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Simas, Pedro
Lab

Herpesvirus Pathogenesis

The overall aim of the Viral Pathogenesis Lab is to gain an understanding of the basic molecular mechanisms involved in the modulation of cellular function by herpesviruses. Herpesviruses are a major cause of disease worldwide and are amongst the most successful human pathogens, with specific viruses infecting more than 90% of the world's population. The main biological feature of these viruses is their ability to persist and reactivate in a primed immunocompetent host.

The control of herpesviruses infections thus represents an important clinical goal. To achieve this we must first understand the basic mechanisms of viral pathogenesis. We use a laboratory animal model of infection with murine gamma-herpesvirus-68 (MHV-68), which establishes latent infection in B-lymphocytes. The ability to genetically manipulate both the virus and the host allows the dissection of the molecular mechanisms involved in the virus/host interaction.

We have recently identified viral proteins that are essential for the effective establishment of latent infection. One of these, M2, functions as an adaptor protein that assembles a signalosome with cellular proteins involved in the activation and differentiation of B lymphocytes, and which we have shown to be essential for the establishment of latent infection.

  • Research Areas

    • Viral Pathogenesis
  • Research Team

    • Ongoing Research Projects

      • 2016/2019  Chimera virus model to investigate the pathogenesis of Kaposi´s sarcoma associated herpesvirus in laboratory mice PTDC/IMI-MIC/0980/2014
      • 2015 Breakthrough Idea Grant, IMM Director´s Fund​
      • 2011/2014 Pathogenesis of Kaposi's sarcoma herpesvirus LANA (Harvard Medical School - Portugal Program; HMSP-ICT/0021/2010)
    • Prizes

