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    Ronald M Iorio PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-5257
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

        Overview 
        Narrative

        Academic Background

        BA, University of Massachusetts
        MS, PhD, Boston College

        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.



        Rotation Projects

        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.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Mirza AM, Iorio RM. A Mutation in the Stalk of the Newcastle Disease Virus Hemagglutinin-Neuraminidase (HN) Protein Prevents Triggering of the F Protein despite Allowing Efficient HN-F Complex Formation. J Virol. 2013 Aug; 87(15):8813-5.
          View in: PubMed
        2. Zhu Q, Biering SB, Mirza AM, Grasseschi BA, Mahon PJ, Lee B, Aguilar HC, Iorio RM. Individual N-Glycans Added at Intervals along the Stalk of the Nipah Virus G Protein Prevent Fusion but Do Not Block the Interaction with the Homologous F Protein. J Virol. 2013 Mar; 87(6):3119-29.
          View in: PubMed
        3. Wei Y, Feng K, Yao X, Cai H, Li J, Mirza AM, Iorio RM, Li J. Localization of a region in the fusion protein of avian metapneumovirus that modulates cell-cell fusion. J Virol. 2012 Nov; 86(21):11800-14.
          View in: PubMed
        4. Aguilar HC, Iorio RM. Henipavirus membrane fusion and viral entry. Curr Top Microbiol Immunol. 2012; 359:79-94.
          View in: PubMed
        5. Mahon PJ, Mirza AM, Iorio RM. Role of the Two Sialic Acid Binding Sites on the Newcastle Disease Virus HN Protein in Triggering the Interaction with the F Protein Required for the Promotion of Fusion. J Virol. 2011 Nov; 85(22):12079-82.
          View in: PubMed
        6. Plemper RK, Brindley MA, Iorio RM. Structural and mechanistic studies of measles virus illuminate paramyxovirus entry. PLoS Pathog. 2011 Jun; 7(6):e1002058.
          View in: PubMed
        7. Mirza AM, Aguilar HC, Zhu Q, Mahon PJ, Rota PA, Lee B, Iorio RM. Triggering of the newcastle disease virus fusion protein by a chimeric attachment protein that binds to nipah virus receptors. J Biol Chem. 2011 May 20; 286(20):17851-60.
          View in: PubMed
        8. Alamares JG, Elankumaran S, Samal SK, Iorio RM. The interferon antagonistic activities of the V proteins from two strains of Newcastle disease virus correlate with their known virulence properties. Virus Res. 2010 Jan; 147(1):153-7.
          View in: PubMed
        9. Corey EA, Iorio RM. Measles virus attachment proteins with impaired ability to bind CD46 interact more efficiently with the homologous fusion protein. Virology. 2009 Jan 5; 383(1):1-5.
          View in: PubMed
        10. Mahon PJ, Mirza AM, Musich TA, Iorio RM. Engineered intermonomeric disulfide bonds in the globular domain of Newcastle disease virus hemagglutinin-neuraminidase protein: implications for the mechanism of fusion promotion. J Virol. 2008 Nov; 82(21):10386-96.
          View in: PubMed
        11. Iorio RM, Mahon PJ. Paramyxoviruses: different receptors - different mechanisms of fusion. Trends Microbiol. 2008 Apr; 16(4):135-7.
          View in: PubMed
        12. Corey EA, Iorio RM. Mutations in the stalk of the measles virus hemagglutinin protein decrease fusion but do not interfere with virus-specific interaction with the homologous fusion protein. J Virol. 2007 Sep; 81(18):9900-10.
          View in: PubMed
        13. Melanson VR, Iorio RM. 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. 2006 Jan; 80(2):623-33.
          View in: PubMed
        14. Alamares JG, Li J, Iorio RM. Monoclonal 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 Microbiol. 2005 Aug; 43(8):4229-33.
