spans both the inner and outer membranes of the bacterial cell. Expression of the T3SS is highly regulated at the transcriptional and post-transcriptional levels. ExsA is the central regulator and directly activates transcription of all T3SS genes. The DNA-binding activity of ExsA is controlled by a partner-switching mechanism that sequesters ExsA and only releases ExsA upon contact of Pa with host cells. Several additional regulators, including Vfr, MvaT/U, VqsM, and PsrA, contribute to T3SS gene regulation by controlling exsA transcription. Translation of ExsA is also highly regulated and is positively stimulated by RsmA/RsmF and an RNA helicase (DeaD), and inhibited by Hfq and small non-coding RNAs. On a more global scale, T3SS gene expression is coordinated to the metabolic state of the cell, anaerobiosis, biofilm development, and motility. The ultimate goal of the lab is to fully characterize the regulatory circuits controlling T3SS gene expression, determine how those circuits integrate environmental signals into the response, and design therapeutic approaches that interfere with the signaling events.

Publications

Williams McMackin, E. A., Marsden, A. E. & Yahr, T. L. (2019). H-NS Family Members MvaT and MvaU Regulate the Pseudomonas aeruginosa Type III Secretion System. J Bacteriol, 201(14), e00054-19. PMID: 30782629.

Williams McMackin, E. A., Djapgne, L., Corley, J. M. & Yahr, T. L. (2019). Fitting Pieces into the Puzzle of Pseudomonas aeruginosa Type III Secretion System Gene Expression. J Bacteriol, 201(13), e00209-19. PMID: 31010903.

Yahr, T. L., Ellermeier, C. D. (2019). 25th Annual Midwest Microbial Pathogenesis Conference. J Bacteriol, pii: JB.00239-1. PMID: 30988032.

Janssen, K. H., Diaz, M. R., Gode, C. J., Wolfgang, M. C. & Yahr, T. L. (2018). RsmV a small non-coding regulatory RNA in Pseudomonas aeruginosa that sequesters RsmA and RsmF from target mRNAs. J Bacteriol, 200(16), e00277-18. PMID: 29866805.

Janssen, K. H., Diaz, M. R., Golden, M., Graham, J. W., Sanders, W., Wolfgang, M. C. & Yahr, T. L. (2018). Functional Analyses of the RsmY and RsmZ Small Noncoding Regulatory RNAs in Pseudomonas aeruginosa. J Bacteriol, 200(11), e00736-17. PMID: 29463606.

Kroken, A. R., Chen, C. K., Evans, D. J., Yahr, T. L. & Fleiszig, S. M. (2018). The Impact of ExoS on Pseudomonas aeruginosa Internalization by Epithelial Cells Is Independent of fleQ and Correlates with Bistability of Type Three Secretion System Gene Expression. MBio, 9(3), e00668-18. PMID: 29717012.

Chakravarty, S., Melton, C. N., Bailin, A., Yahr, T. L. & Anderson, G. G. (2017). Pseudomonas aeruginosa Magnesium Transporter MgtE Inhibits Type III Secretion System Gene Expression by Stimulating rsmYZ Transcription. J Bacteriol, 199(23), e00268-17. PMID: 28847924.

Schulmeyer, K. H., Yahr, T. L. (2017). Post-transcriptional regulation of type III secretion in plant and animal pathogens. Curr Opin Microbiol, 36, 30-36. PMID: 28189908.

Anantharajah, A., Faure, E., Buyck, J. M., Sundin, C., Lindmark, T., Mecsas, J., Yahr, T. L., Tulkens, P. M., Mingeot-Leclercq, M. P., Guery, B. & Van Bambeke, F. (2016). Inhibition of the Injectisome and Flagellar Type III Secretion Systems by INP1855 Impairs Pseudomonas aeruginosa Pathogenicity and Inflammasome Activation. J Infect Dis, 214(7), 1105-16. PMID: 27412581.

Schulmeyer, K. H., Diaz, M. R., Bair, T. B., Sanders, W., Gode, C. J., Laederach, A., Wolfgang, M. C. & Yahr, T. L. (2016). Primary and Secondary Sequence Structure Requirements for Recognition and Discrimination of Target RNAs by Pseudomonas aeruginosa RsmA and RsmF. J Bacteriol, 198(18), 2458-69. PMID: 27381913.

