Graham Hatfull

  • Eberly Family Professor of Biotechnology, HHMI Professor
  • Phages and tuberculosis
×

Error message

  • Warning: include_once(D:\Sites\biology\misc\typo3\phar-stream-wrapper\src\Phar\Stub.ph): failed to open stream: No such file or directory in file_register_phar_wrapper() (line 29 of D:\Sites\biology\includes\file.phar.inc).
  • Warning: include_once(): Failed opening 'D:\Sites\biology/misc/typo3/phar-stream-wrapper/src/Phar/Stub.php' for inclusion (include_path='.;C:\php\pear') in file_register_phar_wrapper() (line 29 of D:\Sites\biology\includes\file.phar.inc).

Contact

Office: (412) 624-6975
Lab: (412) 624-6976
304 Clapp Hall
4249 Fifth Avenue
Pittsburgh, PA 15260

Mycobacterium tuberculosis kills more people than any other single infectious agent. Since antibiotics are available and the BCG vaccine is in widespread use, why do two million people die each year from TB? The answer, in part, is that we really don't understand this curious bacterium or what parts of its genetic instructions make this such a deadly pathogen. At the heart of our strategies to understand mycobacterial genetics is the mycobacteriophages - viruses that infect the mycobacteria. These are easy to grow and manipulate and offer advantages over working with the slow-growing mycobacteria (such as M. tuberculosis) that can take up to a month to produce a colony on an agar plate. Phages are also rich sources of  potential genetic and molecular tools that can be used to study - and to modify - their bacterial hosts.

Corndog: Mycobacteriophage Corndog

Here's just a flavor of some of the current studies going on in the lab:

    Exploring bacteriophage genomics. In collaboration with Dr. Hendrix we have spearheaded an initiative to understand viral diversity and evolution. Our specific focus is on the genomic characterization of mycobactriophages, and a collection of about 250 complete genome sequences have been determined. Many of these phages were isolated and sequenced through three programs in which phage discovery and genomics is a platform for integrating our science and educational missions. These are the Pittsburgh Phage Hunters Integrating Research and Education (PHIRE) program, the Howard Hughes Medical Institute Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (HHMI SEA-PHAGES) program, and a Univiersity of KwaZulu-Natal and KwaZulu-Nalat Research in TB and HIV (UKZN/K-RITH) workshop.  These studies have not only provided valuable insights into phage diveristy and evolution, but present a rich and easily-accessible reservoir of genetic and mechanistic novelty for further study. A database of mycobaectriophage genomic infomration is available at http://www.phagesdb.org.

      Exploiting mycobacteriophages. We are dissecting the mycobacteriophages to understand the functional roles of the thousands of genes we have identified, and to deternine if and when they are expressed, and how this expression is regulated.  We are exploiting this information to develop tools and approaches that not only generate new tools for genetic manipulation for tuberculosis, but also to gain advances in diagnosis, prevention and treatment of the disease.

      Site-specific recombination. Many if not most of the mycobacteriophages we have sequenced integrate their DNA into the host chromosome (and can excise them too). We are studying the mechanism of integrase-mediated site-specific recombination with a primary current focus on the serine-integrases.  We are partiualrly interested in understanding how recomibnational directionality is determine in phage integration systems.

      Tools - Genetic and Clinical. Studying the mycobacteria and their phages has great potential for the development of novel tools for their genetics but also for a more direct clinical involvement. Two systems we have been involved in developing are multivalent recombinant BCG vaccines and Luciferase Reporter Phages, but there are numerous additional strategies awaiting further development!

      E-mail Lab

      Dedrick, R. M., Freem

      Dedrick, R. M., Freeman, K. G., Nguyen, J. A., Bahadirli-Talbott, A., Smith, B. E., Wu, A. E., Ong, A. S., Lin, C. T., Ruppel, L. C., Parrish, N. M., Hatfull. G. F. and Cohen, K. A.  (2021).  Potent antibody mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection.  Nature Medicine.  Jul 8. doi: 10.1038/s41591-021-01403-9

      Guerrero-Bustamante.

