The Hall lab (hall-fungal-research.co.uk) is interested in all things fungal. The current focus of the lab is in addressing how pathogenic fungi sense and respond to the plethora of environmental parameters they are exposed to during colonization and infection. Our favorite pathogenic fungus is Candida albicans, but we also work with Candida glabrata and Cryptococcus spp, and in the future we would also like to work with Aspergillus spp.
Just like us, microorganisms constantly monitor their surroundings and mount a specific response to changes in their external environment. This is particularly important for pathogenic microbes that colonise diverse environments in the human body. Fungi are capable of colonising and subsequently infecting many different human body sites including the skin, nails, lungs, brain, organs and oral, genital and gastrointestinal tracts. Each of these sites has its own environmental characteristics and local defence mechanisms to which the fungus must be able to adapt to, and resist, in order to maintain its position in the niche. Currently, we only have basic knowledge of what these environments are, how they are sensed, and how the fungus uses these environmental signals to drive disease progression. However, what we do know, from in vitro studies dissecting the response of single signals, is that many host-derived signals including serum, pH and temperature drive fungal virulence, while microbe-derived signals dampen these characteristics. In the niche, the fungal pathogen will be simultaneously exposed to both host and microbe-derived signals. Therefore, understanding how the dual response to such opposing traits is orchestrated is an essential goal for the host-pathogen interaction field. We aim to address this fundamental gap in our knowledge of host-pathogen interactions by using one of the major human fungal pathogens, Candida albicans, as a model for fungal infection. We use fundamental pathogen cell biology in order to understand the behaviour of C. albicans in diverse host niches. Specifically, we address how this successful opportunistic fungal pathogen perceives multiple environmental signals encountered during infection, how these combinatorial environments affect the pathobiology of the fungus and how in turn the fungus uses these environments to hide and escape from our immune system.
Poly-microbial interactions and disease
During infection, fungi come into contact with a variety of microorganisms. These may be microbes that comprise the natural microbiota of the niche, or opportunistic pathogens. Bacteria communicate with each other through a cell density dependent process known as quorum sensing. C. albicans was the first eukaryote identified to produce and respond to quorum sensing molecules. Since the identification of fungal quorum sensing, many bacterial quorum-sensing molecules have been shown to impact of fungal pathogenicity. In addition to quorum sensing molecules, poly-microbial interactions include direct cell-cell contact between different organisms. For example, the bacterium Pseudomonas aeruginosa directly binds to and kills hyphae of C. albicans. The Hall lab has a keen interest in identifying the mechanism(s) of fungal quorum sensing, the role of quorum sensing in disease, and the poly-microbial interactions that occur during infection.
Hall RA and Gow NAR. (2013) Mannosylation in Candida albicans: role in cell wall function and immune recognition. Mol. Microbiol. 90, 1147-61
Bates S, Hall RA, Cheetham J, Netea MG, MacCallum DM, Brown AJ, Odds FC, Gow NA. (2013) Role of the Candida albicans MNN1 gene family in cell wall structure and virulence. BMC Res Notes. 6, 294.
Hall RA, Bates S, Lenardon MD, Maccallum DM, Wagener J, Lowman DW, Kruppa MD, Williams DL, Odds FC, Brown AJ, Gow NA. (2013), The Mnn2 mannosyltransferase family modulates mannoprotein fibril length, immune recognition and virulence of Candida albicans. PLoS Pathog. 9(4):e1003276.
Davis RA, Hofmann A, Osman A, Hall RA, Mühlschlegel FA, Vullo D, Innocenti A, Supuran CT, Poulsen SA. (2011) Natural product-based phenols as novel probes for mycobacterial and fungal carbonic anhydrases. J Med Chem. 54, 1682-92.
Hall RA, Turner KJ, Chaloupka J, Cottier F, De Sordi L, Sanglard D, Levin LR, Buck J, Mühlschlegel FA (2011). The quorum-sensing molecules farnesol/homoserine lactone and dodecanol operate via distinct modes of action in Candida albicans. Eukaryotic Cell, 10, 1034-42.
Carta F, Innocenti A, Hall RA, Mühlschlegel FA, Scozzafava A, Supuran CT (2011). Carbonic anhydrase inhibitors. Inhibition of the β-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with branched aliphatic/aromatic carboxylates and their derivatives. Bioorg. Med. Chem. Lett., 21, 2521-2526.
