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Vincent R. Racaniello, PhD
- Higgins Professor of Microbiology and Immunology
Much of our work of the past 17 years has been on poliovirus, the causative agent of poliomyelitis. Poliovirus infection begins when the virus binds to a cell surface receptor and subsequently releases the viral nucleic acid into the cell. Poliovirus is a particularly good model for studying these interactions. The three dimensional structure of poliovirus has been determined by X-ray crystallography, the cell receptor for poliovirus has been identified, and genetic manipulation of the virus is possible with infectious cDNA copies of the viral genome. One goal of our research is to use these experimental tools to identify regions of the capsid and Pvr that initially interact and lead to the structural transitions associated with uncoating of the viral RNA. These questions are addressed by the construction and analysis of mutants of the viral capsid and the cellular receptor. To learn more about how poliovirus causes disease, we have established a new mouse model for poliomyelitis. Mice are normally resistant to poliovirus infection, but transgenic mice expressing Pvr develop poliomyelitis after inoculation with virulent strains of the virus. This mouse model is being used to address questions on the pathogenesis of poliomyelitis, such as how poliovirus infection is restricted to specific cell types such as neurons, how the virus spreads in the infected animal, and the basis for the attenuation phenotype of the live poliovirus vaccines. We are using a similar approach to establish mouse models for diseases caused by other picornaviruses, including echoviruses, rhinoviruses, and enteroviruses. To establish a mouse model for rhinovirus infection, we first examined the ability of the virus to replicate in cultured mouse cells. Rhinovirus type 16 replicates in mouse L cells that express the viral receptor, human intercellular adhesion molecule 1 (ICAM-1). Infection leads to no discernible cytopathic effect, and low virus titers are produced. A variant virus, 16/L, was isolated after passage of rhinovirus in ICAM-1 L cells. Virus 16/L produces higher virus titers and viral RNA, and efficiently kills ICAM-1 L cells. Adaptation to mouse cells maps to two changes in viral protein 2C. How changes in this protein improve replication in mouse cells is currently under investigation. The poliovirus receptor is a member of the immunoglobulin superfamily of proteins and consists of an NH2-terminal signal sequence, three extracellular Ig-like domains, a transmembrane domain, and a cytoplasmic tail. Sequence homologs of pvr have been identified in humans (nectin-1 and nectin-2), monkeys (agm1 and agm2), mice (nectin-1 and nectin-2), and rats (pE4). Only pvr, agm1 and agm2 encode proteins that can function as cell receptors for poliovirus. Pvr, Nectin-1, and Nectin-2 are entry cofactors for alphaherpesviruses. To understand the cell function of members of the Pvr family, we inactivated the nectin-2 gene in the mouse. Nectin-2 is a component of cell-cell adherens junctions, and interacts with afadin, an actin-binding protein. Disruption of both alleles of the murine nectin-2 gene resulted in morphologically aberrant spermatozoa with defects in nuclear and cytoskeletal morphology and mitochondrial localization. As a result, homozygous null males are sterile. The structural defects observed in spermatozoa of mice lacking Nectin-2 suggest a role for this protein in organization and reorganization of the cytoskeleton during spermiogenesis. The interaction of Pvr family members with the cytoskeleton might play a role in axonal transport of poliovirus in the infected animal.
Credentials & Experience
Honors & Awards
1983 Irma T. Hirschl Career Scientist Award 1984 Searle Scholars Award 1991 First Lamb Professor, Vanderbilt University 1991 Harvey Society Lecturer 1992 Eli Lilly Award, American Society for Microbiology 1993 NIH Merit Award 1993 Hilleman Lectureship, University of Chicago 1995 University Lecture, Columbia University 1996 Hilleman-Merck Lecturer, American Society for Virology Annual Meeting 2000 Fellow, American Academy of Microbiology
Research in this laboratory is aimed at understanding the molecular biology of replication and pathogenesis of picornaviruses. These RNA-containing viruses cause a variety of human diseases including paralysis (e.g. poliomyelitis), myocarditis, conjunctivitis, and the common cold. Our studies focus on the interaction of viruses with cell receptors, translation of the viral genome, and the molecular basis of viral pathogenesis.
MECHANISMS OF MUCOSAL TH17 CELL INDUCTION BY SEGMENTED FILAMENTOUS BACTERIA (Federal Gov)
Apr 15 2013 - Aug 31 2023
IDENTIFYING QUANTITATIVE TRAIT LOCI THAT REGULATE ENTEROVIRUS D68 PATHOGENESIS USING THE COLLABORATIVE CROSS (Federal Gov)
Feb 24 2020 - Jan 31 2022
ROLE OF ASTROCYTE INFECTION IN VIRAL NEUROVIRULENCE (Federal Gov)
Sep 10 2019 - Aug 31 2021
MECHANISM OF ZIKA VIRUS INDUCED CORTICOGENESIS DEFECTS (Federal Gov)
Jun 1 2018 - May 31 2020
CELLULAR RECEPTOR FOR ENTEROVIRUS D68 (Federal Gov)
Jan 1 2016 - Dec 31 2017
ANTAGONISM OF INNATE IMMUNITY BY PICORNAVIRUSES (Federal Gov)
May 1 2012 - Apr 30 2017
RHINOVIRUS PATHOGENESIS AND HOST RANGE (Federal Gov)
Feb 1 2002 - Jun 30 2013