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The inflammasome in the host response against intracellular pathogens and the microbial mechanisms for its evasion

Grant number: 14/04684-4
Support Opportunities:Research Projects - Thematic Grants
Duration: September 01, 2014 - February 29, 2020
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Dario Simões Zamboni
Grantee:Dario Simões Zamboni
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated researchers:Djalma de Souza Lima Júnior ; Juliana Issa Hori ; Larissa Dias da Cunha
Associated grant(s):18/04194-8 - Multi-user equipment aproved in grant 2014/04684-4: Odyssey CLX - immunoassay scanner, AP.EMU
14/17660-6 - Multiuser equipment approved in grant 14/04684-4: SpectraMax® i3 multi-mode platform and SpectraMax MiniMax, AP.EMU
Associated scholarship(s):19/21420-4 - Determination of the cell death role in leukocyte recruitment and control of Legionella pneumophila infection, BP.PD
19/21978-5 - Role of STING signaling pathway in recognizing and controling Leishmania spp infection, BP.DR
19/18568-0 - The inflammasome in the host response to intracellular pathogens and the microbial mechanisms for its evasion, BP.TT
+ associated scholarships 18/16777-8 - The role of gasdermin-D in the activation of inflammasome in response to Leishmania (L.) amazonensis infection, BP.DR
18/18726-1 - The inflammasome in the host response to intracellular pathogens and the microbial mechanisms for its evasion, BP.TT
17/20687-1 - Evaluation of the AIM2 role in the innate immune response against Leishmania amazonensis, BP.DR
17/04242-0 - Identification of new molecules in macrophages involved in inflammasome activation in response to intracellular pathogens, BP.DD
17/04243-6 - Investigation of the role of amastins in the inflammasome activation and in the translocation of Leishmania molecules into the macrophage cytoplasm, BP.MS
16/24275-7 - Identification of Coxiella burnetii proteins involved in the modulation of the inflammasome activasion and in the intracellular signaling pathways in macrophages, BP.DD
16/01794-9 - Investigation of the role of rapamicyn in restriction of Leishmania amazonensis replication in macrophages and in vivo., BP.MS
16/00494-1 - Autophagy induction by Leishmania sp via innate immune receptors, BP.PD
15/25404-2 - Role of the Leishmania RNA virus (LRV1-4) present in Leishmania guyanensis M4147 strain in the modulation of the innate immune response, BP.DD
15/24640-4 - Identification of proteins involved in the assembly and activation of the NLRC4 inflammasome in response to Leishmania (L) amazonensis infection, BP.PD
15/10378-6 - The role of inflammasome in the control and pathogenesis of leishmaniasis caused by Leishmania amazonensis and its relation with disease severity in resistant or susceptible hosts, BP.DR - associated scholarships


Coxiella burnetii, Legionella pneumophila and Leishmania are intracellular pathogenic microbes that are etiological agents of important infections in humans. These microbes survive and replicate in macrophages and monocytes, within modified vacuoles showing lysosomal characteristics. Therefore, these pathogens are highly adapted to subvert host cell functions to facilitate intracellular replication. The mechanisms underlying microbial detection by the innate immune system and subversion are still largely unknown. We have previously found that the inflammasome is activated in response to Leishmania spp and L. pneumophila, but is not activated in the C. burnetii-infected macrophages in a process actively modulated by the bacteria (unpublished data). We have also generated preliminary data indicating that inhibition of the inflammasome activation is mediated by a C. burnetii effector