          View in: PubMed
        15. Li J, Melanson VR, Mirza AM, Iorio RM. 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. 2005 Jan; 79(2):1180-90.
          View in: PubMed
        16. Melanson VR, Iorio RM. 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. 2004 Dec; 78(23):13053-61.
          View in: PubMed
        17. Li J, Quinlan E, Mirza A, Iorio RM. 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. 2004 May; 78(10):5299-310.
          View in: PubMed
        18. Wang Z, Mirza AM, Li J, Mahon PJ, Iorio RM. An oligosaccharide at the C-terminus of the F-specific domain in the stalk of the human parainfluenza virus 3 hemagglutinin-neuraminidase modulates fusion. Virus Res. 2004 Feb; 99(2):177-85.
          View in: PubMed
        19. Corey EA, Mirza AM, Levandowsky E, Iorio RM. Fusion deficiency induced by mutations at the dimer interface in the Newcastle disease virus hemagglutinin-neuraminidase is due to a temperature-dependent defect in receptor binding. J Virol. 2003 Jun; 77(12):6913-22.
          View in: PubMed
        20. Iorio RM, Field GM, Sauvron JM, Mirza AM, Deng R, Mahon PJ, Langedijk JP. Structural and functional relationship between the receptor recognition and neuraminidase activities of the Newcastle disease virus hemagglutinin-neuraminidase protein: receptor recognition is dependent on neuraminidase activity. J Virol. 2001 Feb; 75(4):1918-27.
          View in: PubMed
        21. Wang Z, Iorio RM. Amino acid substitutions in a conserved region in the stalk of the Newcastle disease virus HN glycoprotein spike impair its neuraminidase activity in the globular domain. J Gen Virol. 1999 Mar; 80 ( Pt 3):749-53.
          View in: PubMed
        22. Deng R, Wang Z, Mahon PJ, Marinello M, Mirza A, Iorio RM. Mutations in the Newcastle disease virus hemagglutinin-neuraminidase protein that interfere with its ability to interact with the homologous F protein in the promotion of fusion. Virology. 1999 Jan 5; 253(1):43-54.
          View in: PubMed
        23. Deng R, Mirza AM, Mahon PJ, Iorio RM. Functional chimeric HN glycoproteins derived from Newcastle disease virus and human parainfluenza virus-3. Arch Virol Suppl. 1997; 13:115-30.
          View in: PubMed
        24. Mahon PJ, Deng R, Mirza AM, Iorio RM. Cooperative neuraminidase activity in a paramyxovirus. Virology. 1995 Oct 20; 213(1):241-4.
          View in: PubMed
        25. Deng R, Wang Z, Mirza AM, Iorio RM. Localization of a domain on the paramyxovirus attachment protein required for the promotion of cellular fusion by its homologous fusion protein spike. Virology. 1995 Jun 1; 209(2):457-69.
          View in: PubMed
        26. Deng R, Wang Z, Glickman RL, Iorio RM. Glycosylation within an antigenic site on the HN glycoprotein of Newcastle disease virus interferes with its role in the promotion of membrane fusion. Virology. 1994 Oct; 204(1):17-26.
          View in: PubMed
        27. Mirza AM, Deng R, Iorio RM. Site-directed mutagenesis of a conserved hexapeptide in the paramyxovirus hemagglutinin-neuraminidase glycoprotein: effects on antigenic structure and function. J Virol. 1994 Aug; 68(8):5093-9.
          View in: PubMed
        28. Mirza AM, Sheehan JP, Hardy LW, Glickman RL, Iorio RM. Structure and function of a membrane anchor-less form of the hemagglutinin-neuraminidase glycoprotein of Newcastle disease virus. J Biol Chem. 1993 Oct 5; 268(28):21425-31.
          View in: PubMed
        29. Iorio RM, Glickman RL. Fusion mutants of Newcastle disease virus selected with monoclonal antibodies to the hemagglutinin-neuraminidase. J Virol. 1992 Nov; 66(11):6626-33.