      Guerrero-Bustamante. C.A., Dedrick, R. M., Garlena, R. A., Russell, D. A., & Hatfull, G. F.  (2021).  Towards a phage cocktail for tuberculosis: Susceptibility and tuberculocidal action of mycobacteriophages against diverse Mycobacterium tuberculosis strains.  mBio 12 e00973-21

      Dedrick, R. M., Aull, H. G., Jacobs-Sera, D., Garl

      Dedrick, R. M., Aull, H. G., Jacobs-Sera, D., Garlena, R. A., Russell, D. A., Smith, B. E., Mahalingam, V., Abad, L., Gauthier, C. H., & Hatfull, G. F. (2021). The prophage and plasmid mobilome as a likely driver of Mycobacterium abscessus diversity. mBio 12:e03441-20. doi: 10.1128/mBio.03441-20. PMID: 33785627

      Dedrick, R. M., Smith, B. E., Garlena, R. A., Russ

      Dedrick, R. M., Smith, B. E., Garlena, R. A., Russell, D. A., Aull, H. G., Mahalingam, V., Divens, A. M., Guerrero-Bustamante, C., Zack, K., Abad, L., Gauthier, C. H., Jacobs-Sera, D., & Hatfull, G. F. (2021). Mycobacterium abscessus strain morphotype determines phage susceptibility, the repertoire of therapeutically useful phages, and phage resistance. mBio 12:e03431-20. doi: 10.1128/mBio.03431-20. PMID: 33785625

      Pezo, V., Jaziri, F., Bourguignon, P-Y., Louis,

      Pezo, V., Jaziri, F., Bourguignon, P-Y., Louis, D., Jacobs-Sera, D., Rozenski, J. Pochet, S., Herdewijn, P., Hatfull, G. F., Kaminski, P. A., & Marliere, P. (2021). Non-canonical DNA polymerization by aminoadenine-based siphoviruses. Science 372, 520-524.

      Amarh, E. D., Dedrick, R. M., Garlena, R. A., Russ

      Amarh, E. D., Dedrick, R. M., Garlena, R. A., Russell, D. A., Jacobs-Sera, D., Hatfull, G. F. (2021). Genome Sequence of Mycobacterium abscessus Phage phiT45-1. Microbiol Resour Announc 10:e00155-21. doi: 10.1128/MRA.00155-21. PMID: 33707330.

      Judd, J., Canestrari, J., Clark, R., Joseph, A., L

      Judd, J., Canestrari, J., Clark, R., Joseph, A., Lapierre, P., Lasek-Nesselquist, E., Mir, M., M. Palumbo, Smith, C., Stone,, M., Upadhyay, A., Wirth, S., Dedrick, R., Meier, C., Russell, D. A., Dills, A.,, Dove, E., Kester, J., Wolf, I., Zhu, J., Rubin, E., Fortune, S., Hatfull, G. F., Gray, T., Wade, J., & Derbyshire, K. M. (2021). A Mycobacterial Systems Resource for the Research Community. 12:e02401-20. doi: 10.1128/mBio.02401-20. PMID: 33653882

      Wetzel, K.S., Aull, H.G., Zack, K.M., Garlena, R.A

      Wetzel, K.S., Aull, H.G., Zack, K.M., Garlena, R.A. & Hatfull, G.F. (2020) Protein-Mediated and RNA-Based Origins of Replication of Extrachromosomal Mycobacterial Prophages. mBio 11. pii: e00385-20. doi: 10.1128/mBio.00385-20. PMID: 32209683

