Vincent Racaniello, Ph.D.
Higgins Professor of Microbiology & Immunology
Ph.D., Mt. Sinai School of Medicine of CUNY
Molecular biology of picornavirus replication and pathogenesis
Picornaviruses are RNA-containing viruses that cause a variety of human diseases including paralysis (e.g. poliomyelitis), myocarditis, conjunctivitis, and the common cold. Our research focuses on the interaction of viruses with the innate immune system, viral pathogenesis, and viral discovery in wild animals.
Role in rhinovirus replication of cell proteins that interact with the viral 2B and 3A proteins. Adaptation of rhinovirus to growth in mouse cells requires amino acid changes in viral proteins 2B and 3A. These viral proteins, together with 2C, cause membrane rearrangements in the infected cell that lead to destruction of the normal architecture of the ER and Golgi and massive membrane proliferation. As a consequence the infected cell cytoplasm becomes filled with vesicles, which serve as focal points for the assembly of the viral replication complex. The mechanisms by which viral proteins cause these changes in the cell are unknown. The 3A protein of rhinovirus interacts with GCP60 and FinGER6, proteins involved in vesicle traffic, and with an enzyme involved in lipid biosynthesis phosphatidylinositol synthase. The role of these cell proteins in viral replication, alteration of membrane ultrastructure, and inhibition of ER-to-Golgi traffic will be determined by reducing the levels of these proteins in the cell with siRNAs.
Picornaviruses in wild mice. There is little information on the prevalence and diversity of picornaviruses in wild mice. To answer this question, we will trap wild mice in the northeastern United States and extract total RNA from lungs and intestine. The RNA will be subjected to deep-sequencing and bioinformatic analysis to identify new picornaviruses. Complete genomes will be constructed and virus recovered in cell culture for further studies.
Interaction of picornaviruses with the innate immune system. Innate responses to viral infection are triggered when cellular pattern recognition receptors engage viral macromolecules. The ensuing signal transduction cascade leads to induction of IFN and other cytokines and establishment of an antiviral state. We have found that RIG-I, MDA-5, and IPS-1 are degraded in cells infected with picornaviruses. We wish to determine whether cleavage of these sensor molecules benefits viral replication. Our studies have also shown that poliovirus proteinase 2Apro antagonizes the activity of one or more interferon-induced proteins. The identity of the target proteins will be established, and the mechanism of antagonism determined.
Mouse model of rhinovirus infection. We have adapted rhinovirus to mouse cells and demonstrated that the virus replicates in the respiratory tract of mice. Because rhinoviruses are a major cause of asthma exacerbation, we will determine whether infection of mice leads to signatures of the asthmatic response, and if so, which cytokines are involved.
Francisco, E., Suthar, M., Gale, M., Jr., Rosenfeld, A.B. and Racaniello, V.R. (2018) Cell-type specificity and functional redundancy of RIG-I-like receptors in innate immune sensing of Coxsackievirus B3 and encephalomyocarditis virus. Virology 528: 7-18.
Rosenfeld, A.B., Doobin, D.J., Warren, A.L., Racaniello, V.R. and Vallee, R.B. (2017) Replication of early and recent Zika virus isolates throughout mouse brain development. Proc. Natl. Acad. Sci. U.S.A. 114: 12273-12278.
Lin, Y. and Racaniello, V.R. (2017) Polioviruses that bind a chimeric Pvr-nectin-2 protein identify capsid residues involved in receptor interaction. Virology 510: 305-315.
Shugart, E.C. and Racaniello, V.R. (2015) Scientists: Engage the public! mBio 6: e01989-01915.
Schoggins, J.W., MacDuff, D.A., Imanaka, N., Gainey, M.D., Shrestha, B., Eitson, J.L., Mar, K.B., Richardson, R.B., Ratushny, A.V., Litvak, V., Dabelic, R., Manicassamy, B., Aitchison, J.D., Aderem, A., Elliott, R.M., Garcia-Sastre, A., Racaniello, V., Snijder, E.J., Yokoyama, W.M., Diamond, M.S., Virgin, H.W. and Rice, C.M. (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505: 691-695.
Schuler, B.A., Schreiber, M.T., Li, L., Mokry, M., Kingdon, M.L., Raugi, D.N., Smith, C., Hameister, C., Racaniello, V.R. and Hall, D.J. (2014) Major and minor group rhinoviruses elicit differential signaling and cytokine responses as a function of receptor-mediated signal transduction. PLoS One 9: e93897.
Racaniello, V.R. (2012) Science should be in the public domain. MBio 3: e00004-12.
Racaniello, V.R. (2011) An exit strategy for measles virus. Science 334: 1650-1651. Virology Perspective.
Rasmussen, A.L. and Racaniello, V.R. (2011) Selection of rhinovirus 1A variants adapted for growth in mouse lung epithelial cells. Virology 420: 82-88. Epub 2011 Sep 22.
Rosenfeld, A.B. and Racaniello, V.R. (2010) Components of the multifactor complex needed for internal initiation by the IRES of hepatitis C virus in Saccharomyces cerevisiae. RNA Biology7: 596-605. Epub 2010 Sep 1.
Drahos, J. and Racaniello, V.R. (2009) Cleavage of IPS-1 in cells infected with human rhinovirus. J. Virol. 83: 11581-11587.
Barral, P.M., Sarkar, D., Fisher, P.B. and Racaniello, V.R. (2009) RIG-I is cleaved during picornavirus infection. Virology 391: 171-176.
Morrison, J.M. and Racaniello, V.R. (2009) Proteinase 2Apro is essential for enterovirus replication in type I interferon-treated cells. J. Virol. 83: 4412-4422.
Kim, M.S. and Racaniello, V.R. (2007) Enterovirus 70 receptor utilization is controlled by capsid residues that also regulate host range and cytopathogenicity. J. Virol. 81: 8648-8655.
Barral, P.M., Morrison, J.M., Drahos, J., Gupta, P., Sarkar, D., Fisher, P.B. and Racaniello, V.R. (2007) MDA-5 Is Cleaved in Poliovirus-Infected Cells. J. Virol. 81: 3677-3684.
Kauder, S., Kan, S. and Racaniello, V.R. (2006) Age-dependent poliovirus replication in the mouse central nervous system is determined by internal ribosome entry site-mediated translation. J. Virol. 80: 2589-2595.
Harris, J.R. and Racaniello, V.R. (2005) Amino acid changes in proteins 2B and 3A mediate rhinovirus type 39 growth in mouse cells. J. Virol. 79: 5363-5373.
Ren, R., Costantini, F., Gorgacz, E.J., Lee, J.J. and Racaniello, V.R. (1990) Transgenic mice expressing a human poliovirus receptor: A new model for poliomyelitis. Cell 63: 353-362.