protein that we named IcaA (Inhibition of Caspase Activation). In the current research proposal, we aim to investigate, characterize and determine the molecular mechanisms by which the inflammasome is activated in response to these pathogens as well as the mechanisms by which IcaA inhibits the inflammasome activation. Finally, we aim to develop and optimize an experimental model of C. burnetii infection in primary mouse alveolar macrophages to evaluate the importance of innate immune components (including those dependent on inflammasomes) in the restriction of microbial replication of in macrophages. The results generated may significantly contribute to our understanding of the biology and host response against these pathogenic microbes. Moreover, the identification of novel biological molecules that target the inflammasome may generate important information for a putative therapy for inflammasome-driven diseases such as Gout, type 2 diabetes and Alzheimer's. (AU)

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Scientific publications (22)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MASCARENHAS, DANIELLE P. A.; ZAMBONI, DARIO S.. Inflammasome biology taught by Legionella pneumophila. Journal of Leukocyte Biology, v. 101, n. 4, p. 841-849, . (14/50268-2, 13/08216-2, 14/04684-4, 14/00794-0)
MASCARENHAS, DANIELLE P. A.; PEREIRA, MARCELO S. F.; MANIN, GRAZIELE Z.; HORI, JULIANA I.; ZAMBONI, DARIO S.. Interleukin 1 Receptor-Driven Neutrophil Recruitment Accounts to MyD88-Dependent Pulmonary Clearance of Legionella pneumophila Infection In Vivo. Journal of Infectious Diseases, v. 211, n. 2, p. 322-330, . (13/08216-2, 14/04684-4, 12/09363-6)
CERQUEIRA, DAIANE M.; PEREIRA, MARCELO S. F.; SILVA, ALEXANDRE L. N.; CUNHA, LARISSA D.; ZAMBONI, DARIO S.. Caspase-1 but Not Caspase-11 Is Required for NLRC4-Mediated Pyroptosis and Restriction of Infection by Flagellated Legionella Species in Mouse Macrophages and In Vivo. JOURNAL OF IMMUNOLOGY, v. 195, n. 5, p. 2303-2311, . (12/14456-3, 11/22617-4, 13/08216-2, 14/04684-4, 12/15932-3, 12/16941-6)
FERNANDES, TALITA D.; CUNHA, LARISSA D.; RIBEIRO, JULIANA M.; MASSIS, LILIANA M.; LIMA-JUNIOR, DJALMA S.; NEWTON, HAYLEY J.; ZAMBONI, DARIO S.. Murine Alveolar Macrophages Are Highly Susceptible to Replication of Coxiella burnetii Phase II In Vitro. Infection and Immunity, v. 84, n. 9, p. 2439-2448, . (14/50268-2, 13/08216-2, 14/04684-4)
ZOCCAL, KARINA F.; SORGI, CARLOS A.; HORI, JULIANA I.; PAULA-SILVA, FRANCISCO W. G.; ARANTES, ELIANE C.; SEREZANI, CARLOS H.; ZAMBONI, DARIO S.; FACCIOLI, LUCIA H.. Opposing roles of LTB4 and PGE(2) in regulating the inflammasome-dependent scorpion venom-induced mortality. NATURE COMMUNICATIONS, v. 7, . (14/07125-6, 11/51023-5, 14/03332-7, 14/04684-4)
DE CARVALHO, RENAN V. H.; ANDRADE, WARRISON A.; LIMA-JUNIOR, DJALMA S.; DILUCCA, MARISA; DE OLIVEIRA, V, CAROLINE; WANG, KUN; NOGUEIRA, PAULA M.; RUGANI, JERONIMO N.; SOARES, RODRIGO P.; BEVERLEY, STEPHEN M.; et al. Leishmania Lipophosphoglycan Triggers Caspase-11 and the Non-canonical Activation of the NLRP3 Inflammasome. CELL REPORTS, v. 26, n. 2, p. 429+, . (13/08216-2, 14/04684-4)
ZAMBONI, DARIO S.; LIMA-JUNIOR, DJALMA S.. Inflammasomes in host response to protozoan parasites. IMMUNOLOGICAL REVIEWS, v. 265, n. 1, SI, p. 156-171, . (13/08216-2, 14/04684-4)
CUNHA, LARISSA D.; RIBEIRO, JULIANA M.; FERNANDES, TALITA D.; MASSIS, LILIANA M.; KHOO, CHEN AI; MOFFATT, JENNIFER H.; NEWTON, HAYLEY J.; ROY, CRAIG R.; ZAMBONI, DARIO S.. Inhibition of inflammasome activation by Coxiella burnetii type IV secretion system effector IcaA. NATURE COMMUNICATIONS, v. 6, . (14/50268-2, 13/08216-2, 14/04684-4)
