Faculty & Research
- Contact Information
- Contact Pranav Danthi by pdanthi [at] indiana [dot] edu
- By telephone: 812-856-2449
- SI 220B
- Research Areas
- Eukaryotic Cell Biology, Cytoskeleton and Signaling
- Microbial Interactions and Pathogenesis
Postdoctoral Research: Vanderbilt University, 2003-2008
Ph.D.: University of Arkansas for Medical Sciences, 2003
The Danthi laboratory investigates how mammalian reovirus interacts with host cells. Reoviruses infect a variety of mammals, including humans, and are known to produce neurological disease in young animals. These viruses serve as a versatile experimental system for studies of events at the virus-cell interface, including virus entry, activation of the innate immune response, and viral pathogenesis. We are specifically interested in understanding how reoviruses bypass host membranes to initiate infection and how infection of host cells by reovirus results in programmed cell death or apoptosis.
Reovirus entry. The reovirus genome, which is composed of 10 segments of dsRNA, is encompassed within two concentric protein shells but lacks a surrounding lipid envelope. Successful initiation of infection by reovirus requires delivery of the genome-containing reovirus inner shell (or core) across the host cell membrane. This process occurs via a series of changes to the reovirus particle. These include exposure and cleavage of the reovirus outer capsid m1 protein, conformational changes in the m1 protein which allow release of membrane-targeting peptides generated as a consequence of m1 cleavage, and disruption of the host membrane by the released peptides. Much remains unknown about how cleavage of m1 is regulated, how conformational changes are triggered and controlled, and how a large macromolecular cargo, the viral core, is transported across the considerably smaller pores formed by the peptides released from m1. We use a combination of genetic, biochemical and biophysical approaches to understand these questions. Because the overall strategy for entering cells used by other nonenveloped viruses is similar, our studies will uncover conserved mechanisms by which phylogenetically distinct viruses initiate infection.
Reovirus-induced apoptosis. Reovirus infection of cultured cells or cells within organs of infected animals results in apoptosis. Blockade of apoptosis diminishes reovirus disease suggesting that virus-induced cell death is a determinant of viral pathogenesis. Initiation of prodeath signaling following reovirus infection occurs subsequent to membrane penetration but prior to synthesis of viral RNA and proteins and is dependent on the function of the m1 C-terminal fragment f. Delivery of f to the post-endosomal compartment results in activation of the transcription factor NF-kB. Once activated, NF-kB drives the expression of genes that stimulate the host apoptotic machinery. We are interested in elucidating how f stimulates a signaling pathway that leads to NF-kB activation and culminates in cell death. These studies are of interest for three reasons. First, although apoptosis occurs commonly following infection by many viruses, how viral components engage host factors to initiate death signaling is not well understood. Second, these studies will facilitate an understanding of the biology of NF-kB. NF-kB activation usually promotes cell survival and contributes to the development of cancer and other inflammatory diseases. Because activation of NF-kB by reovirus triggers a diametrically opposite death response, our work will help understand how different outcomes of NF-kB signaling are controlled. Third, reovirus is currently in clinical trials due to its remarkable preference for replicating in and killing transformed cells. Since the capacity of reovirus to induce apoptosis is critical to its oncolytic efficiency, a better understanding of host and viral factors that regulate death signaling may prove useful in development of an optimized anti-cancer therapeutic.
- Hiller BE, Berger AK and P. Danthi (2015) Viral gene expression potentiates reovirus-induced necrosis. Virology. In press.