    • Selected Publications

      • Fontinha D, Lopes FB, Marques S, Simas JP. Murid Gammaherpesvirus Latency-Associated Protein M2 Promotes the Formation of Conjugates between Transformed B Lymphoma Cells and T Helper Cells. PLoS ONE. 2015 Nov 6; 10(11): e0142540. doi:10.1371/journal.pone.0142540
      • Ponnusamy R, Petoukhov MV, Correia B, Custodio TF, Juillard F, Tan M, Pires de Miranda M, Carrondo MA, Simas JP, Kaye KM, Svergun DI, McVey CE. KSHV but not MHV-68 LANA induces a strong bend upon binding to terminal repeat viral DNA. Nucleic Acids Res. 2015 Sep 30. pii: gkv987. [Epub ahead of print].
      • Li S, Tan M, Juillard F, Ponnusamy R, Correia B, Simas JP, Carrondo MA, McVey CE, Kaye KM. The Kaposi's sarcoma herpesvirus latency-associated nuclear antigen DNA binding domain dorsal positive electrostatic patch facilitates DNA replication and episome persistence. J Biol Chem. 2015 Sep 29. pii: jbc.M115.674622. [Epub ahead of print]
      • Orge L, Machado CG, Ramalho L, Carvalho R, Silva J, Almeida P, Tavares P, Ochoa C, Lima C, Pinto MJ, Simas JP. Identification of H-type BSE in Portugal. Prion. 2015;9(1):22-8.
      • Decalf J, Godinho-Silva C, Fontinha D, Marques S, Simas JP. Establishment of murine gammaherpesvirus latency in B cells is not a stochastic event. PLoS Pathog. 2014 Jul 31;10(7):e1004269.
      • Godinho-Silva C, Marques S, Fontinha D, Veiga-Fernandes H, Stevenson PG, Simas JP.Defining immune engagement thresholds for in vivo control of virus-driven lymphoproliferation. PLoS Pathog. 2014 Jun 26;10(6):e1004220.
      • van de Pavert SA, Ferreira M, Domingues RG, Ribeiro H, Molenaar R, Moreira-Santos L, Almeida FF, Ibiza S, Barbosa I, Goverse G, Labão-Almeida C, Godinho-Silva C, Konijn T, Schooneman D, O'Toole T, Mizee MR, Habani Y, Haak E, Santori FR, Littman DR, Schulte-Merker S, Dzierzak E, Simas JP, Mebius RE, Veiga-Fernandes H. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature. 2014 Apr 3;508(7494):123-7
      • Figueiredo N, Chora A, Raquel H, Pejanovic N, Pereira P, Hartleben B, Neves-Costa A, Moita C, Pedroso D, Pinto A, Marques S, Faridi H, Costa P, Gozzelino R, Zhao JL, Soares MP, Gama-Carvalho M, Martinez J, Zhang Q, Döring G, Grompe M, Simas JP, Huber TB, Baltimore D, Gupta V, Green DR, Ferreira JA, Moita LF. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity. 2013 Nov 14;39(5):874-84.​
      • Correia B, Cerqueira SA, Beauchemin C, Pires de Miranda M, Li S, Ponnusamy R, Rodrigues L, Schneider TR, Carrondo MA, Kaye KM, Simas JP, McVey CE. Crystal structure of the gamma-2 herpesvirus LANA DNA binding domain identifies charged surface residues which impact viral latency. PLoS Pathog. 2013;9(10):e1003673. Epub 2013 Oct 17.
      • Rodrigues L, Popov N, Kaye KM, Simas JP. Stabilization of Myc through heterotypic poly-ubiquitination by mLANA is critical for gamma-herpesvirus lymphoproliferation. PLoS Pathog. 2013;9(8):e1003554. Epub 2013 Aug 8.
      • Pires de Miranda M, Lopes FB, McVey CE, Bustelo XR, Simas JP. Role of Src homology domain binding in signaling complexes assembled by the murid gamma-herpesvirus M2 protein. J Biol Chem. 2013;288(6):3858-70. Epub 2012 Dec 20.
      • Habison AC, Beauchemin C, Simas JP, Usherwood EJ, Kaye KM. Murine gammaherpesvirus 68 LANA acts on terminal repeat DNA to mediate episome persistence. J Virol. 2012;86(21):11863-76. Epub 2012 Aug 22.
      • Sehrawat S, Kirak O, Koenig PA, Isaacson MK, Marques S, Bozkurt G, Simas JP, Jaenisch R, Ploegh HL. CD8(+) T cells from mice transnuclear for a TCR that recognizes a single H-2K(b)-restricted MHV68 epitope derived from gB-ORF8 help control infection. Cell Rep. 2012;1(5):461-71. Epub 2012 Apr 26.
      • Stevenson PG, Simas JP, Efstathiou S. Immune control of mammalian gamma-herpesviruses: lessons from murid herpesvirus-4. J Gen Virol. 2009 Oct;90(Pt 10):2317-30. Epub 2009 Jul 15. Review.
      • Rodrigues L, Filipe J, Seldon MP, Fonseca L, Anrather J, Soares MP, Simas JP. Termination of NF-kappaB activity through a gammaherpesvirus protein that assembles an EC5S ubiquitin-ligase. EMBO J. 2009 May 6;28(9):1283-95. Epub 2009 Mar 26.
      • Milho R, Smith CM, Marques S, Alenquer M, May JS, Gillet L, Gaspar M, Efstathiou S, Simas JP, Stevenson PG. In vivo imaging of murid herpesvirus-4 infection. J Gen Virol. 2009 Jan;90(Pt 1):21-32.
      • Marques S, Alenquer M, Stevenson PG, Simas JP. A single CD8+ T cell epitope sets the long-term latent load of a murid herpesvirus. PLoS Pathog. 2008 Oct;4(10):e1000177. Epub 2008 Oct 10.
      • Pires de Miranda M, Alenquer M, Marques S, Rodrigues L, Lopes F, Bustelo XR, Simas JP. The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly. PLoS One. 2008 Feb 27;3(2):e1654.
      • Rodrigues L, Pires de Miranda M, Caloca MJ, Bustelo XR, Simas JP. Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes. J Virol. 2006 Jun;80(12):6123-35.
      • Simas JP, Marques S, Bridgeman A, Efstathiou S, Adler H. The M2 gene product of murine gammaherpesvirus 68 is required for efficient colonization of splenic follicles but is not necessary for expansion of latently infected germinal centre B cells. J Gen Virol. 2004 Oct;85(Pt 10):2789-97.
      • Marques S, Efstathiou S, Smith KG, Haury M, Simas JP. Selective gene expression of latent murine gammaherpesvirus 68 in B lymphocytes. J Virol. 2003 Jul;77(13):7308-18.

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