Lysosomes are acidic, hydrolase-rich cellular organelles that represent the final destination for endocytic, secretory and autophagic pathways. As such, it has been thought for many years that these organelles represent a “dead end” that does not allow cargo that reach this organelle from going further to other cellular destinations without prior degradation to metabolically usable or easily disposable building blocks. Lysosomal malfunction has been described to be involved in several human chronic pathologies and some infectious diseases.
The main interests of my laboratory are to contribute to the better understanding of the biology/physiology and pathophysiology of two lysosomal related diseases: Atherosclerosis and Tuberculosis.
Atherosclerosis is one of those chronic pathologies that begin as a lysosomal pathology in that it involves irreversible accumulation of lipid in these organelles, a form of lipidosis. In general, our long term goals in this area are: 1) to identify the etiological factors that are involved in lysosome malfunction; 2) to identify the causes of failure of efferocytosis; and 3) to understand the formation of irreversible atherosclerotic lesions. Identifying the inflammatory signals that result from lysosomal stress is also another concern that we are actively interested in. Once we know the etiological factors that initiate atherogenesis, we are interested in developing analytical tools that will permit their diagnostic detection in humans.
Fig 1: LDL loaded with Cholesteryl hemisuccinate induce endolysosomal lipid accumulation in macrophages. A and F, Raw macrophages incubated with Acetylated-LDL. B, C-E and G, Raw macrophages incubated with LDL loaded with cholesteryl hemisuccinate. A-E, Confocal images. F and G, Electron microscopic pictures.
Some human pathogens, such as Mycobacterium tuberculosis, have evolved strategies to avoid lysosome-based destruction of the pathogen, permitting it to live and proliferate in the endolysosomal compartment, while subverting host cell repair mechanisms. In recent years it has been recognized that lysosomes are heterogeneous, some of them being able to trasnlocate to the plasma membrane and thereby playing a critical role in plasma membrane repair. Virulent Mycobacteria are known to be able to subvert plasma membrane repair while non-virulent Mycobacteria are not. We wish to be able to define regulatory mechanisms of endocytic intracellular vesicular trafficking including translocation of lysosomes to plasma membrane for plasma membrane repair and their role in infection by M. tuberculosis.
To achieve our goals, we use primary cell cultures and cultures of established “eternalized” cell lines as well as animal models and human tissues from healthy and diseased individuals. Our research currently applies some state-of-the-art techniques including High-Throughput Screening of lentiviral trafficking libraries, Live-Cell Imaging, Electron Microscopy, Shot-gun Lipidomics, Biochemical, Biophysical, Pharmacological, and Cell Biological approaches to advance our knowledge in the areas of interest.
European Union’s Horizon Twinning project 2020 (No 811087) [2018-2022]: "LYSOCIL - Excel in Rare Diseases’ Research: Focus on LYSOsomal Disorders and CILiopathies "
PTDC/MED-PAT/29395/2017 (2018-2021): “Exocytosis of Dysfunctional Lysosomes as a New Paradigm Shift in the Pathogenesis of Atherosclerosis”
PTDC/BIA/MIC/31561/2017 (2018-2021): “Development and evaluation of a surfactant-hydrogel for preventing direct contact transmitted infections”
03/SAICT/2015 (2016 – 2019): “New Targets in DIAstolic heart failure: from coMOrbidities to persoNalizeD medicine”
2015 – 2017: “The role of cholesteryl hemiesters in the etiology, development and instability of atheromata”.
HMSP-ICT/0024/2010 (2012 – 2015): “A New Approach to Fight Tuberculosis”
2012: Prémio Arrisca C 2011- Prémio ACIC – Concurso de ideias de negócio. Projecto. “Synthesis and assessment of new microbicides for topical use in sexually transmitted infections”.
PTDC/BIA-BCM/112138/2009 (2011 – 2014): “Role of RabGTPases On Phagocytosis And Phagosomal Maturation Of IgG-Opsonized Heat-killed and Mycobacterium tuberculosis”.
2011: Bolsa de Ignição da Universidade de Coimbra. “Surfactants in the Prophylaxis of Sexually Transmitted Infections”.
PTDC/SAU-MII/66285/2006 (2007 – 2010): “Role and Molecular Mechanisms Underlying CD36-Mediated Phagocytosis of Apoptotic Cells: Implications for Atherosclerosis”
- Marques, ARA; Ramos, C; Machado-Oliveira, G; Vieira, OV. Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle. Frontiers in Cell and Developmental Biology Vol. 9, 29 March 2021. doi: 10.3389/fcell.2021.658995.