      Jacobs-Sera, D., Abad, L. A., Alvey, R. M., Anders

      Jacobs-Sera, D., Abad, L. A., Alvey, R. M., Anders, K.R., Aull, H. G., Bhalla, S. S., Blumer, L. A, Bollivar, D. W., Alfred Bonilla, J., Butela, K.A., Coomans, R. J., Cresawn, S. G. , D'Elia, T., Diaz, A., Divens, A. M., Edgington, N. P., Frederick, G. D., Gainey, M. D., Garlena, R. A., Grant, K.W., Gurney, S. M. R., Hendrickson, H. L., Hughes, L. E.18, Kenna, M. A., Klyczek, K. K., Kotturi, H., Mavrich, T. N., McKinney, A. L., Merkhofer, E. C., Parker, J. M., Molloy, S. D., Monti, D. L., Pape-Zambito, D. A., Pollenz, R. S., Pope, W. H., Reyna, N. S., Rinehart, C. A., Russell, D. A., Shaffer, C. D., Sivanathan, V., Stoner, T. H., Stukey, J., Sunnen, C. N., Tolsma, S. S., K. Tsourkas, P., Wallen, J. R., Ware, V. C., Warner. M. H., Washington, J. M., Westover, K. M., Whitefleet-Smith, J. L., Wiersma-Koch, H. I., Williams, D. C., Zack, K. M., and Hatfull, G. F. (2020) Genomic diversity of bacteriophages infecting Microbacterium spp. PLoS One 15(6), e0234636. PMID: 32555720

      Ko, C. C. and Hatfull, G. F. (2020). Identificat

      Ko, C. C. and Hatfull, G. F. (2020). Identification of mycobacteriophage toxic genes reveals new features of mycobacterial physiology and morphology. Sci Rep. Sep 4;10,14670. doi: 10.1038/s41598-020-71588-5. PMID: PMID: 32887931

      Mavrich, T. N., Gauthier, C., Abad, L., Bowman, C.

      Mavrich, T. N., Gauthier, C., Abad, L., Bowman, C. A., Cresawn, S. G., and Hatfull, G. F. (2020). pdm_utils: a SEA-PHAGES MySQL phage database management toolkit. Bioinformatics. Nov 23:btaa983. doi: 10.1093/bioinformatics/btaa983. PMID: 33226064

      Wetzel, K. S., Guerrero-Bustamante, C. A., Dedrick

      Wetzel, K. S., Guerrero-Bustamante, C. A., Dedrick, R. M., Ko C-C., Freeman, K. G., Aull, H. G., Divens, M. A. M., Rock, J. M., Zack, K. M., & Hatfull, G. F. (2021). CRISPY-BRED and CRISPY-BRIP: Efficient bacteriophage engineering. Sci. Reports. 24, 11:6796. doi: 10.1038/s41598-021-86112-6. PMID: 33762639

      Zaworski, J., McClung, C., Ruse, C., Weigele, P. R

      Zaworski, J., McClung, C., Ruse, C., Weigele, P. R., Hendrix, R. W., Ko, C-C., Edgar, R., Hatfull, G. F., Casjens, S. R., Raleigh, E. A. (2021). Genome analysis of Salmonella enterica serovar Typhimurium bacteriophage L, indicator for StySA (StyLT2III) restriction-modification system action. G3 Genes|Genomes|Genetics 11. https://doi.org/10.1093/g3journal/jkaa037. PMID: 33561243

      Podgorski, J., Calabrese, J., Alexandrescu, L., Ja

      Podgorski, J., Calabrese, J., Alexandrescu, L., Jacobs-Sera, D., Pope, W., Hatfull, G. F., & White, S. (2020). Structures of Three Actinobacteriophage Capsids: Roles of Symmetry and Accessory Proteins. Viruses 12. pii: E294. doi: 10.3390/v12030294. PMID: 32182721

      Amarh, E. D., Dedrick, R. M., Garlena, R. A., Russ

      Amarh, E. D., Dedrick, R. M., Garlena, R. A., Russell, D. A., Jacobs-Sera, D., Hatfull, G. F. (2021). Genome Sequence of Mycobacterium abscessus Phage phiT46-1. Microbiol Resour Announc 10. Doi: 10.1128/MRA.01421-20. PMID: 33446600