Thete D, and P. Danthi (2015) Conformation changes required for reovirus cell entry are sensitive to low pH. Virology 483: 291-301
- Sarkar, P. and P. Danthi (2013) The mu1 72-96 loop regulated conformational transitions during reovirus cell entry. Journal of Virology. Epub
- Berger, A.K. and P. Danthi (2013). Reovirus activates a caspase-independent cell death pathway mBio 4: e00178-13
- Doyle, J.D., Danthi, P., Kendall, E.A., Ooms, L.S., Wetzel, J.D., and T. S. Dermody (2012). Molecular Determinants Of Proteolytic Disassembly Of The Reovirus Outer Capsid. Journal of Biological Chemistry. 287: 8029-8038
- Madren, J.A., Sarkar, P. and P. Danthi (2012). Cell entry-associated conformational changes in reovirus particles are controlled by host protease activity. Journal of Virology. 86: 3466-3473
- Barlan A.U, P. Danthi, and C.M. Wiethoff (2011). Lysosomal localization and mechanism of membrane penetration influence nonenveloped virus activation of the NLRP3 inflammasome. Virology 412: 306-314
Danthi, P. Enter the kill zone: Initiation of death signaling during virus entry (2011). Virology: 411: 316-24
Danthi P., K.M. Guglielmi, E. Kirchner, B. Mainou, T. Stehle, and T.S. Dermody (2010). From touchdown to transcription: The reovirus cell entry pathway. Current Topics in Microbiology and Immunology. 343: 91-119
Danthi, P.*, A.J. Pruijssers, A. K. Berger, G. H. Holm, S. S. Zinkel, and T. S. Dermody*(2010). Bid regulates the pathogenesis of neurotropic reovirus. (* corresponding author) PLoS Pathogens 6: e1000980
Holm G.H, A.J. Pruijssers, L. Li, P. Danthi, B. Sherry and T.S. Dermody (2010). Interferon Regulatory Factor-3 attenuates reovirus myocarditis and contributes to viral clearance. Journal of Virology. 84: 6900-6908
Sarkar, P. and P. Danthi. Determinants of strain-specific differences in reovirus cell entry (2010). Journal of Virology. 84: 12723-32. Selected as spotlight article by the editors
- Danthi, P., T. Kobayashi, G. H. Holm, M. W. Hansberger, T. W. Abel, and T. S. Dermody (2008). Reovirus apoptosis and virulence are regulated by host cell membrane-penetration efficiency. Journal of Virology 82: 161-172.
- Danthi, P*, C. M. Coffey, J. S. L. Parker, T. W .Abel and T. S. Dermody*(2008) Independent regulation of reovirus membrane penetration and apoptosis by the μ1 φ domain. PLoS Pathogens: 4(12): e1000248. *corresponding authors
- Holm G.H., J. Zurney, V. Tumilasci, P. Danthi, J. Hiscott, B. Sherry, and T.S. Dermody (2007). RIG-I and IPS-1 augment proapoptotic responses following mammalian reovirus infection via IRF-3. Journal of Biological Chemistry 282: 21953-21961.
- Hansberger, M.W., J.A.Campbell, P. Danthi, P. Arrate, K.N. Pennington, K.B. Marcu, D.W. Ballard and T.S. Dermody (2007). IkB kinase subunits a and g are required for activation of NF-kB and induction of apoptosis by mammalian reovirus. Journal of Virology 81: 1360-1371.
- Kobayashi T., A. A. R. Antar, K. W. Boehme, P. Danthi, E. A. Eby, K. M. Guglielmi, G. H. Holm, E. M. Johnson, M. S. Maginnis, S. Naik, W. B. Skelton, J. D. Wetzel, G. J. Wilson, J. D. Chappell, and T. S. Dermody (2007). A plasmid-based reverse genetics system for animal double-stranded RNA viruses. Cell Host and Microbe 1: 147-157.
- Danthi, P., G. H. Holm, T. Stehle and T. S. Dermody (2006). Reovirus receptors, cell entry, and signaling. In: Pöhlmann, S., and G. Simmons (eds.): Viral Entry into Cells. Landes Bioscience, Georgetown, TX.
- Danthi P., M. W. Hansberger, J. A. Campbell, J. C. Forrest and T.S. Dermody (2006). JAM-A-independent, antibody-mediated uptake of reovirus into cells leads to apoptosis. Journal of Virology 80: 1261-1270.