Invasive candidiasis: new insights presaging new therapeutic approaches?

The expanding universe of amyloid has revealed an intriguing new galaxy, invasive candidiasis, with the publication by Gilchrist et al in this issue of the Journal. Invasive infection of the gut by Candida albicans is a serious, intractable condition that occurs most commonly but not exclusively in neutropenic patients and for which there is very poorly effective treatment. Gilchrist et al now report that amyloid fibrils are produced on the surface of the invading fungal cells in vivo, just as they are in vitro, and that human serum amyloid P component binds to the fibrils both in vitro and in vivo. What does this mean? Amyloid, used in the strict sense, which is essential for correct diagnosis and management of sick patients, is a pathological extracellular deposit composed predominantly of characteristic protein fibrils [1]. About 30 different, unrelated human proteins are now known to form amyloid fibrils in different clinical conditions. Despite widely different structures among their precursor molecules, all amyloid fibrils share the same cross–β core structure and all bind alkaline alcoholic Congo red to produce unique red-green birefringence when observed in strong cross-polarized light. This pathognomonic tinctorial property is the gold standard for histopathological diagnosis of amyloid. The fibrillar cross–β aggregate is a very stable protein assembly, and almost any polypeptide can form amyloid-like fibrils in vitro if subjected to suitable denaturing conditions that enable refolding. In vivo most types of amyloid fibrils are formed by misfolding of native globular proteins, often associated with limited proteolytic cleavage, and some are derived from natively unfolded precursors, but it is not known why only approximately 30 among all human proteins form amyloid in vivo. Regardless of their different protein compositions, all amyloid fibrils are rigid, non–branching, of indeterminate length, about 10 nm in diameter, and composed of 2–6 twisted protofibrils. In addition to the fibrils, amyloid deposits in vivo also always contain abundant heparan and dermatan sulfate proteoglycan and free glycosaminoglycan chains, some of which are tightly associated with the fibrils. Amyloid deposits also always contain serum amyloid P component (SAP), a normal plasma protein of the pentraxin family that shows avid specific calcium dependent binding to amyloid fibrils of all types [2]. Indeed, such binding by SAP is an essential feature, along with birefringence after Congo red staining, for identification of protein fibrils as amyloid. Amyloid deposits disrupt the structure and function of tissues and organs, leading to disease, known as amyloidosis. In systemic amyloidosis, the deposits can occur very widely in connective tissue, including blood vessel walls, and in the parenchymal tissue of any organ except in the brain. Systemic amyloidosis is a very serious condition and is usually fatal, causing about 1 of 1000 deaths in developed countries. There are several different acquired forms of systemic amyloidosis that complicate various primary diseases, by far the most common being AL type caused by monoclonal immunoglobulin light chains in the various plasma cell dyscrasias. There are also many very rare hereditary forms caused by mutations that destabilize the native fold of the respective amyloidogenic precursor protein. In local amyloidosis, the deposits are confined to a single anatomical site, tissue, or organ, for example, focal AL type amyloidomas can occur anywhere; another example is cerebral amyloid angiopathy, a very common and important cause of cerebral hemorrhage. In addition to systemic and local amyloidosis, in which the amyloid deposits are definitely the cause of disease, microscopic amyloid deposits are also always present in the brain in Alzheimer’s disease and in Received and accepted 13 August 2012; electronically published 22 August 2012. Correspondence: Sir Mark Pepys, Prof, FRS, FMedSci, Wolfson Drug Discovery Unit, Centre for Amyloidosis & Acute Phase, Proteins, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK ([email protected]). The Journal of Infectious Diseases 2012;206:1339–41 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jis521