- Galderisi S, Cicaloni V, Milella MS, Millucci L, Geminiani M, Salvini L, Tinti L, Tinti C, Vieira OV, Alves LS, Crevenna AH, Spiga O, Santucci A. Homogentisic acid induces cytoskeleton and extracellular matrix alteration in alkaptonuric cartilage. J Cell Physiol. 2021 Jan 20. doi: 10.1002/jcp.30284. Online ahead of print.PMID: 33469937
- Domingues N, Calado RDA, Brito PH, Matthiesen R, Ramalho J, Soares MLS, Pereira T, Oliveira L, Vicente JR, Wong LH, Cho SM, Simões ICM, Sampaio J, Klose C, Surma MA, Almeida MS, Rodrigues G, Gonçalves PA, Ferreira J, Simons K, Melo e Pinho TMVD, Peden A. Cholesteryl Hemiazelate Induces Lysosome Dysfunction and Exocytosis in Macrophages. bioRXiv 2021 Jan 5. doi:https://doi.org/10.1101/2021.01.05.422575
- Oliveira GM, Ramos C, Marques ARA, Vieira OV. Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis.Cells, 2020 Sep 23;9(10):2146. doi: 10.3390/cells9102146.
- Gerl MJ, Vaz WLC, Domingues N, Klose C, Surma MA, Sampaio JL, Almeida MS, Rodrigues G, Araújo-Gonçalves P, Ferreira J, Borbinha C, Marto JP, Viana-Baptista M, Simons K, Vieira OV.Cholesterol is Inefficiently Converted to Cholesteryl Esters in the Blood of Cardiovascular Disease Patients. Sci Rep. 2018 Oct 3;8(1):14764. doi: 10.1038/s41598-018-33116-4.
- Gibson MS, Domingues N, Vieira OV. Lipid and Non-lipid Factors Affecting Macrophage Dysfunction and Inflammation in Atherosclerosis. Front Physiol. 2018 Jun 26;9:654. doi: 10.3389/fphys.2018.00654. eCollection 2018.
- Santarino, I. B. and Vieira, O. V., Maturation of phagosomes containing different erythrophagocytic particles in primary macrophages. FEBS Open Bio. Accepted Author Manuscript. doi:10.1002/2211-5463.12262
- Santarino IB, Viegas MS, Domingues NS, Ribeiro AM, Soares MP, Vieira OV. Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis. Sci Rep. 2017 Jul 19;7(1):5812. doi: 10.1038/s41598-017-05687-1
- N. Domingues, L. Estronca, J. Silva, M. Encarnação, R. Mateus, D. Silva, I. Santarino, M. Saraiva, M. Soares, T. Pinho e Melo, A. Jacinto, W. Vaz and O.V. Vieira. (2016) Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages. BBA - Molecular and Cell Biology of Lipids. Volume 1862, Issue 2, February 2017, Pages 210–220. doi: 10.1016/j.bbalip.2016.10.009
- O.V. Vieira (2016). Rab3a and Rab10 are regulators of lysosome exocytosis and plasma membrane repair. Small GTPases. 2016 Sep 29:0. [Epub ahead of print]
- M. Encarnação, L. Espada, C. Escrevente, D. Mateus, J. Ramalho, X. Michelet, I. Santarino, V. W. Hsu, M. B. Brenner, D. Barral and O. V. Vieira. (2016).* Encarnação M, Espada L, Escrevente C, Mateus D, Ramalho J, Michelet X, Santarino I, Hsu VW, Brenner MB, Barral D, Vieira OV. (2016) A Rab3a-dependent complex essential for lysosome positioning and plasma membrane repair. J Cell Biol. 2016 Jun 20;213(6):631-40. doi: 10.1083/jcb.201511093. J. Cell Biol. 213 (6) 631-640.
* Spotlight in J. Cell Biol. 2016 213:613-615.
Recommended in F1000Prime.
- Â. Inácio, A. Nunes, C. Milho C, L. J. Mota, M. J. Borrego, J. P. Gomes, W. L. C. Vaz and O. V. Vieira (2016). In vitro activity of quaternary ammonium surfactants against streptococcal, chlamydial, and gonococcal infective agents. Antimicrob Agents Chemother. 23;60(6):3323-32.
- Â. Inácio, N. S. Domingues, A. Nunes, P. T. Martins, M. J. Moreno, L. M. Estronca, R. Fernandes, A. J. M. Moreno, M. J. Borrego, J. P. Gomes, W. L. C. Vaz and O. V. Vieira (2016). Quaternary ammonium surfactant structure determines selective toxicity towards bacteria: mechanisms of action and clinical implications in antibacterial prophylaxis. J Antimicrob Chemother 2016; 71(3):641-54.
- A. Inácio, G. Costa, M. S. Santos, A. J. M. Moreno, W.L.C. Vaz and O.V. Vieira (2013). Mitochondrial Dysfunction is the Focus of Quaternary Ammonium Surfactant Toxicity to Mammalian Epithelial Cells. Antimicrobial Agents and Chemotherapy. 2013; 57 (6):2631-9
* This article was featured online on Global Medical Discovery [ISSN 1929-8536] (http://globalmedicaldiscovery.com).
