The thioredoxin reductase system in Acanthamoeba

Amoebae of the genus Acanthamoeba are very common inhabitants of soil and water all around the world. They are generally free-living, but when they accidentally have contact to the human eye, lung or skin, they can cause severe diseases. First, acanthamoebae are the causative agents of a very serious inflammation of the eye occurring mainly in contact lens wearers, and secondly they can cause fatal encephalitis in individuals with a compromised immune system, e.g. in AIDS patients. Moreover, acanthamoebae can function as Trojan horses for pathogenic bacteria which reside within the amoebae and are, thereby, protected from disinfectants or antibiotics. The co-habitation of Acanthamoeba and Legionella pneumophila, the causative agent of life-threatening Legionnaires disease, is of particular medical relevance. Due to their global omnipresence and their relevance for human health acanthamoebae are interesting objects of research. Recently, the first genome of an Acanthamoeba was completed and published. The genome sequence showed that acanthamoebae have a peculiar defence system against oxidative stress. One of the central enzymes of this system is thioredoxin reductase (TrxR), a key-player in the regulation of the oxidative defence. To date, two different types of TrxR have been described: a large type, mainly present in higher organisms, and a small type, mainly present in bacteria. Practically all organisms known have either type but not both. However, Acanthamoeba, as the only exception, possesses both types. In this project, we will comprehensively study the TrxR system of Acanthmaoeba and delineate the physiological functions of the two distinct TrxRs. We will further combine fundamental research with practical aspects and test both TrxRs for their potential as targets for chemotherapy against acanthamoebae. This is a pressing issue because all Acanthamoeba infections are notoriously difficult to treat as no specific drugs are available.

Amoebae of the genus Acanthamoeba are very common inhabitants of soil and water all around the world. They are generally free-living, but when they accidentally have contact to the human eye, lung or skin, they can cause severe diseases. First, acanthamoebae are the causative agents of a very serious inflammation of the eye occurring mainly in contact lens wearers, and secondly they can cause fatal encephalitis in individuals with a compromised immune system, e.g. in AIDS patients. Moreover, acanthamoebae can function as "Trojan horses" for pathogenic bacteria which reside within the amoebae and are, thereby, protected from disinfectants or antibiotics. The co-habitation of Acanthamoeba and Legionella pneumophila, the causative agent of life-threatening Legionnaires' disease, is of particular medical relevance. Due to their global omnipresence and their relevance for human health acanthamoebae are interesting objects of research. Recently, the first genome of an Acanthamoeba was completed and published. The genome sequence showed that acanthamoebae have a peculiar defence system against oxidative stress. One of the central enzymes of this system is thioredoxin reductase (TrxR), a key-player in the regulation of the oxidative defence. To date, two different types of TrxR have been described: a large type, mainly present in higher organisms, and a small type, mainly present in bacteria. Practically all organisms known have either type but not both. However, Acanthamoeba, as a rare exception, possesses both types. In this project, we studied the TrxR system of Acanthmaoeba and delineated the physiological functions of the two distinct TrxRs. Moreover, we tested both TrxRs for their potential as targets for chemotherapy against acanthamoebae. We could demonstrated that auranofin is highly effective against Acanthamoeba spp. in vitro at very low concentrations. This is a pressing issue because all Acanthamoeba infections are notoriously difficult to treat as no specific drugs are available.