IU Biology Faculty: Pranav Danthi

Pranav Danthi

Assistant Professor

Postdoctoral Research: Vanderbilt University, 2003-2008
Ph.D.: University of Arkansas for Medical Sciences, 2003
M.Sc.: M.S. University, Baroda, India, 1998
B.Sc.: St. Xavier’s College, Bombay, India, 1996

Program Affiliation: Molecular Biology & Genetics | Microbiology

Research Groups Affiliation: Biochemistry | Cell Biology | Microbiology

Email Pranav

Arriving November, 2008

Viral and Cellular Determinants of Virus-Induced Cell Death and Disease

Figure 1. The reovirus particle. A. Schematic diagram of the reovirus virion, showing the attachment protein s1 and the outer capsid proteins l2, s3 and m1. The inner core containing ten segments of genomic dsRNA is also shown. Short, or S segments encode the s proteins, medium or M segments encode the m proteins, and long or L segments encode the l proteins. B. Cryoelectron micrograph reconstruction of the reovirus virion showing l2 (yellow), s3 (blue) and m1 (green) [Nason et al (2001) J Virol 75:6625]. The m1 protein serves as a key viral modulator of host cell apoptosis.

Figure 2. Histopathologic analysis of hippocampus of mice infected with reovirus. Swiss Webster mice were inoculated intracranially with wild-type reovirus. At 10 days post-inoculation, brains from infected mice were resected, fixed, and embedded in paraffin. The Hematoxylin and Eosin (H & E)-stained hippocampus region of the brain shows damage to the pyramidal cell layer with sharp demarcation between areas of viable and dead cells. The dying neurons show condensed or fragmented nuclei characteristic of apoptotic cells. The region of the hippocampus displaying maximal inflammatory damage also shows presence of reovirus antigen and the apoptosis marker, activated caspase-3. Original magnification, ×100 (top panels) and ×400 (bottom panels).

Mechanisms by which viruses injure and kill their host cells are of critical importance to an understanding of viral pathogenesis. Infection of host cells by many viruses results in programmed cell death or apoptosis. Although general features of virus-induced cell death are understood, little is known about the viral intermediaries and cellular sensors that trigger cell killing. A better understanding of these pathological virus-host interactions will likely provide opportunities for therapeutic intervention against viral infections. Our laboratory utilizes mammalian reovirus to clarify how intracellular signaling pathways are activated by viruses to cause cell death and disease.

Analogous to their medically and economically important relatives - rotavirus and bluetongue virus - reovirus forms nonenveloped particles that contain a segmented dsRNA genome encapsidated within concentric protein shells. Following infection of newborn mice, reovirus disseminates systemically producing injury to a variety of organs, including the central nervous system (CNS), heart, and liver. Infection of mice with type 3 reovirus results in fatal encephalitis which is associated with extensive apoptosis at sites of efficient viral replication. This experimental model is highly amenable to investigation since reovirus can be easily cultivated in vitro and uses similar mechanisms to induce apoptotic cell death in cultured cells and in vivo. Furthermore, a wealth of structural information about reovirus proteins, the existence of well-characterized biochemical and cell biological reagents and assays, and the recent development of a tractable system to manipulate the reovirus genome greatly facilitates investigation of structure-function relationships within reovirus proteins.

Ongoing work in our laboratory is aimed at elucidating molecular mechanisms by which reovirus infection culminates in apoptotic cell death. Our studies indicate that early events during reovirus infection mediated by the reovirus membrane-penetration protein activate signaling pathways that are central to the host innate immune response. We seek to define how the physicochemical properties of the reovirus membrane-penetration protein contribute to the initiation of the cell-death response. Experiments are underway to identify cellular sensors that detect host cell intrusion by reovirus and stimulate a signal transduction cascade that culminates in cell death. We also are studying how innate immune signal transducers connect reovirus to the effectors of apoptotic cell death. In addition to identification and characterization of viral and cellular determinants that regulate the apoptosis, we also are defining the physiological consequences of apoptosis to viral pathogenesis. Together, our studies will enhance an understanding of the molecular basis of reovirus-induced apoptosis and disease pathogenesis and provide detailed insight into events at the virus host-host interface that will guide development of new therapeutics that modulate apoptotic pathways.

Representative Publications:

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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.

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.

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.

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.

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: 1261-70.