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
• Start date: September 01, 2014
• End date: 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
• City of the host institution: Ribeirão Preto
• Associated researchers: Djalma de Souza Lima Júnior ; Juliana Issa Hori ; Larissa Dias da Cunha
• Associated research 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; 17/04243-6 - Investigation of the role of amastins in the inflammasome activation and in the translocation of Leishmania molecules into the macrophage cytoplasm, BP.MS; 17/04242-0 - Identification of new molecules in macrophages involved in inflammasome activation in response to intracellular pathogens, BP.DD; 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

Abstract

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)

Scientific publications

(28)

(The scientific publications listed on this page originate from the Web of Science or SciELO databases. Their authors have cited FAPESP grant or fellowship project numbers awarded to Principal Investigators or Fellowship Recipients, whether or not they are among the authors. This information is collected automatically and retrieved directly from those bibliometric databases.)

ZAMBONI, DARIO S.; LIMA-JUNIOR, DJALMA S.. Inflammasomes in host response to protozoan parasites. IMMUNOLOGICAL REVIEWS, v. 265, n. 1, SI, p. 156-171, MAY 2015. (13/08216-2, 14/04684-4)

MASCARENHAS, DANIELLE P. A.; ZAMBONI, DARIO S.. Inflammasome biology taught by Legionella pneumophila. Journal of Leukocyte Biology, v. 101, n. 4, p. 841-849, APR 2017. (14/50268-2, 13/08216-2, 14/04684-4, 14/00794-0)

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, AUG 2017. (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, SEP 15 2017. (13/08216-2, 14/04684-4, 13/15994-1)

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, DEC 2015. (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, JUN 2019. (13/08216-2, 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+, JAN 8 2019. (13/08216-2, 14/04684-4)

ANDRADE, WARRISON A.; ZAMBONI, DARIO S.. NLRC4 biology in immunity and inflammation. Journal of Leukocyte Biology, v. 108, n. 4, p. 11-pg., 2020-06-12. (19/11342-6, 14/04684-4, 13/08216-2, 18/14398-0)

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, FEB 2016. (14/07125-6, 11/51023-5, 14/03332-7, 14/04684-4)

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, SEP 2016. (14/50268-2, 13/08216-2, 14/04684-4)

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, SEP 1 2015. (12/14456-3, 11/22617-4, 13/08216-2, 14/04684-4, 12/15932-3, 12/16941-6)

LOTERIO, ROBSON K.; THOMAS, DAVID R.; ANDRADE, WARRISON; LEE, YI WEI; SANTOS, LEONARDO L.; MASCARENHAS, DANIELLE P. A.; STEINER, THIAGO M.; CHIARATTO, JESSICA; FIELDEN, LAURA F.; LOPES, LETICIA; et al. Coxiella co-opts the Glutathione Peroxidase 4 to protect the host cell from oxidative stress-induced cell death. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 120, n. 36, p. 11-pg., 2023-09-05. (19/11342-6, 13/08216-2, 14/04684-4, 16/07870-9, 16/24275-7)

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, JAN 15 2015. (13/08216-2, 14/04684-4, 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, DEC 2014. (13/08216-2, 14/04684-4, 12/09363-6)

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, SEP 2019. (14/04684-4)

ANDRADE, WARRISON A.; ZAMBONI, DARIO S.. NLRC4 biology in immunity and inflammation. Journal of Leukocyte Biology, JUN 2020. (13/08216-2, 18/14398-0, 19/11342-6, 14/04684-4)

DE CASTRO-JORGE, LUIZA A.; DE CARVALHO, RENAN V. H.; KLEIN, TALINE M.; HIROKI, CARLOS H.; LOPES, ALEXANDRE H.; GUIMARAES, RAFAELA M.; FUMAGALLI, MARCILIO JORGE; FLORIANO, VITOR G.; AGOSTINHO, MAYARA R.; SLHESSARENKO, RENATA DEZENGRINI; et al. The NLRP3 inflammasome is involved with the pathogenesis of Mayaro virus. PLOS PATHOGENS, v. 15, n. 9, SEP 2019. (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, FEB 1 2017. (13/08216-2, 14/04684-4, 10/20600-4, 14/50268-2, 12/09363-6)

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, MAY 2020. (13/08216-2, 18/14398-0, 14/04684-4)

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, AUG 11 2017. (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, 2018. (14/50268-2, 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, DEC 2019. (13/08216-2, 14/04684-4)

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, NOV 21 2019. (13/08216-2, 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, DEC 2021. (16/24275-7, 14/04684-4, 19/11342-6)

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. 7-pg., 2019-12-01. (13/08216-2, 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, p. 10-pg., 2019-09-01. (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, p. 16-pg., 2015-05-01. (13/08216-2, 14/04684-4)

CUNHA, LARISSA D.; ZAMBONI, DARIO S.. Recognition of Legionella pneumophila nucleic acids by innate immune receptors. Microbes and Infection, v. 16, n. 12, p. 6-pg., 2014-12-01. (13/08216-2, 14/04684-4, 12/09363-6)