          View in: PubMed
        30. Sheehan JP, Iorio RM. A single amino acid substitution in the hemagglutinin-neuraminidase of Newcastle disease virus results in a protein deficient in both functions. Virology. 1992 Aug; 189(2):778-81.
          View in: PubMed
        31. Iorio RM, Glickman RL, Sheehan JP. Inhibition of fusion by neutralizing monoclonal antibodies to the haemagglutinin-neuraminidase glycoprotein of Newcastle disease virus. J Gen Virol. 1992 May; 73 ( Pt 5):1167-76.
          View in: PubMed
        32. Iorio RM, Syddall RJ, Sheehan JP, Bratt MA, Glickman RL, Riel AM. Neutralization map of the hemagglutinin-neuraminidase glycoprotein of Newcastle disease virus: domains recognized by monoclonal antibodies that prevent receptor recognition. J Virol. 1991 Sep; 65(9):4999-5006.
          View in: PubMed
        33. Iorio RM, Syddall RJ, Glickman RL, Riel AM, Sheehan JP, Bratt MA. Identification of amino acid residues important to the neuraminidase activity of the HN glycoprotein of Newcastle disease virus. Virology. 1989 Nov; 173(1):196-204.
          View in: PubMed
        34. Iorio RM, Glickman RL, Riel AM, Sheehan JP, Bratt MA. Functional and neutralization profile of seven overlapping antigenic sites on the HN glycoprotein of Newcastle disease virus: monoclonal antibodies to some sites prevent viral attachment. Virus Res. 1989 Jul; 13(3):245-61.
          View in: PubMed
        35. Iorio RM. Mechanisms of neutralization of animal viruses: monoclonal antibodies provide a new perspective. Microb Pathog. 1988 Jul; 5(1):1-7.
          View in: PubMed
        36. Glickman RL, Syddall RJ, Iorio RM, Sheehan JP, Bratt MA. Quantitative basic residue requirements in the cleavage-activation site of the fusion glycoprotein as a determinant of virulence for Newcastle disease virus. J Virol. 1988 Jan; 62(1):354-6.
          View in: PubMed
        37. Sheehan JP, Iorio RM, Syddall RJ, Glickman RL, Bratt MA. Reducing agent-sensitive dimerization of the hemagglutinin-neuraminidase glycoprotein of Newcastle disease virus correlates with the presence of cysteine at residue 123. Virology. 1987 Dec; 161(2):603-6.
          View in: PubMed
        38. Iorio RM, Borgman JB, Glickman RL, Bratt MA. Genetic variation within a neutralizing domain on the haemagglutinin-neuraminidase glycoprotein of Newcastle disease virus. J Gen Virol. 1986 Jul; 67 ( Pt 7):1393-403.
          View in: PubMed
        39. Iorio RM, Bratt MA. Selection of unique antigenic variants of Newcastle disease virus with neutralizing monoclonal antibodies and anti-immunoglobulin. Proc Natl Acad Sci U S A. 1985 Oct; 82(20):7106-10.
          View in: PubMed
        40. Iorio RM, Lawton KA, Nicholson PM, Bratt MA. Monoclonal antibodies identify a strain-specific epitope on the HN glycoprotein of Newcastle disease virus strain Australia-Victoria. Virus Res. 1984 Oct; 1(7):513-25.
          View in: PubMed
        41. Iorio RM, Bratt MA. Monoclonal antibodies as functional probes of the HN glycoprotein of Newcastle disease virus: antigenic separation of the hemagglutinating and neuraminidase sites. J Immunol. 1984 Oct; 133(4):2215-9.
          View in: PubMed
        42. Iorio RM, Bratt MA. Neutralization of Newcastle disease virus by monoclonal antibodies to the hemagglutinin-neuraminidase glycoprotein: requirement for antibodies to four sites for complete neutralization. J Virol. 1984 Aug; 51(2):445-51.
          View in: PubMed
        43. Iorio RM, Bratt MA. Monoclonal antibodies to newcastle disease virus: delineation of four epitopes on the HN glycoprotein. J Virol. 1983 Nov; 48(2):440-50.
          View in: PubMed
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