Marsden, A. E., Intile, P. J., Schulmeyer, K. H., Simmons-Patterson, E. R., Urbanowski, M. L., Wolfgang, M. C. & Yahr, T. L. (2016). Vfr Directly Activates exsA Transcription To Regulate Expression of the Pseudomonas aeruginosa Type III Secretion System. J Bacteriol, 198(9), 1442-50. PMID: 26929300.

Marsden, A. E., King, J. M., Spies, M. A., Kim, O. K. & Yahr, T. L. (2015). Inhibition of Pseudomonas aeruginosa ExsA DNA-Binding Activity by N-Hydroxybenzimidazoles. Antimicrob Agents Chemother, 60(2), 766-76. PMID: 26574012.

Jorth, P., Staudinger, B. J., Wu, X., Hisert, K. B., Hayden, H., Garudathri, J., Harding, C. L., Radey, M. C., Rezayat, A., Bautista, G., Berrington, W. R., Goddard, A. F., Zheng, C., Angermeyer, A., Brittnacher, M. J., Kitzman, J., Shendure, J., Fligner, C. L., Mittler, J., Aitken, M. L., Manoil, C., Bruce, J. E., Yahr, T. L. & Singh, P. K. (2015). Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs. Cell Host Microbe, 18(3), 307-19. PMID: 26299432.

Intile, P. J., Balzer, G. J., Wolfgang, M. C. & Yahr, T. L. (2015). The RNA helicase DeaD stimulates ExsA translation to promote expression of the Pseudomonas aeruginosa type III secretion system. J Bacteriol, 197(16), 2664-74. PMID: 26055113.

Ince, D., Sutterwala, F. S. & Yahr, T. L. (2015). Secretion of Flagellar Proteins by the Pseudomonas aeruginosa Type III Secretion-Injectisome System. J Bacteriol, 197(12), 2003-11. PMID: 25845843.

Marsden, A. E., Schubot, F. D. & Yahr, T. L. (2014). Self-association of ExsA is required for occupation of adjacent binding sites on Pseudomonas aeruginosa type III secretion system promoters. J Bacteriol, 196(20), 3546-55. PMID: 25070741.

Intile, P. J., Diaz, M. R., Urbanowski, M. L., Wolfgang, M. C. & Yahr, T. L. (2014). The AlgZR Two-Component System Recalibrates the RsmAYZ Posttranscriptional Regulatory System To Inhibit Expression of the Pseudomonas aeruginosa Type III Secretion System. J Bacteriol, 196(2), 357-66. PMID: 24187093.

King, J. M., Schesser Bartra, S., Plano, G. & Yahr, T. L. (2013). ExsA and LcrF recognize similar consensus binding sites, but differences in their oligomeric state influence interactions with promoter DNA. J Bacteriol, 195(24), 5639-50. PMID: 24142246.

Heimer, S. R., Evans, D. J., Stern, M. E., Barbieri, J. T., Yahr, T. & Fleiszig, S. M. (2013). Pseudomonas aeruginosa Utilizes the Type III Secreted Toxin ExoS to Avoid Acidified Compartments within Epithelial Cells. PLoS One, 8(9), e73111. PMID: 24058462.

Marden, J. N., Diaz, M. R., Walton, W. G., Gode, C. J., Betts, L., Urbanowski, M. L., Redinbo, M. R., Yahr, T. L. & Wolfgang, M. C. (2013). An unusual CsrA family member operates in series with RsmA to amplify posttranscriptional responses in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A, 110(37), 15055-60. PMID: 23980177.

Olson, M. E., King, J. M., Yahr, T. L. & Horswill, A. R. (2013). Sialic Acid Catabolism in Staphylococcus aureus. J Bacteriol, 195(8), 1779-88. PMID: 23396916.

Berhards, R. C., Marsden, A. E., Esher, S. K., Yahr, T. L. & Schubot, F. D. (2013). Self-trimerization of ExsD limits inhibition of the Pseudomonas aeruginosa transcriptional activator ExsA in vitro. FEBS J, 280(4), 1084-94. PMID: 23279839.

