Areas of focus

With the development of modern societies, the incidence of life-threatening opportunistic infections has increased.  The proliferation of drug-resistant microbes together with the ageing population and the development of immunosenescence and “inflamm-aging”, rendering elderly more susceptible to infection, are critical factors contributing to the observed high morbidity and mortality rates and increase in the pathogenicity of microbes.

The main interests and scientific activities of the Medical Microbiology Group are thus centered in the study of different microbial agents of human disease, in particular fungi, and its biological traits relevant to infection and colonization: mostly, Alternaria infectoria, an environmental mould responsible for opportunistic fungal infections in immunocompromised hosts, but especially involved in respiratory allergies; and Candida albicans, responsible for 60% of fungal disseminated infections with 40-70% associated mortality. Moreover, due to the urgent need to overcome these challenges, the search for innovative therapies is also one of our major focus. To accomplish these major goals, the group is using both in vivo and in vitro infection models and human samples, to study, e.g., gut inflammation and respiratory diseases, in collaboration with clinicians fostering interdisciplinarity and translation.

Ongoing projects

As a result, we are now developing our research in three different areas of expertise:

i) the control of fungi considered major agents of respiratory allergic and invasive diseases, focusing in melanin and chitin modulation;
ii) the role of purines and adenosine receptors in the switch between passive colonization and infection and disruption of gut mycobiota/age-related gut imbalance, as a novel therapeutic approach to control gut chronic inflammation and prevent opportunistic infections in susceptible hosts;
iii) seeking for novel antimicrobials extracted from natural resources, an effort aligned with one of the UN 2030 Agenda, in the quest for effective infection control drugs.

Research highlights
i) We proved that the inhibition of fungal DHN-melanin synthesis synergizes with other antifungals resulting in higher efficiency, especially with echinocandins one of the major antifungal classes used in human health. We also identified and characterized genes coding for the cell wall chitin, glucan and melanin, in Alternaria, one of the major fungal agents of respiratory allergic diseases such as severe asthma. In this group of agents, we proved the production of exosome like-extracellular vesicles; its proteomics indicates a cargo relevant to its pathogenesis.

ii) Using an in vivo model of infection, we proved that adenosine A2A receptor modulates gut infection/colonization by Candida albicans, the most important human fungal pathogen, and that, senescence associated with ageing, leads to a lower density of A2AR in the elderly, increasing the virulence of C. albicans and inflammation. In vitro, we described the importance of extracellular purines metabolism by C. albicans, especially the use 3'AMP as a substrate, indicating resistance to Neutrophil Extracellular Traps (NETs). 




iii) Together with algae specialists, we identified several red algae extracts with antimicrobial properties, namely the antifungal effect of carrageenans, molecules first described as anti-respiratory viral effect. Using Antimicrobial Photodynamic Therapy (aPDT) we also described a chlorophyll derivate that leads to eradication of mixed biofilms of Enterococcus faecalis and C. albicans, especially important in oral biofilms.
 

Microbiology at FMUC:
http://www.uc.pt/fmuc/microbiologia

Collaborations

Acácio Gonçalves-Rodrigues
Faculty of Medicine, University of Oporto

Ana Paula Piedade
CEMMPRE - Centre for Mechanical Engineering, Materials and Processes, University of Coimbra  

Ana Todo-Bom Ferreira
Faculty of Medicine, University of Coimbra

António Carlos Miguéis
Faculty of Medicine, University of Coimbra

Arturo Casadevall
Albert Einstein School of Medicine, NY, USA

Célia Quintas
ISE, University of Algarve

Cidália Pina-Vaz
Faculty of Medicine, University of Oporto

Isabel Ferreira
BioChemCore, Polytechnic Institute of Bragança

Isabel Miranda
Faculty of Medicine, University of Oporto

João Miguel Santos
Faculty of Medicine (Dept Dentistry), University of Coimbra

José Augusto Medeiros
Faculty of Medicine, University of Coimbra

José Roberto Meyer-Fernandes
Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Brazil

Leonel Pereira
MARE / IMAR, Faculty of Sciences and Technology, University of Coimbra

