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    Last Name

    Ricardo T Gazzinelli DSc, DVM

    InstitutionUniversity of Massachusetts Medical School
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program



        Ricardo Gazinelli

        Many parasites target antigens as well as mechanisms involving acquired immunity in host resistance to protozoan infections have been defined over the years. However, the same cannot be said about innate immune mechanisms involved in initial host resistance, initiation of immune responses and pathogenesis during infection with this class of pathogens. The lack of information in this area seems to be an important impediment for development of effective prophylactic as well as therapeutic immunologic-based protocols to prevent or treat these diseases. Therefore, the main scientific interests of my laboratory are: (i) to understand the role of innate immunity on host resistance and pathogenesis to infection with protozoan parasites; and (ii) to develop vaccines that induce cell-mediated immunity and protection against protozoan infections. When possible, we try to address our questions regarding host-parasite interactions, employing cellular systems, experimental rodent models and primary cells derived from well-characterized patients undergoing specific protozoan infection. My research program is developed at the Division of Infectious Diseases and Immunology, Department of Medicine, UMASS Medical School and at Oswaldo Cruz Foundation / Federal University of Minas Gerais, in Brazil.

        Innate Immunity

        Innate Immunity Image

        IFNgseems to be a primary cytokine involved in host resistance and infection with protozoan parasites. The early studies describing the counter-regulatory role of IL-10 and IL-12 were important to understand the induction of IFNg by Natural Killer cells as well as on differentiation of CD4+ T lymphocytes towards the Th1 phenotype during infection with protozoan parasites. These studies were also essential to understand induction/evasion of cell mediated immunity, and thus explain a major mechanism of susceptibility/resistance as well as pathogenesis of infection with distinct parasitic protozoa. Currently, we are very interestedin identifying cognate innate immune receptors for protozoan parasites and how they participate in the induction phase of cell mediated immunity and development of protective acquired immunity against this class of pathogens. We hope that these studies will contribute with a more rational design of effective vaccines against protozoan parasites, and new strategies to interfere with hypo-responsiveness (may favor parasite growth) or hyper-responsiveness (may be deleterious to the host), immunological status that are often associated with pathogenesis and lethality observed during protozoan infections. Below I provide a short summary of the research performed in my laboratory, which employ different protozoan parasites.

        Chagas Disease Image

        Chagas Disease- We have characterized the structure and function protozoan-derived glycosylphosphatidylinositol anchors (GPIs) as well as genomic unmethylated CpG motifs derived from T. cruziparasites, which possess potent pro-inflammatory activities. We have also defined Toll-Like Receptors 2 and 9 as the host counterpart receptors for GPIs and CpG motifs both in mouse and human systems. In addition, we demonstrated the role of MyD88, TLR2 and TLR9 in early pro-inflammatory response and host resistance to infection with T. cruzi in mice and potential implications on immunopathology of Chagas' disease in humans are being considered. Questions regarding the involvement of TLRs and other innate immune receptors on pathogenesis of Chagas disease, the mechanisms of induction of cell mediated immunity as well as the use of T. cruzi derived agonists as vaccine adjuvants are currently being approached in my lab.

        Malaria Image

        Malaria- We have also investigated the role of different TLRs and MyD88 in host resistance to infection and malaria pathogenesis. Together, our findings suggest that MyD88 and possibly its associated TLRs expressed by dendritic cells play an important role in pro-inflammatory responses, T cell activation, and pathogenesis of malaria, but are not critical for the immunological control of the erythrocytic stage of P. chabaudi. By in silico analysis and in vitro assays, we have defined CpG as well as AT rich motifs that activate human TLR9 and a new category of cytoplasmatic receptors. We have also shown that TLR responses are boosted in febrile patients during natural infection with P. falciparum. Microarray analyses demonstrated that an extraordinary percentage of the up-regulated genes, including genes of TLR signaling pathway, had sites for IFN-inducible transcription factors. Consistently, acutely infected wild-type mice were highly susceptible to LPS-induced lethality while TLR9-/-, and to a greater extent,IFNg -/- mice were protected. Our data provide unprecedented evidence that TLR9 and MyD88 are essential to initiate IFNγ responses and favor host hyper-responsiveness to TLR agonists resulting in overproduction of pro-inflammatory cytokines and the sepsis-like symptoms of acute malaria. We are currently trying to map the array of innate immune receptors and signaling pathways involved on early pro-inflammatory responses and sepsis symptoms/signs observed during P. falciparum malaria.