- L.M.B.B. Estronca, J. Silva, J. Sampaio, A. Shevchenko, P. Verkade, W.L.C. Vaz and O.V. Vieira (2012). Molecular Etiology of Atherogenesis - In Vitro Induction of Lipidosis in Macrophages with a New LDL Model. PLoS One. 2012;7(4):e34822.
- A. Inácio, K. Mesquita, M. Baptista, J. Ramalho-Santos, W.L.C. Vaz and O.V. Vieira1 (2011). In vitro surfactant structure-toxicity relationships: implications for surfactant use in sexually transmitted infection prophylaxis and contraception. PloS ONE 6(5):e19850.
- C.M. Cardoso, L. Jordão and O.V. Vieira1 (2010). Rab10 is required for phagosome maturation and its overexpression can change the fate of Mycobacterium-containing phagosomes. Traffic 11(2):221-35.
- O.V. Vieira, D.O. Hartmann, C.M. Cardoso, D. Oberdoerfer, M. Baptista, M. Santos, L. Almeida, J. Ramalho-Santos and W.L.C. Vaz (2008). Surfactants as microbicides and contraceptive agents: a systematic in vitro study. PloS ONE 3(8):e2913.
- D. Halter, S. Neumann, S.M. van Dijk, J. Wolthoorn, A.M. de Mazière, O.V. Vieira, P. Mattjus, J. Klumperman, G. van Meer, and H. Sprong (2007). * Pre- and Post-Golgi Translocation of Glucosylceramide in Glycosphingolipid Synthesis. J. Cell Biol. 179(1):101-115.
* Spotlight in J. Cell Biol. 179(1):11-13.
- O.V. Vieira, K. Gaus, P. Verkade, W.L.C. Vaz and K. Simons (2006) * FAPP2, cilium formation and the compartmentalization of the apical membrane in polarized MDCK cells. Proc. Natl. Acad. Sci. USA 103(49):18556-18561.
* Comment in Proc. Natl. Acad Sci USA 103(49):18383-18384.
This article was also highlighted in the cover of the Journal.
- O.V. Vieira, P. Verkade, A. Manninen and K. Simons (2005). * FAPP2 is part of the apical transport machinery in polarized MDCK cells. J. Cell Biol. 170(4):521-526.
* Exceptional rating in Faculty of 1000 Biology.
- O.V. Vieira, R. Harrison, C. Scott, H. Stenmark, D. Alexander , J. Liu , J. Gruenberg, A.D. Schreiber, and S. Grinstein (2004). Acquisition of Hrs, an essential component of phagosomal maturation, is impaired by mycobacteria. Mol. Cell. Biol. 24(10):4593-4604.
- O.V. Vieira, C. Bucci, R. Harrison, W.S. Trimble, L. Lanzetti, J. Gruenberg, A. D. Schreiber, P.D. Stahl, and S. Grinstein (2003). Modulation of Rab5 and Rab7 recruitment to phagosomes by phosphatidyl-inositol 3-kinase. Mol. Cell. Biol. 23(7):2501-2514.
- M.R. Terebiznik, O.V.Vieira, S. Marcus, W.S. Trimble, T. Meyer, B.B. Finlay, and S. Grinstein (2002)*. Elimination of host cell PI(4,5)P2 by the phosphatase SopB/SigD promotes membrane fission during invasion by Salmonella. Nature Cell Biol. 4(10):766-773.
* Comment in J. Cell Biol. 159(2):200.
Exceptional rating in Faculty of 1000 Biology.
- O.V. Vieira, R.J. Botelho, L. Rameh, S.M. Brachmann, T. Matsuo, H.W. Davidson, A. Schreiber, J.M. Backer, L. Cantley, and S. Grinstein (2001).* Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J. Cell Biol. 155(1):19-25.
* Comment in J. Cell Biol. 155 (1):15-17.
Exceptional rating in Faculty of 1000 Biology.
• Prof. Teresa Pinho e Melo and Dr. Isabel Soares, Department of Chemistry, University of Coimbra, Portugal.
• Prof. Kai Simons, Lipotype, Dresden, Germany.
• Dr. Margarida Saraiva, Life and Health Sciences Research Institute (ICVS). School of Health Sciences, University of Minho, Portugal.
• Dr. João Paulo Gomes, Dr. Alexandra Nunes and Dr. Maria José Borrego, Instituto Nacional de Saúde “Ricardo Jorge” (INSA), Lisbon, Portugal.
• Prof. Clare Futter, Department of Cell Biology, University College London Institute of Ophthalmology, London, United Kingdom.
• Prof. Anthony H. Futerman, Department of Biomolecular Sciences, Weizmann Insitute, Israel.
• Dr. Jorge Ferreira, Dr. Manuel Almeida and Prof. Pedro Gonçalves, Hospital Santa Cruz, Carnaxide, Lisboa.
• Dr. Miguel Viana Baptista, Hospital Egas Moniz, Lisboa.
• Prof. Nuno Santos, IMM and Faculdade de Medicina, Universidade de Lisboa.