King, J. M., Brutinel, E. D., Marsden, A. E., Schubot, F. D. & Yahr, T. L. (2012). Orientation of Pseudomonas aeruginosa ExsA monomers bound to promoter DNA and base-specific contacts with the P(exoT) promoter. J Bacteriol, 194(10), 2573-85. PMID: 22408167.

Brutinel, E. D., King, J. M., Marsden, A. E. & Yahr, T. L. (2012). The distal ExsA-binding site in Pseudomonas aeruginosa type III secretion system promoters is the primary determinant for promoter-specific properties. J Bacteriol, 194(10), 2564-72. PMID: 22408165.

Zheng, Z., Ma, D., Yahr, T. L. & Chen, L. (2012). The transiently ordered regions in intrinsically disordered ExsE are correlated with structural elements involved in chaperone binding. Biochem Biophys Res Commun, 417(1), 129-34. PMID: 22138394.

Pezzulo, A. A., Gutiérrez, J., Duschner, K. S., McConnell, K. S., Taft, P. J., Ernst, S. E., Yahr, T. L., Rahmouni, K., Klesney-Tait, J., Stoltz, D. A. & Zabner, J. (2011). Glucose depletion in the airway surface liquid is essential for sterility of the airways. PLoS One, 6(1), e16166. PMID: 21311590.

Diaz, M. R., King, J. M. & Yahr, T. L. (2011). Intrinsic and Extrinsic Regulation of Type III Secretion Gene Expression in Pseudomonas aeruginosa. Front Microbiol, 2, 89. PMID: 21833328.

Jones, A. K., Fulcher, N. B., Balzer, G. J., Urbanowski, M. L., Pritchett, C. L., Schurr, M. J., Yahr, T. L. & Wolfgang, M. C. (2010). Activation of the Pseudomonas aeruginosa AlgU regulon through mucA mutation inhibits cyclic AMP/Vfr signaling. J Bacteriol, 192(21), 5709-17. PMID: 20817772.

Vakulskas, C. A., Brutinel, E. D. & Yahr, T. L. (2010). ExsA recruits RNA polymerase to an extended -10 promoter by contacting region 4.2 of sigma-70. J Bacteriol, 192(14), 3597-607. PMID: 20453093.

Fuchs, E. L., Brutinel, E. D., Jones, A. K., Fulcher, N. B., Urbanowski, M. L., Yahr, T. L. & Wolfgang, M. C. (2010). The Pseudomonas aeruginosa Vfr regulator controls global virulence factor expression through cyclic AMP-dependent and -independent mechanisms. J Bacteriol, 192(14), 3553-64. PMID: 20494996.

Fuchs, E. L., Brutinel, E. D., Klem, E. R., Fehr, A. R., Yahr, T. L. & Wolfgang, M. C. (2010). In vitro and in vivo characterization of the Pseudomonas aeruginosa cyclic AMP (cAMP) phosphodiesterase CpdA, required for cAMP homeostasis and virulence factor regulation. J Bacteriol, 192(11), 2779-90. PMID: 20348254.

Brutinel, E. D., Vakulskas, C. A. & Yahr, T. L. (2010). ExsD inhibits expression of the Pseudomonas aeruginosa type III secretion system by disrupting ExsA self-association and DNA binding activity. J Bacteriol, 192(6), 1479-86. PMID: 20008065.

Anderson, G. G., Yahr, T. L., Lovewell, R. R. & O'Toole, G. A. (2010). The Pseudomonas aeruginosa magnesium transporter MgtE inhibits transcription of the type III secretion system. Infect Immun, 78(3), 1239-49. PMID: 20028803.

Vakulskas, C. A., Brady, K. M. & Yahr, T. L. (2009). Mechanism of transcriptional activation by Pseudomonas aeruginosa ExsA. J Bacteriol, 191(21), 6654-64. PMID: 19717612.

Brutinel, E. D., Vakulskas, C. A. & Yahr, T. L. (2009). Functional domains of ExsA, the transcriptional activator of the Pseudomonas aeruginosa type III secretion system. J Bacteriol, 191(12), 3811-21. PMID: 19376850.