        Toxoplasmosis Image

        Toxoplasmosis – MyD88 has also been shown critical in eliciting IL-12/IFNg production and host resistance to infection with T. gondii. However, none of the single TLR deficient mice seem to recapitulate the susceptibility of MyD88-/- mice to infection with this parasite. Our main goal is to establish what receptor(s) are responsible for MyD88 dependent activity during T. gondiiinfection. In parallel we are studying the innate immune responses to patients with asymptomatic and ocular toxoplasmosis. We have currently shown that human TLR2 / TLR4 and TLR9 are responsive to T. gondii derived GPI anchors as well as unmethylated CpG motifs, respectively. Further, the presence of specific gene variants (polymorphisms) associated with outcome of acquired immune responses and ocular disease are under evaluation.

        Vaccine Development

        In regard to vaccine development two main issues have been investigated in my lab: (i) the question of appropriate antigen delivery and (ii) the use of specific TLR agonists as vaccine adjuvants to induce a strong cell-mediated immunity, including CD8+ T cell responses. For the first question, we have engineered protective antigens from T. cruzi (ASP and TS); T. gondii (SAG1, SAG2 and SAG3); and Leishmania sp. (A2) into different viral vectors, i.e. adenovirus, MVA and influenza. In addition, these same antigens are being tested in association with well defined TLR agonists. The different protocols are being tested in the rodent model, as well as in primates and dogs in the case of leishmaniasis. The involvement of different components of innate as well as acquired immunity are being defined in various knockout mice that receive vaccination protocols that are effective protecting wild type controls against experimental challenges. Finally, GPI anchors and CpG motifs derived from T. cruzi are being tested as potential novel immunological adjuvants in vaccine formulations.

        Financial Support: My current research is supported by Conselho Nacional de Desenvolvimento Cinetifico e Tecnologico-CNPq, Fundacao de Amparo a Pesquisa do Estado de Minas Gerais-FAPEMIG, the National Institutes of Health-NIH and the Atlantic Philanthropies / Ludwig Institute for Cancer Research.

