Farokh Dotiwala, M.B.B.S., Ph.D.

Farokh Dotiwala, M.B.B.S., Ph.D.

  • Assistant Professor, Vaccine & Immunotherapy Center
  • fdotiwala@wistar.org
Summary

The Dotiwala lab focuses on the mechanisms by which cell based innate and adaptive immunity destroy diverse non-viral pathogens, such as intra- and extracellular bacteria, fungi and protozoa. Dotiwala’s previous research centered on mechanisms of killer immune cells—such as natural killer and CD8 T cells—and how they use pore forming protein perforin, antimicrobial peptide granulysin and immune protease granzyme B in synergy to destroy pathogens in host cells. This research could result in promising therapeutic strategies against infections that were once thought to be drug-resistant or that currently do not have effective treatments.

Dotiwala’s work on the activity of Granzyme B, in different bacterial species, revealed multiple key metabolic and synthetic pathways as targets, making it improbable for bacteria to develop resistance to these immune proteases.  The lab is interested in using cellular, molecular, biochemical and omics approaches, as well as sophisticated in vivo imaging and live animal studies, in dissecting the mechanism by which cell-based immunity (neutrophils, macrophages and killer lymphocytes) activates in the presence of different pathogenic bacteria and systematically measure the immune response. This research is designed to adapt the use of different immune proteases coupled with antimicrobial peptides as therapies for drug-resistant bacterial infections such as MRSA. The lab is also interested in delivering immune proteases to cancer cells thereby restricting their ability to develop resistance. These mechanistic insights would hopefully aid in designing better antimicrobial and anti-cancer therapies.

Dotiwala joined Wistar from Boston Children’s Hospital and Harvard Medical School where he was an Instructor in Pediatrics. He received an M.B.B.S. in Medicine from Grant Medical College, Mumbai, India, and a Ph.D. in Molecular and Cell Biology from Brandeis University. His Ph.D. research studied different factors in DNA damage and activation of cell cycle checkpoints which prevent cancer by halting cell division in DNA-damaged cells. Dotiwala was appointed a postdoctoral research fellow at Harvard University in the lab of Judy Lieberman, M.D., Ph.D., and completed training in immunology and cancer research. His research focused on the mechanisms killer immune cells use to destroy bacteria and protozoan pathogens.

Opportunities

We are always on the look out for highly motivated researcher. The Dotiwala laboratory investigates the role of anti-microbial peptides and immune proteases in the killing of extracellular and intracellular bacterial, fungal and protozoan pathogens with the aim of developing novel therapeutic strategies to combat the worldwide threat of antibiotic resistance.

Applicants should have strong background in one or more of the following disciplines: biochemistry, molecular and cellular biology, infectious diseases, immunology, proteomics / lipidomics approach to biology, or mouse models of infectious diseases. Strong candidates will have at least one-two publications in internationally recognized peer-reviewed journals. Candidates eligible for NRSA funding are strongly encouraged to apply.

Candidates should have a Ph.D. (or equivalent) degree or should be close to obtaining their doctoral degree. Interested individuals should apply by submitting:

  • A CV including a list of publications and manuscripts in preparation
  • One-page cover letter detailing the reason for their scientific interest in the lab, outline potential post-doctoral research projects and career goals
  • Three reference letters

Email your submissions to Dr. Farokh Dotiwala Email: fdotiwala@wistar.org with the subject line: Postdoc application. Applicants are also encouraged to apply online. 

Selected Publications

1. Basu R, Whitlock BM, Husson J, Le Floc'h A, Jin W, Oyler-Yaniv A, Dotiwala F, Giannone G, Hivroz C, Biais N, Lieberman J, Kam LC, Huse M. Cytotoxic T Cells Use Mechanical Force to Potentiate Target Cell Killing. Cell. 2016 Mar 24;165(1):100-10. doi: 10.1016/j.cell.2016.01.021. Epub 2016 Feb 25. PMID: 26924577

2. Dotiwala F, Mulik S, Polidoro RB, Ansara JA, Burleigh BA, Walch M, Gazzinelli RT, Lieberman J. Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites. Nat Med. 2016 Feb;22(2):210-6. doi: 10.1038/nm.4023. Epub 2016 Jan 11. PMID: 26752517

3. Dotiwala F, Fellay I, Filgueira L, Martinvalet D, Lieberman J, Walch M. A High Yield and Cost-efficient Expression System of Human Granzymes in Mammalian Cells. J Vis Exp. 2015 Jun 10;(100):e52911. doi: 10.3791/52911. PMID: 26132420

4. Walch M, Dotiwala F, Mulik S, Thiery J, Kirchhausen T, Clayberger C, Krensky AM, Martinvalet D, Lieberman J. Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell. 2014 Jun 5;157(6):1309-23. doi: 10.1016/j.cell.2014.03.062. Erratum in: Cell. 2015 May 21;161(5):1229. PMID: 24906149

5. Lee MN, Roy M, Ong SE, Mertins P, Villani AC, Li W, Dotiwala F, Sen J, Doench JG, Orzalli MH, Kramnik I, Knipe DM, Lieberman J, Carr SA, Hacohen N. Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach. Nat Immunol. 2013 Feb;14(2):179-85. doi: 10.1038/ni.2509. Epub 2012 Dec 23. PMID: 23263557 

6. Dotiwala F, Eapen VV, Harrison JC, Arbel-Eden A, Ranade V, Yoshida S, Haber JE. DNA damage checkpoint triggers autophagy to regulate the initiation of anaphase. Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):E41-9. doi: 10.1073/pnas.1218065109. Epub 2012 Nov 19. PMID: 23169651

7. Dotiwala F, Harrison JC, Jain S, Sugawara N, Haber JE. Mad2 prolongs DNA damage checkpoint arrest caused by a double-strand break via a centromere-dependent mechanism. Curr Biol. 2010 Feb 23;20(4):328-32. doi: 10.1016/j.cub.2009.12.033. Epub 2010 Jan 21. PMID: 20096585

8. Kim JA, Kruhlak M, Dotiwala F, Nussenzweig A, Haber JE. Heterochromatin is refractory to gamma-H2AX modification in yeast and mammals. J Cell Biol. 2007 Jul 16;178(2):209-18. PMID: 17635934

9. Dotiwala F, Haase J, Arbel-Eden A, Bloom K, Haber JE. The yeast DNA damage checkpoint proteins control a cytoplasmic response to DNA damage. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11358-63. Epub 2007 Jun 22. PMID: 17586685

10. De Piccoli G, Cortes-Ledesma F, Ira G, Torres-Rosell J, Uhle S, Farmer S, Hwang JY, Machin F, Ceschia A, McAleenan A, Cordon-Preciado V, Clemente-Blanco A, Vilella-Mitjana F, Ullal P, Jarmuz A, Leitao B, Bressan D, Dotiwala F, Papusha A, Zhao X, Myung K, Haber JE, Aguilera A, Aragón L. Smc5-Smc6 mediate DNA double-strand-break repair by promoting sister-chromatid recombination. Nat Cell Biol. 2006 Sep;8(9):1032-4. Epub 2006 Aug 6. PMID: 16892052