Patogenicidade Microbiana e Imunidade Inata

Linhas gerais/General outline
Investigação das interações moleculares entre patógenos intracelulares e células do sistema imune inato.

Investigation of the molecular interactions between intracellular pathogens and innate immune system cells

Linhas de pesquisa/Research areas

Patógenos intracelulares desenvolveram sofisticados mecanismos para subverter as funções normais da célula hospedeira e se multiplicar em seu interior. Em contrapartida, células do sistema imune inato desenvolveram estratégias para detectar a presença desses patógenos e controlar sua multiplicação. Recentemente foi revelada uma nova família de receptores citoplasmáticos que participam ativamente desse processo, os receptores NOD, ou NLR (do inglês, nod-like receptors). Patógenos intracelulares como Legionella pneumophila e Coxiella burnetii são utilizados como modelo para compreendermos os mecanismos de função dos NLRs assim como suas vias de sinalização celular. Utilizamos uma abordagem integrativa por meio de técnicas de microbiologia celular e molecular visando investigar a interação entre bactéria e célula hospedeira, interferindo ora em genes celulares ora em genes bacterianos. As linhas de pesquisa principais incluem:

1) identificação de moléculas microbianas responsáveis pela ativação de NLR;

2) determinação dos mecanismos de função e conseqüências da ativação desses receptores no complexo processo de interação patógeno-célula hospedeira.

 

Intracellular pathogens have developed sophisticated mechanisms to subvert the normal functions of the host cell and multiply in its interior. To counteract this effect, innate immune system cells have developed strategies to detect the presence of these pathogens and control their multiplication. A new family of cytoplasmic receptors taking an active part in this process has been revealed, namely the receptors NOD, or NLR (nod-like receptors). Intracellular pathogens like Legionella pneumophila and Coxiella burnetii are employed as models in our studies, so that better understanding about the function mechanisms of NLRs as well as their signaling pathways can be achieved. An integrated approach using molecular and cell biology techniques is employed by us, in order to investigate the interaction between the bacterium and the host cell that interferes with either the cell genes or the bacterial genes. Our main research lines include:

1) identification of microbial molecules responsible for NLR activation;

2) determination of the function mechanisms and the implications of receptor activation for the complex process of pathogen-host cell interaction

Artigos Relevantes/Suggestions for further reading 

1. Lima-Junior DS, Costa DL, Carregaro V, Cunha LD, Silva AL, Mineo TW, Gutierrez FR, Bellio M, Bortoluci KR, Flavell RA, Bozza MT, Silva JS, Zamboni DS. Inflammasome-derived IL-1β production induces nitric oxide-mediated resistance to Leishmania. Nat Med. 2013;19(7):909-15.

2. Hori JI, Pereira MS, Roy CR, Nagai H, Zamboni DS. Identification and functional characterization of K₊ transporters encoded by Legionella pneumophila kup genes. Cell Microbiol. 2013 Jul 15. doi: 10.1111/cmi.12168. (Epub ahead of print).

3. Silva GK, Cunha LD, Horta CV, Silva AL, Gutierrez FR, Silva JS, Zamboni DS. A Parent-of-Origin Effect Determines the Susceptibility of a Non-Informative F1 Population to Trypanosoma cruzi Infection In Vivo. PLoS One. 2013;8(2):e56347.

4. Case CL, Kohler LJ, Lima JB, Strowig T, de Zoete MR, Flavell RA, Zamboni DS, Roy CR. Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proc Natl Acad Sci U S A. 2013;110(5):1851-6.

5. Hori JI, Zamboni DS. 2013. The mouse as a model for pulmonary Legionella infection. Methods Mol Biol. 2013;954:493-503.

6. Moreira LO, Zamboni DS. 2012. NOD1 and NOD2 Signaling in Infection and Inflammation. Front Immunol. 2012;3:328.

7. Franco LH, Beverley SM, Zamboni DS. 2012.  Innate immune activation and subversion of Mammalian functions by leishmania lipophosphoglycan. J Parasitol Res. 2012;2012:165126.

8. Pereira MS, Morgantetti GF, Massis LM, Horta CV, Hori JI, Zamboni DS. 2011.  Activation of NLRC4 by flagellated bacteria triggers caspase-1-dependent and -independent responses to restrict Legionella pneumophila replication in macrophages and in vivo. J Immunol. 2011 Dec 15;187(12):6447-55.

