Postdoctoral Position Available

Ronald Iorio, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Molecular Genetics and Microbiology

Other Affiliation(s):
   Program in Immunology and Virology

Viral pathogenesis and virulence; viral entry and the mechanism of virus-induced membrane fusion; viral glycoproteins and receptors

Paramyxoviruses are enveloped, negative-stranded RNA viruses, which include clinically important human pathogens such as measles, mumps, parainfluenza, and respiratory syncytial viruses; important animal pathogens, such as Newcastle disease (NDV), and Sendai viruses; and, emerging viruses such as Nipah and Hendra.  Though primarily respiratory pathogens, several members of the group are capable of causing central nervous system disease.  We are interested in understanding the molecular basis for the pathogenesis and virulence of this group of viruses.

Paramyxoviruses gain entry into the cell by mediating direct fusion of the virus and cell membranes.  Fusion involves a virus-specific interaction between the two viral surface glycoprotein spikes, the attachment protein and the fusion protein.  Mediated through this interaction, receptor binding by the attachment protein is thought to trigger a conformational change in the fusion protein from a metastable, pre-fusion form to a fusion-active form.  We are exploring various aspects of the fusion process for several paramyxoviruses.  We have developed a sensitive co-immunoprecipitation assay to detect the attachment-fusion protein complex at the cell surface and have identified mutations in several paramyxovirus attachment proteins that block fusion by modulating the interaction between the two surface glycoproteins.  Our evidence is consistent with the idea that the attachment protein - fusion protein interaction regulates fusion by a different mechanism in viruses such as NDV, which recognize the ubiquitous sugar sialic acid as receptor, and viruses such as measles, which recognize specific proteins as receptors.

NDV virulence involves contributions from at least three viral proteins.  The site of cleavage activation of the fusion protein is a major determinant of virulence.  However, recent evidence has revealed that the attachment protein also plays a role.  In addition, the V protein, produced by RNA editing from the P gene, is an interferon antagonist and thereby also plays a role in virulence.  We are interested in understanding the mechanisms by which all three proteins exert their effects on NDV virulence, as well as the basis for the differences in virulence observed among members of the NDV serotype.

Representative Publications

Corey, E. A., and R. M. Iorio.  (2009).  Measles virus attachment proteins with impaired ability to bind CD46 interact more efficiently with the homologous fusion protein. Virology 383: 1-5.

Mahon, P. J., A. M. Mirza, T. A. Musich, and R. M. Iorio.  (2008).  Engineered intermonomeric disulfide bonds in the globular domain of Newcastle disease virus hemagglutinin-neuraminidase protein: Implications for the mechanism of fusion promotion.  J. Virol. 82: 10386-10396.

Iorio, R. M., and P. J. Mahon.  (2008).  Paramyxoviruses: Different receptors - different mechanisms of fusion.  Trends in Microbiology 16: 135-137.

Corey, E. A., and R. M. Iorio (2007). Mutations in the stalk of the measles virus hemagglutinin protein decrease fusion but do not interfere with the interaction with the virus-specific interaction with the homologous fusion protein. J. Virol. 81:9900-9910.

Melanson, V.R. and R.M. Iorio. (2006). Addition of N-glycans in the stalk of the Newcastle disease virus HN protein blocks its interaction with the F protein and prevents fusion J. Virol. 80: 623-633.

Alamares, J.G., J. Li, and R.M. Iorio (2005) Monoconal antibody routinely used to identify avirulent strains of Newcastle disease virus binds to an epitope at the carboxy terminus of the hemagglutinin-neuraminidase protein and recognizes individual mesogenic and velogenic strains J. Clin. Micro 43: 4229-4233. 

Li, J., V. R. Melanson, A. M. Mirza, and R. M. Iorio.  (2005).  Decreased dependence on receptor recognition for the fusion promotion activity of L289A-mutated Newcastle disease virus fusion protein correlates with a monoclonal antibody-detected conformational change.  J. Virol. 79: 1180-1190.

Melanson, V. R., and R. M. Iorio.  (2004).  Amino acid substitutions in the F-specific domain in the stalk of the Newcastle disease virus HN protein modulate fusion and interfere with its interaction with the F protein. J. Virol. 78: 13053-13061.

Li, J., E. Quinlan, A. M. Mirza, and R. M. Iorio.  (2004).  Mutated form of the Newcastle disease virus hemagglutinin-neuraminidase interacts with the homologous fusion protein despite deficiencies in both receptor recognition and fusion promotion. J. Virol. 78: 5299-5310.

Rotation Projects

Rotation projects will involve construction of site-directed mutants or chimeras of either the attachment, fusion or V proteins and evaluation of their ability to promote the functions attributed to that protein. Depending on the target protein, the structure and function of each mutated or chimeric protein will be evaluated using several functional assays. These include flow cytometry (cell surface expression and antibody recognition), hemadsorption of red blood cells (receptor recognition activity), neuraminidase (receptor destroying activity), content mixing reporter gene assay (fusion), immunoprecipitation and SDS-PAGE (protein structure) and co-immunoprecipitation (determination of the ability of the mutated proteins to interact with a co-expressed protein). For the V protein, we will be evaluating various aspects of its interferon inhibitory activity.

Personnel

Postdoctoral Fellow:   Qiyun Zhu, Ph.D.
Technician:  Anne Mirza
Visiting Professor:  Paul Mahon, Ph.D.

Academic Background

Office: S5-210
Phone: 508-856-5257
Fax: 508-856-5920
E-mail: Ronald.Iorio@umassmed.edu
Keywords: Structural Biology, Biochemistry, Virology

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Postdoctoral Position Available A postdoctoral position is available to investigate the molecular mechanism of viral entry and fusion utilized by the attachment and fusion proteins of the paramyxoviruses, a group of negative-stranded RNA viruses which includes measles, mumps, Sendai, Newcastle disease and the parainfluenza viruses, as well as the emerging nipah and hendra viruses. The ideal candidate will be expected to have recently received a Ph.D. degree, be highly motivated and to have a strong background in virology and molecular biology.