      Pope, W. H., Butela, K. A., Garlena, R. A., Jacobs

      Pope, W. H., Butela, K. A., Garlena, R. A., Jacobs-Sera, D., Russell, D. A., Warner, M.H. University of Pittsburgh SEA-PHAGES, and Hatfull, G. F. (2020). Genome Sequences of 20 Bacteriophages Isolated on Gordonia terrae. Microbial. Resource Announcements, 16 pii: e01489-19. doi: 10.1128/MRA.01489-19. PMID: 31948974

      Carrigy, N. B., Larsen, S. E., Reese, V., Pecor, T

      Carrigy, N. B., Larsen, S. E., Reese, V., Pecor, T., Harrison, M., Kuehl, P. J., Hatfull, G. F. Sauvageau, D., Finlay, W. H., Coler, R. N., and Vehring, R. (2019). Prophylaxis of Mycobacterium tuberculosis H37Rv Infection in a Preclinical Mouse 1 Model via Inhalation of Nebulized Bacteriophage D29. Antimicrobial. Agents Chemo. pii: AAC.00871-19. doi: 10.1128/AAC.00871-19. PMID: 31527037

      Hutinet, G., Kot, W., Cui, L., Hillebrand, R., Bal

      Hutinet, G., Kot, W., Cui, L., Hillebrand, R., Balamkundu, S., Gnanakalai, S., Neelakandan., R., Carstens, A. B., Chuan., L., Tremblay, D., Jacobs-Sera, D., Sassanfar. M., Weigele, P., Moineau, S. Hatfull, G. F., Dedon, P. C., Hansen, L. H., and de Crécy-Lagard. V. (2019). 7-Deazaguanine modifications protect phage DNA from host restriction systems. Nat. Commun. 10, 5442. doi: 10.1038/s41467-019-13384-y. PMID: 31784519

      Evolution of Superinfection Immunity in Cluster

      Evolution of Superinfection Immunity in Cluster A Mycobacteriophages.  (2019).  Mavrich, T.N. and Hatfull, G.F.  mBio. 2019 Jun 4; 10 (3). pii: e00971-19. doi: 10.1128/mBio.00971-19.  PMID:  31164468

      Oliveira, H., Sampaio, M., Melo, L.

      Oliveira, H., Sampaio, M., Melo, L. D. R., Dias, O., Pope, W. H., Hatfull, G. F. and Azeredo, J.  (2019).  Staphylococci phages display vast genomic diversity and evolutionary relationships.  BMC Genomics 20, 357. doi: 10.1186/s12864-019-5647-8.  PMID: 31072320

      Dedrick, R. M., Guerrero-Bustamante, C. A., Gar

      Dedrick, R. M., Guerrero-Bustamante, C. A., Garlena, R. A., Russell, D. A., Ford, K., Harris, K., Gilmour, K. C., Soothill, J., Jacobs-Sera, D., Schooley, R. R., Hatfull, G. F. and Spencer, H.  (2019).  Use of engineered bacteriophages for personalized treatment of a patient with a disseminated drug resistant Mycobacterium abscessus infection.  Nature Med. 25, 730-733. doi: 10.1038/s41591-019-0437-z.  PMID: 31068712

      Mycobacteriophage Z

      Mycobacteriophage ZoeJ: A broad host-range close relative of mycobacteriophage TM4.  (2019).  Dedrick, R.M., Guerrero Bustamante, C.A., Garlena, R.A., Pinches, R.S., Cornely, K. and Hatfull, G.F.  Tuberculosis (Edinb). 115:14-23. doi: 10.1016/j.tube. 2019.01.002.  PMID: 30948168
      Dr. Hatfull received his Ph.D. in 1981 with Willie Donachie at the University of Edinburgh, Scotland, performed postdoctoral studies with Nigel Grindley at Yale University and with Fred Sanger at the MRC, and joined the Department in 1988.