        selected publications
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        1. Dotiwala F, Mulik S, Polidoro RB, Ansara JA, Burleigh BA, Walch M, Gazzinelli RT, Lieberman J. Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites. Nat Med. 2016 Feb; 22(2):210-6.
          View in: PubMed
        2. Rocha BC, Marques PE, Leoratti FM, Junqueira C, Pereira DB, Antonelli LR, Menezes GB, Golenbock DT, Gazzinelli RT. Type I Interferon Transcriptional Signature in Neutrophils and Low-Density Granulocytes Are Associated with Tissue Damage in Malaria. Cell Rep. 2015 Dec 29; 13(12):2829-41.
          View in: PubMed
        3. Hirako IC, Gallego-Marin C, Ataide MA, Andrade WA, Gravina H, Rocha BC, de Oliveira RB, Pereira DB, Vinetz J, Diamond B, Ram S, Golenbock DT, Gazzinelli RT. DNA-Containing Immunocomplexes Promote Inflammasome Assembly and Release of Pyrogenic Cytokines by CD14+ CD16+ CD64high CD32low Inflammatory Monocytes from Malaria Patients. MBio. 2015; 6(6):e01605-15.
          View in: PubMed
        4. Pereira IR, Vilar-Pereira G, Marques V, da Silva AA, Caetano B, Moreira OC, Machado AV, Bruna-Romero O, Rodrigues MM, Gazzinelli RT, Lannes-Vieira J. A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy. PLoS Pathog. 2015 Jan; 11(1):e1004594.
          View in: PubMed
        5. Gazzinelli RT, Kalantari P, Fitzgerald KA, Golenbock DT. Innate sensing of malaria parasites. Nat Rev Immunol. 2014 Nov; 14(11):744-57.
          View in: PubMed
        6. Antonelli LR, Leoratti FM, Costa PA, Rocha BC, Diniz SQ, Tada MS, Pereira DB, Teixeira-Carvalho A, Golenbock DT, Gonçalves R, Gazzinelli RT. The CD14+CD16+ inflammatory monocyte subset displays increased mitochondrial activity and effector function during acute Plasmodium vivax malaria. PLoS Pathog. 2014 Sep; 10(9):e1004393.
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        7. Grimaldi G, Teva A, Porrozzi R, Pinto MA, Marchevsky RS, Rocha MG, Dutra MS, Bruña-Romero O, Fernandes AP, Gazzinelli RT. Clinical and parasitological protection in a Leishmania infantum-macaque model vaccinated with adenovirus and the recombinant A2 antigen. PLoS Negl Trop Dis. 2014 Jun; 8(6):e2853.
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        8. Gazzinelli RT, Mendonça-Neto R, Lilue J, Howard J, Sher A. Innate resistance against Toxoplasma gondii: an evolutionary tale of mice, cats, and men. Cell Host Microbe. 2014 Feb 12; 15(2):132-8.
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        9. Ataide MA, Andrade WA, Zamboni DS, Wang D, Souza Mdo C, Franklin BS, Elian S, Martins FS, Pereira D, Reed G, Fitzgerald KA, Golenbock DT, Gazzinelli RT. Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog. 2014 Jan; 10(1):e1003885.
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        10. Andrade WA, Souza Mdo C, Ramos-Martinez E, Nagpal K, Dutra MS, Melo MB, Bartholomeu DC, Ghosh S, Golenbock DT, Gazzinelli RT. Combined action of nucleic acid-sensing Toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to Toxoplasma gondii in mice. Cell Host Microbe. 2013 Jan 16; 13(1):42-53.
          View in: PubMed
        11. Fernandes AP, Coelho EA, Machado-Coelho GL, Grimaldi G, Gazzinelli RT. Making an anti-amastigote vaccine for visceral leishmaniasis: rational, update and perspectives. Curr Opin Microbiol. 2012 Aug; 15(4):476-85.
          View in: PubMed
        12. Junqueira C, Santos LI, Galvão-Filho B, Teixeira SM, Rodrigues FG, DaRocha WD, Chiari E, Jungbluth AA, Ritter G, Gnjatic S, Old LJ, Gazzinelli RT. Trypanosoma cruzi as an effective cancer antigen delivery vector. Proc Natl Acad Sci U S A. 2011 Dec 6; 108(49):19695-700.
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        13. Caetano BC, Carmo BB, Melo MB, Cerny A, dos Santos SL, Bartholomeu DC, Golenbock DT, Gazzinelli RT. Requirement of UNC93B1 reveals a critical role for TLR7 in host resistance to primary infection with Trypanosoma cruzi. J Immunol. 2011 Aug 15; 187(4):1903-11.
          View in: PubMed
        14. Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, Rose J, Zheng W, Ataíde MA, de Oliveira RB, Golenbock DT, Gazzinelli RT. Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. Proc Natl Acad Sci U S A. 2011 Mar 1; 108(9):3689-94.
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        15. Junqueira C, Caetano B, Bartholomeu DC, Melo MB, Ropert C, Rodrigues MM, Gazzinelli RT. The endless race between Trypanosoma cruzi and host immunity: lessons for and beyond Chagas disease. Expert Rev Mol Med. 2010; 12:e29.
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        16. Franklin BS, Parroche P, Ataíde MA, Lauw F, Ropert C, de Oliveira RB, Pereira D, Tada MS, Nogueira P, da Silva LH, Bjorkbacka H, Golenbock DT, Gazzinelli RT. Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function. Proc Natl Acad Sci U S A. 2009 Apr 7; 106(14):5789-94.
          View in: PubMed
        17. Fernandes AP, Costa MM, Coelho EA, Michalick MS, de Freitas E, Melo MN, Luiz Tafuri W, Resende Dde M, Hermont V, Abrantes Cde F, Gazzinelli RT. Protective immunity against challenge with Leishmania (Leishmania) chagasi in beagle dogs vaccinated with recombinant A2 protein. Vaccine. 2008 Oct 29; 26(46):5888-95.
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        18. Parroche P, Lauw FN, Goutagny N, Latz E, Monks BG, Visintin A, Halmen KA, Lamphier M, Olivier M, Bartholomeu DC, Gazzinelli RT, Golenbock DT. Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proc Natl Acad Sci U S A. 2007 Feb 6; 104(6):1919-24.
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        19. Gazzinelli RT, Denkers EY. Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism. Nat Rev Immunol. 2006 Dec; 6(12):895-906.
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        20. Campos MA, Closel M, Valente EP, Cardoso JE, Akira S, Alvarez-Leite JI, Ropert C, Gazzinelli RT. Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J Immunol. 2004 Feb 1; 172(3):1711-8.
          View in: PubMed
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