Davis RA, Hofmann A, Osman A, Hall RA, Mühlschlegel FA, Vullo D, Innocenti A, Supuran CT, Poulsen SA (2011). Natural product-based phenols as novel probes for mycobacterial and fungal carbonic anhydrases. J. Med. Chem. 54, 1682-1692.
Sheth CC, Hall R, Lewis L, Brown AJ, Odds FC, Erwig LP, Gow NA (2011). Glycosylation status of the C. albicans cell wall affects the efficiency of neutrophil phagocytosis and killing but not cytokine signaling. Med. Mycol., 49, 513-524.
Hall RA, De Sordi L, Eaton R, Bloor JW, Steegborn C, and Mühlschlegel FA (2010). CO(2) acts as a signalling molecule in populations of the fungal pathogen Candida albicans. PLoS Pathog., 6 :e1001193.
Hall RA, Mühlschlegel FA (2010). A multi-protein complex controls cAMP signalling and filamentation in the fungal pathogen Candida albicans. Mol. Microbiol., 75, 579-591.
Güzel O, Maresca A, Hall RA, Scozzafava A, Mastrolorenzo A, Mühlschlegel FA, Supuran CT (2010). Carbonic anhydrase inhibitors. The beta-carbonic anhydrases from the fungal pathogens Cryptococcus neoformans and Candida albicans are strongly inhibited by substituted-phenyl-1H-indole-5-sulfonamides. Bioorg. Med. Chem. Lett., 20, 2508-2511
Innocenti A, Hall RA, Scozzafava A, Mühlschlegel FA, Supuran CT (2010). Carbonic anhydrase activators: activation of the beta-carbonic anhydrases from the pathogenic fungi Candida albicans and Cryptococcus neoformans with amines and amino acids. Bioorg. Med. Chem., 18, 1034-1037.
Hall RA, Cottier F, Mühlschlegel FA (2009). Molecular networks in the pathogen Candida albicans. Advances in Applied Microbiology, 67, 191-212
Schlicker C, Hall RA, Vullo D., Middelhaufe S, Gertz M, Supuran CT, Mühlschlegel FA, Steegborn C (2009). Structure and inhibition of the CO2-sensing carbonic anhydrase Can2 from the pathogenic fungus Cryptococcus neoformans. J. Mol. Biol., 385, 1207–1220
Innocenti A, Hall RA, Schlicker C, Scozzafava A, Steegborn C, Mühlschlegel FA, Supuran CT (2009). Carbonic anhydrase inhibitors. Inhibition and homology modeling studies of the fungal beta-carbonic anhydrase from Candida albicans with sulfonamides. Bioorg. Med. Chem., 17, 4503-4509.
Innocenti A, Hall RA, Schlicker C, Mühlschlegel FA, Supuran CT (2009). Carbonic anhydrase inhibitors. Inhibition of the beta-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with aliphatic and aromatic carboxylates. Bioorg. Med. Chem., 17, 2654-2657.
Güzel O, Innocenti A, Hall RA, Scozzafava A, Mühlschlegel FA, Supuran CT (2009). Carbonic anhydrase inhibitors. The nematode alpha-carbonic anhydrase of Caenorhabditis elegans CAH-4b is highly inhibited by 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides. Bioorg. Med. Chem., 17, 3212-3215.
Innocenti A, Winum JY, Hall RA, Mühlschlegel FA, Scozzafava A, Supuran CT (2009). Carbonic anhydrase inhibitors. Inhibition of the fungal beta-carbonic anhydrases from Candida albicans and Cryptococcus neoformans with boronic acids. Bioorg. Med. Chem. Lett., 19, 2642-2645.
Crocetti L, Maresca A, Temperini C, Hall RA, Scozzafava A, Mühlschlegel FA, Supuran CT (2009). A thiabendazole sulfonamide shows potent inhibitory activity against mammalian and nematode alpha-carbonic anhydrases. Bioorg. Med. Chem. Lett., 19, 1371-1375.
Innocenti A, Mühlschlegel FA, Hall RA, Steegborn C, Scozzafava A, Supuran CT (2008). Carbonic anhydrase inhibitors: inhibition of the beta-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with simple anions. Bioorg. Med. Chem. Lett., 18, 5066-5070.
Hall RA, Vullo D, Innocenti A, Scozzafava A, Supuran CT, Klappa P, Mühlschlegel FA (2008). External pH influences the transcriptional profile of the carbonic anhydrase, CAH-4b in Caenorhabditis elegans. Mol. Biochem. Parasitol., 161, 140-149.