9.  Massis LM, Zamboni DS. 2011. Innate Immunity to Legionella pneumophila. Frontiers in Microbiology. 2011; 2:109. doi: 10.3389/fmicb.2011.00109

10.  Pereira MS, Marques GG, DelLama JE, Zamboni DS. 2011. The Nlrc4 Inflammasome contributes to restriction of pulmonary infection by flagellated Legionella spp. that trigger pyroptosis. Frontiers in Microbiology. 2011; 2:33. doi: 10.3389/fmicb.2011.00033.

11. Marim FM, Silveira TN, Lima DS Jr, Zamboni DS. 2010. A method for generation of bone marrow-derived macrophages from cryopreserved mouse bone marrow cells. PLoS One. 2010;5(12):e15263.

12. Frutuoso MS, Hori JI, Pereira MS, Junior DS, Sônego F, Kobayashi KS, Flavell RA, Cunha FQ, Zamboni DS. 2010. The pattern recognition receptors Nod1 and Nod2 account for neutrophil recruitment to the lungs of mice infected with Legionella pneumophila. Microbes Infect. 2010 Oct;12(11):819-27.

13. Silveira TN, Zamboni DS. 2010. Pore formation triggered by Legionella spp. is an Nlrc4 inflammasome-dependent host cell response that precedes pyroptosis. Infect Immun. 2010 Mar;78(3):1403-13.

14. Silva GK, Gutierrez FR, Guedes PM, Horta CV, Cunha LD, Mineo TW, Santiago-Silva J, Kobayashi KS, Flavell RA, Silva JS, Zamboni DS. 2010. Cutting edge: nucleotide-binding oligomerization domain 1-dependent responses account for murine resistance against Trypanosoma cruzi infection. J Immunol. 2010;184(3):1148-52.

15. Shin S, Case CL, Archer KA, Nogueira CV, Kobayashi KS, Flavell RA, Roy CR, Zamboni DS. 2008. Type IV secretion-dependent activation of host MAP kinases induces an increased proinflammatory cytokine response to Legionella pneumophila.  PLoS Pathogen. 2008; 4(11):e1000220.

16.  Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, Dietrich WF, Roy CR. 2006. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nature Immunology. 2006;7(3):318-325.

17. Roy CR, Zamboni DS. 2006. Cytosolic detection of flagellin: a deadly twist.  Nature Immunology. 2006;7(6):549-551.

18.  Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE. 2006. Flagellin-Deficient Legionella Mutants Evade Caspase-1- and Naip5-Mediated Macrophage Immunity. PLoS Pathogen. 2006; 2(3): e18.

19.  Sutterwala FS, Ogura Y, Zamboni DS, Roy CR, Flavell RA. 2006. NALP3: a key player in caspase-1 activation. J Endotoxin Res. 2006; 12(4):251-6.

20.  Zamboni DS, Campos MA, Torrecilhas AC, Kiss K, Samuel JE, Golenbock DT, Lauw FN, Roy CR, Almeida IC, and Gazzinelli RT. 2004. Stimulation of toll-like receptor 2 by Coxiella burnetii is required for macrophage production of pro-inflammatory cytokines and resistance to infection. The Journal of Biological Chemistry. 2004; 279(52): 54405-54415.

21.  Zamboni DS. 2004. Genetic control of natural resistance of mouse macrophages to Coxiella burnetii infection in vitro: macrophages from restrictive strains control parasitophorous vacuole maturation. Infection and Immunity. 2004; 72(4): 2395-2399.

22.  Zamboni DS, and Rabinovitch M. 2004.  Phagocytosis of apoptotic cells increases the susceptibility of macrophages to infection with Coxiella burnetii phase II through down-modulation of nitric oxide production. Infection and Immunity. 2004; 72(4): 2075-2080.

23.  Zamboni DS, McGrath S, Rabinovitch M, and Roy CR. 2003. Coxiella burnetii express type IV secretion system proteins that function similarly to components of the Legionella pneumophila Dot/Icm system. Molecular Microbiology. 2003; 49(4): 965-976.

24.  Zamboni DS, and Rabinovitch M. 2003. Nitric oxide partially controls Coxiella burnetii phase II infection in mouse primary macrophages. Infection and Immunity. 2003; 71(3): 1225-1233.