Brutinel, E. D., Vakulskas, C. A., Brady, K. M. & Yahr, T. L. (2008). Characterization of ExsA and of ExsA-dependent promoters required for expression of the Pseudomonas aeruginosa type III secretion system. Mol Microbiol, 68(3), 657-71. PMID: 18373522.

Brutinel, E. D., Yahr, T. L. (2008). Control of gene expression by type III secretory activity. Curr Opin Microbiol, 11(2), 128-33. PMID: 18396449.

Urbanowski, M. L., Yahr, T. L. (2008). Limiting too much of a good thing: a negative feedback mechanism prevents unregulated translocation of type III effector proteins. (Vols. 190). (8), pp. 2643-4. J Bacteriol. PMID: 18083800.

Urbanowski, M. L., Brutinel, E. D. & Yahr, T. L. (2007). Translocation of ExsE into Chinese hamster ovary cells is required for transcriptional induction of the Pseudomonas aeruginosa type III secretion system. Infect Immun, 75(9), 4432-9. PMID: 17635873.

Ashare, A., Monick, M. M., Nymon, A. B., Morrison, J. M., Noble, M., Powers, L. S., Yarovinsky, T. O., Yahr, T. L. & Hunninghake, G. W. (2007). Pseudomonas aeruginosa delays Kupffer cell death via stabilization of the X-chromosome-linked inhibitor of apoptosis protein. J Immunol, 179(1), 505-13. PMID: 17579071.

Wu, Y., Xu, Z., Henderson, F. C., Ryan, A. J., Yahr, T. L. & Mallampalli, R. K. (2007). Chronic Pseudomonas aeruginosa infection reduces surfactant levels by inhibiting its biosynthesis. Cell Microbiol, 9(4), 1062-72. PMID: 17166234.

Zheng, Z., Chen, G., Joshi, S., Brutinel, E. D., Yahr, T. L. & Chen, L. (2007). Biochemical characterization of a regulatory cascade controlling transcription of the Pseudomonas aeruginosa type III secretion system. J Biol Chem, 282(9), 6136-42. PMID: 17197437.

Yahr, T. L., Wolfgang, M. C. (2006). Transcriptional regulation of the Pseudomonas aeruginosa type III secretion system. Mol Microbiol, 62(3), 631-40. PMID: 16995895.

Lykken, G. L., Chen, G., Brutinel, E. D., Chen, L. & Yahr, T. L. (2006). Characterization of ExsC and ExsD self-association and heterocomplex formation. J Bacteriol, 188(19), 6832-40. PMID: 16980486.

Yahr, T. L. (2006). A critical new pathway for toxin secretion?. (Vols. 355). (11), pp. 1171-2. N Engl J Med. PMID: 16971725.

Dasgupta, N., Ashare, A., Hunninghake, G. W. & Yahr, T. L. (2006). Transcriptional induction of the Pseudomonas aeruginosa type III secretion system by low Ca2+ and host cell contact proceeds through two distinct signaling pathways. Infect Immun, 74(6), 3334-41. PMID: 16714561.

Yahr, T. L., Parsek, M. R. (2006). Pseudomonas aeruginosa. In M. Dworkin , S. Falkow , E. Rosenberg , K. Schleifer , E. Stackebrandt (Eds.) The Prokaryotes. pp. 704-13. Springer. DOI: 10.1007/0-387-30746-x_22.

Urbanowski, M. L., Lykken, G. L. & Yahr, T. L. (2005). A secreted regulatory protein couples transcription to the secretory activity of the Pseudomonas aeruginosa type III secretion system. Proc Natl Acad Sci U S A, 102(28), 9930-5. PMID: 15985546.

Yahr, T. L., Greenberg, E. P. (2004). The genetic basis for the commitment to chronic versus acute infection in Pseudomonas aeruginosa. (Vols. 16). (4), pp. 497-8. Mol Cell. PMID: 15546607.

Dasgupta, N., Lykken, G. L., Wolfgang, M. C. & Yahr, T. L. (2004). A novel anti-anti-activator mechanism regulates expression of the Pseudomonas aeruginosa type III secretion system. Mol Microbiol, 53(1), 297-308. PMID: 15225323.

McCaw, M. L., Lykken, G. L., Singh, P. K. & Yahr, T. L. (2002). ExsD is a negative regulator of the Pseudomonas aeruginosa type III secretion regulon. Mol Microbiol, 46(4), 1123-33. PMID: 12421316.

