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SUMMARY The ergot diseases of grasses, caused by members of the genus Claviceps, have had a severe impact on human history and agriculture, causing devastating epidemics. However, ergot alkaloids, the toxic components of Claviceps sclerotia, have been used intensively (and misused) as pharmaceutical drugs, and efficient biotechnological processes have been developed for their in vitro production. Molecular genetics has provided detailed insight into the genetic basis of ergot alkaloid biosynthesis and opened up perspectives for the design of new alkaloids and the improvement of production strains; it has also revealed the refined infection strategy of this biotrophic pathogen, opening up the way for better control. Nevertheless, Claviceps remains an important pathogen worldwide, and a source for potential new drugs for central nervous system diseases. that give the fungus its significance. In the Middle Ages, vast epidemics of so-called St. Anthony’s Fire disease were caused by the consumption of ergot-contaminated rye bread (Fig. 1). However, midwives used ergot sclerotia as an aid in child birth (and abortion).This dual role of ergot persisted over the centuries. Ergot disease is feared by farmers as, in most countries, regulatory limits of between 0.05% and 0.3% of ergot in grain are standard and can render the grain too poisonous for use, whereas seed loss (5–10%) is almost negligible (Alderman et al., 1998). There has also been considerable commercial interest because of the effects of ergot alkaloids on the mammalian vasculature and central nervous system (CNS); these effects can be used to treat several diseases (Mukherjee and Menge, 2000). Scientific interest in this fungus continues, because the development of new defence strategies against ergot disease and strain improvement programmes for biotechnological purposes require a detailed understanding of the biology, physiology and genetics of this fungus. 1.2 The story of ergot: use, abuse and poisoning 1. INTRODUCTION 1.1 Claviceps spp.—the ergot fungi Members of the fungal ascomycetous genus Claviceps parasitize more than 600 monocotyledonous plants of the Poaceae, Juncaceae and Cyperaceae, including economically important crop plants such as rye, wheat, barley, rice, corn, millet and oat (Bové, 1970). Most of the 30–36 species in this group (Taber, 1985) have a defined, narrow host range. Claviceps purpurea (Fries ex Fries) Tulasne, the most widely known species in Europe, is exceptional, as it infects more than 400 plant species with a disease known as ergot. The common name ‘Ergot Fungus’ is derived from the French word for spur (‘argot’) and refers to the dark sclerotia protruding from the ripe grass ear in the final disease stages (Fig. 5I). These structures contain the physiologically highly active ergot alkaloids, tri- or tetracyclic derivatives of prenylated tryptophan, *Correspondence: E-mail: [email protected] †Present address: AB Enzymes GmbH, Feldbergstr. 78, D-64293 Darmstadt, Germany. ‡Present address: Institute of Molecular Biosciences, Massey University, Private bag 11-222, Palmerston North 4442, New Zealand. There are very early references to ergot in history: for example, a description on an Assyrian tablet in 600 BC referred to it as a ‘noxious pustule in the ear of grain’. Around 350 BC, in one of the sacred books of the Parsees, descriptions were found of ‘noxious grasses that cause pregnant women to drop the womb and die in childbed’ (reviewed, for example, in de Costa, 2002; Schiff, 2006). The intake of ergot alkaloids through the consumption of sclerotia by humans (usually caused by eating contaminated rye bread) or animals causes ergotism. The symptoms of this malady vary, probably depending on the particular profiles of the alkaloids present in the contaminated flour (Eadie, 2003). Two syndromes with different symptoms have been described: convulsive ergotism (Ergotismus convulsivus), characterized by paranoia and hallucinations, twitches and spasms, and gangrenous ergotism (Ergotismus gangraenosus), which causes loss of peripheral sensation, oedema and, finally, the loss of affected tissues (described, for example, in Eadie, 2003). Ergotism is thought to have occurred in ancient times (de Costa, 2002; van Dongen and de Groot, 1995), but had its peak level in Europe in the Middle Ages when the disease affected many thousands of Fig. 1 The temptation of St. Antonius. Detail of the ‘retable d’Issenheim’ (Grünewald, Agression de saint Antoine par les démons, 1512–1516 © musée d’Unterlinden, Colmar). The painting describes the symptoms of an ergot alkaloid poisoning: hallucinations and ‘burning’ limbs/gangrene. people. A monastic order especially cared for the afflicted, the patron saint of which was St. Anthony (Fig. 1). The malady itself was known at that time as