GONCALVES, AUGUSTO V.; MARGOLIS, SHALLY R.; QUIRINO, GUSTAVO F. S.; MASCARENHAS, DANIELLE P. A.; RAUCH, ISABELLA; NICHOLS, RANDILEA D.; ANSALDO, EDUARD; FONTANA, MARY F.; VANCE, RUSSELL E.; ZAMBONI, DARIO S.. Gasdermin-D and Caspase-7 are the key Caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of Legionella pneumophila. PLOS PATHOGENS, v. 15, n. 6, . (13/08216-2, 14/04684-4)
MASCARENHAS, DANIELLE P. A.; CERQUEIRA, DAIANE M.; PEREIRA, MARCELO S. F.; CASTANHEIRA, FERNANDA V. S.; FERNANDES, TALITA D.; MANIN, GRAZIELE Z.; CUNHA, LARISSA D.; ZAMBONI, DARIO S.. Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the Naip5/NLRC4/ASC inflammasome. PLOS PATHOGENS, v. 13, n. 8, . (13/08216-2, 14/04684-4, 12/09363-6)
LIMA-JUNIOR, DJALMA S.; MINEO, TIAGO W. P.; CALICH, VERA L. G.; ZAMBONI, DARIO S.. Dectin-1 Activation during Leishmania amazonensis Phagocytosis Prompts Syk-Dependent Reactive Oxygen Species Production To Trigger Inflammasome Assembly and Restriction of Parasite Replication. JOURNAL OF IMMUNOLOGY, v. 199, n. 6, p. 2055-2068, . (13/08216-2, 14/04684-4, 13/15994-1)
DE CARVALHO, RENAN V. H.; LIMA-JUNIOR, DJALMA S.; DA SILVA, MARCUS VINICIUS G.; DILUCCA, MARISA; RODRIGUES, TAMARA S.; HORTA, CATARINA V.; SILVA, ALEXANDRE L. N.; DA SILVA, PATRICK F.; FRANTZ, FABIANI G.; LORENZON, LUCAS B.; et al. Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition. NATURE COMMUNICATIONS, v. 10, . (13/08216-2, 14/04684-4)
ZAMBONI, DARIO S.; SACKS, DAVID L.. Inflammasomes and Leishmania: in good times or bad, in sickness or in health. Current Opinion in Microbiology, v. 52, p. 70-76, . (13/08216-2, 14/04684-4)
MASSIS, LILIANA M.; ASSIS-MARQUES, MARIANA A.; CASTANHEIRA, FERNANDA V. S.; CAPOBIANCO, YASMIN J.; BALESTRA, ANDIAMIRA C.; ESCOLL, PEDRO; WOOD, REBECCA E.; MANIN, GRAZIELE Z.; CORREA, VANI M. A.; ALVES-FILHO, JOSE C.; et al. Legionella longbeachae Is Immunologically Silent and Highly Virulent In Vivo. Journal of Infectious Diseases, v. 215, n. 3, p. 440-451, . (13/08216-2, 14/04684-4, 10/20600-4, 14/50268-2, 12/09363-6)
CUNHA, LARISSA D.; ZAMBONI, DARIO S.. Recognition of Legionella pneumophila nucleic acids by innate immune receptors. Microbes and Infection, v. 16, n. 12, SI, p. 985-990, . (13/08216-2, 14/04684-4, 12/09363-6)
FRANCO, LUIS H.; FLEURI, ANNA K. A.; PELLISON, NATALIA C.; QUIRINO, GUSTAVO F. S.; HORTA, CATARINA V.; DE CARVALHO, RENAN V. H.; OLIVEIRA, SERGIO C.; ZAMBONI, DARIO S.. Autophagy downstream of endosomal Toll-like receptor signaling in macrophages is a key mechanism for resistance to Leishmania major infection. Journal of Biological Chemistry, v. 292, n. 32, p. 13087-13096, . (13/08216-2, 14/04684-4)
ANDRADE, WARRISON A.; ZAMBONI, DARIO S.. Inflammasome-dependent Mechanisms Involved in Sensing and Restriction of Bacterial Replication. CURRENT ISSUES IN MOLECULAR BIOLOGY, v. 25, p. 99-131, . (14/50268-2, 13/08216-2, 14/04684-4)
DE CARVALHO, RENAN V. H.; ZAMBONI, DARIO S.. Inflammasome Activation in Response to Intracellular Protozoan Parasites. Trends in Parasitology, v. 36, n. 5, p. 459-472, . (13/08216-2, 18/14398-0, 14/04684-4)
LOTERIO, ROBSON KRIIGER; ZAMBONI, DARIO S.; NEWTON, HAYLEY J.. eeping the host alive - lessons from obligate intracellular bacterial pathogen. PATHOGENS AND DISEASE, v. 79, n. 9, . (16/24275-7, 14/04684-4, 19/11342-6)
ANDRADE, WARRISON A.; ZAMBONI, DARIO S.. NLRC4 biology in immunity and inflammation. Journal of Leukocyte Biology, . (13/08216-2, 18/14398-0, 19/11342-6, 14/04684-4)
DE CARVALHO, RENA N. V. H.; SILVA, ALEXANDRE L. N.; SANTOS, LEONARDO L.; ANDRADE, WARRISON A.; DE SA, KEYLA S. G.; ZANNBONI, DARIO S.. Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication. Journal of Leukocyte Biology, v. 106, n. 3, SI, p. 631-640, . (14/04684-4)

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