Neil AR Gow
Institute of Medical Sciences, University of Aberdeen, UK

Olga Borges
CNC and  Faculty of Pharmacy,  University of Coimbra

Paula Morais
Faculty of Sciences and Technology, University of Coimbra

Paula Simões-WÜst
Zurich University, Switzerland

Rodrigo Cunha
CNC and Faculty of Medicine, University of Coimbra

Selected Publications

Diogo P, Fernandes C, Caramelo F, Mota M, Miranda IM, Faustino MAF, Neves MGPMS, Uliana MP, de Oliveira KT, Santos JM and Gonçalves T. (2017) Antimicrobial Photodynamic Therapy against Endodontic Enterococcus faecalis and Candida albicans Mono and Mixed Biofilms in the Presence of Photosensitizers: A Comparative Study with Classical Endodontic Irrigants. Front. Microbiol. doi: 10.3389/fmicb.2017.00498.

Rodrigues L, Miranda IM, Andrade GM, Mota M, Cortes L, Rodrigues AG, Cunha RA and Gonçalves T. (2016) Blunted dynamics of adenosine A2A receptors is associated with increased susceptibility to Candida albicans infection in the elderly. Oncotarget. doi: 10.18632/oncotarget.11760.

Costa AL, Silva BM, Soares R, Mota D, Alves V, Mirante A, Ramos JC, Maló de Abreu J, Santos-Rosa M, Caramelo F, Gonçalves T. (2016) Type 1 diabetes in children is not a predisposing factor for oral yeast colonization. Med Mycol. doi: 10.1093/mmy/myw092.

Fernandes C, Gow NAR, Gonçalves T. (2016) MMD-Chs, chitin synthase enzymes with myosin-like domains and the pathogenesis of filamentous fungi. Fungal Biol Rev. doi:10.1016/j.fbr.2016.03.002

Soares F, Fernandes C, Silva P, Pereira L and Gonçalves T. (2016). Antifungal activity of carrageenan extracts from the red alga Chondracanthus teedei var. lusitanicus. J Appl Phycol. doi: 10.1007/s10811-016-0849-9.

Rodrigues L, Russo-Abrahão T, Cunha RA, Gonçalves T and Meyer-Fernandes JR (2016) Characterisation of extracellular nucleotide metabolism in Candida albicans. FEMS Microbiol Lett. doi: http://dx.doi.org/10.1093/femsle/fnv212.

Fernandes C, Prados-Rosales R, Silva B, Nakouzi-Naranjo A, Zuzarte M, Chatterjee S, Stark RE, Casadevall A and Gonçalves T. (2016) Activation of melanin synthesis in Alternaria infectoria by antifungal drugs. Antimicrob Agents Chemother. doi: 10.1128/AAC.02190-15.

Coelho C, Souza AC, Derengowski L, Leon-Rodriguez C, Wang B, Leon-Rivera R, Bocca AL, Gonçalves T and Casadevall A. (2015) Macrophage Mitochondrial and Stress Response to Ingestion of Cryptococcus neoformans. J of Immunology. doi: 10.4049/jimmunol.1402350.

Fernandes C, Anjos J, Walker LA, Silva BMA, Cortes L, Mota M, Munro CA, Gow NAR and Gonçalves T. (2014) Modulation of Alternaria infectoria cell wall chitin and glucan synthesis by cell wall synthase inhibitors. Antimicrob Agents Chemother. doi: 10.1128/AAC.02647-13.

Silva BMA, Prados-Rosales R, Espadas-Moreno J, Wolf JM, Luque-Garcia JL, Gonçalves T and Casadevall A. (2014) Characterization of Alternaria infectoria extracellular vesicles. Med Mycol. doi: 10.1093/mmy/myt003.

Miranda I, Silva-Dias A, Rocha R, Teixeira-Santos R, Coelho C, Gonçalves T, Santos MAS, Pina-Vaz C, Solis NV, Filler SG and Rodrigues AG. (2013) Candida albicans CUG Mistranslation Is a Mechanism To Create Cell Surface Variation. mBio. doi: 10.1128/mBio.00285-13.

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