ignis sacer (holy fire), or St. Anthony’s Fire, because of the burning sensations in the limbs (Matossian, 1989). The first well-documented epidemic of ergotism was in AD 944–945, when about 20 000 people living in Paris and the Aquitane region of France, at that time about one-half of the population, died of the effects of ergot poisoning (Matossian, 1989; Schiff, 2006). Matossian (1989) also speculates that the slow recovery after the plague epidemics in Europe in the 14th century was at least partly caused by reduced fertility as a result of ergot toxifications. Ergot poisoning is nowadays widely believed to have influenced social history, such as the witch trials of Salem and in Norway during the 17th century (Alm, 2003; Caporael, 1976) and even mystic religious movements (Packer, 1998). Already in the late 16th and beginning of the 17th centuries, observations of the link between ergot-contaminated rye and disease were made (Bauer, 1973), but it was not until the 19th century that the mycologist Louis Rene Tulasne revealed the correlation between infected rye and ergotism (Tulasne, 1853). This led to increased efforts to reduce ergot contamination in rye (for example, by flotation of seeds to remove sclerotia); therefore the occurrence of larger epidemics became rare. The most recent epidemic in Germany occurred in 1879–1881; however, there have been more recent epidemics in parts of Russia (1926–1927) (Barger, 1931; Eadie, 2003) and Ethiopia (1977–1978) (Urga et al., 2002), and, in India, outbreaks continued until the late 20th century (Tulpule and Bhat, 1978). Even today, ergot alkaloid contamination represents a major problem in agriculture and requires continuous control measures (Krska and Crews, 2008). In contrast with this deleterious impact on human history, ergot alkaloids also have benefits for humankind, such as the ancient use of ergot alkaloids for medicinal purposes. Ergot was used as an aid to accelerate parturition or to initiate abortion by midwives in Europe; the first written reference of this is by Adam Lonicer (1582) in his ‘Kreuterbuch’ (reviewed, for example, in van Dongen and de Groot, 1995). This was a risky treatment because the dosage of active ingredients in sclerotia is difficult to control, ranging from 0.01% to 1% of dry weight (Didek-Brumek et al., 1996). Rupture of the uterus as a result of hypercontraction was a significant risk. Since the 19th century, ergot alkaloids have mainly been used to prevent excessive bleeding during or after childbirth, which, even today, accounts for almost one-half of all the postpartum maternal mortalities in developing countries (Li et al., 1996). In addition, ergot alkaloids have been used for the treatment of migraine since the second half of the 19th century (Waokes, 1868; Eulenburg, 1883; cited in Eadie, 2003) and for Parkinson’s disease (see below). With an increased understanding of the chemistry and pharmacology of ergot alkaloids and the first isolation of ergotamine as a pure substance by Stoll in 1918, a significant role in modern medicine for this class of compounds began to emerge (Gröger and Floss, 1998; Sinz, 2008). The ergot alkaloids produced by C. purpurea (mainly ergotamine, ergocryptine and related ergopeptine alkaloids, plus simpler lysergyl amides; all derivatives of the basic ergoline ring structure; see Figs 2 and 3) can be readily converted to D-lysergic acid by alkaline or acid hydrolysis, providing a convenient starting material for pharmaceuticals or illicit drugs. The most famous semi-synthetic ergot alkaloid is the lysergic acid diethylamide (LSD). This compound, first synthesized accidentally in a series of lysergyl amides by Albert Hofmann in 1938 (Hofmann, 1978), is the most potent hallucinogen known (Nichols, 2001). Originally tested as an experimental antidepressant drug and for the treatment of alcoholism and schizophrenia, early tests revealed severe problems, including paranoia, potentially fatal loss of judgement and flashbacks. Nevertheless, the drug was widely used by psychotherapists and psychiatrists for the therapy of neuroses, sexual dysfunctions and anxiety, by scientists for the study of neuronal signal transmission, hallucinations and schizophrenia, and even by the secret service for special interrogation techniques (Hofmann, 1993; Stafford and Golightly, 1967). Based on the work of Leary (1969) and others, LSD became a widely consumed psychedelic drug. Thus, C. purpurea had an impact on a whole generation of drug-using youngsters until, starting from 1966, the drug was declared illegal and most dangerous by the United Nations (UN) and by the US government (Flieger et al., 1997). Quite recently, clinical interest in the therapeutic potential of ergoline hallucinogens is beginning to emerge again, for example in the treatment of autism (Fantegrossi et al., 2008; Sigafoos et al., 2007).