Yahr, T. L., Wickner, W. T. (2001). Functional reconstitution of bacterial Tat translocation in vitro. EMBO J, 20(10), 2472-9. PMID: 11350936.

Yahr, T. L., Wickner, W. T. (2000). Evaluating the oligomeric state of SecYEG in preprotein translocase. EMBO J, 19(16), 4393-401. PMID: 10944122.

Olson, J. C., Fraylick, J. E., McGuffie, E. M., Dolan, K. M., Yahr, T. L., Frank, D. W. & Vincent, T. S. (1999). Interruption of multiple cellular processes in HT-29 epithelial cells by Pseudomonas aeruginosa exoenzyme S. Infect Immun, 67(6), 2847-54. PMID: 10338490.

Sawa, T., Yahr, T. L., Ohara, M., Kurahashi, K., Gropper, M. A., Wiener-Kronish, J. P. & Frank, D. W. (1999). Active and passive immunization with the Pseudomonas V antigen protects against type III intoxication and lung injury. Nat Med, 5(4), 392-8. PMID: 10202927.

Vallis, A. J., Finck-Barbançon, V., Yahr, T. L. & Frank, D. W. (1999). Biological effects of Pseudomonas aeruginosa type III-secreted proteins on CHO cells. Infect Immun, 67(4), 2040-4. PMID: 10085057.

Vallis, A. J., Yahr, T. L., Barbieri, J. T. & Frank, D. W. (1999). Regulation of ExoS production and secretion by Pseudomonas aeruginosa in response to tissue culture conditions. Infect Immun, 67(2), 914-20. PMID: 9916108.

Finck-Barbançon, V., Yahr, T. L. & Frank, D. W. (1998). Identification and characterization of SpcU, a chaperone required for efficient secretion of the ExoU cytotoxin. J Bacteriol, 180(23), 6224-31. PMID: 9829931.

Yahr, T. L., Vallis, A. J., Hancock, M. K., Barbieri, J. T. & Frank, D. W. (1998). ExoY, an adenylate cyclase secreted by the Pseudomonas aeruginosa type III system. Proc Natl Acad Sci U S A, 95(23), 13899-904. PMID: 9811898.

Yahr, T. L., Mende-Mueller, L. M., Friese, M. B. & Frank, D. W. (1997). Identification of type III secreted products of the Pseudomonas aeruginosa exoenzyme S regulon. J Bacteriol, 179(22), 7165-8. PMID: 9371466.

Liu, S., Yahr, T. L., Frank, D. W. & Barbieri, J. T. (1997). Biochemical relationships between the 53-kilodalton (Exo53) and 49-kilodalton (ExoS) forms of exoenzyme S of Pseudomonas aeruginosa. J Bacteriol, 179(5), 1609-13. PMID: 9045820.

Yahr, T. L., Goranson, J. & Frank, D. W. (1996). Exoenzyme S of Pseudomonas aeruginosa is secreted by a type III pathway. Mol Microbiol, 22(5), 991-1003. PMID: 8971719.

Yahr, T. L., Barbieri, J. T. & Frank, D. W. (1996). Genetic relationship between the 53- and 49-kilodalton forms of exoenzyme S from Pseudomonas aeruginosa. J Bacteriol, 178(5), 1412-9. PMID: 8631719.

Yahr, T. L., Hovey, A. K., Kulich, S. M. & Frank, D. W. (1995). Transcriptional analysis of the Pseudomonas aeruginosa exoenzyme S structural gene. J Bacteriol, 177(5), 1169-78. PMID: 7868588.

Yahr, T. L., Frank, D. W. (1994). Transcriptional organization of the trans-regulatory locus which controls exoenzyme S synthesis in Pseudomonas aeruginosa. J Bacteriol, 176(13), 3832-8. PMID: 8021164.

Kulich, S. M., Yahr, T. L., Mende-Mueller, L. M., Barbieri, J. T. & Frank, D. W. (1994). Cloning the structural gene for the 49-kDa form of exoenzyme S (exoS) from Pseudomonas aeruginosa strain 388. J Biol Chem, 269(14), 10431-7. PMID: 8144626.