Indoleamine 2,3-Dioxygenase Is Involved in Defense against Neospora caninum in Human and Bovine Cells

Neospora caninum is an apicomplexan parasite closely related to Toxoplasma gondii. In nature this parasite is found especially in dogs and cattle, but it may also infect other livestock. The growth of N. caninum, which is an obligate intracellular parasite, is controlled mainly by the cell-mediated immune response. During infection the cytokine gamma interferon (IFN-γ) plays a prominent role in regulating the growth of N. caninum in natural and experimental disease. The present study showed that induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) is responsible for the inhibition of parasite growth that is mediated by IFN-γ-activated bovine fibroblasts and endothelial cells. This antiparasite effect could be abrogated by addition of tryptophan, as well as by the IDO-specific inhibitor 1-l-methyltryptophan. In conclusion, our data show that human and bovine cells use the same effector mechanism to control the growth of N. caninum.Toxoplasma gondii, a protozoan belonging to the apicomplexan phylum, is one of the most successful parasites on earth. This parasite is capable of infecting nearly all warm-blooded animals, including humans. T. gondii can be transmitted via tissue cysts, raw meat, and environmental-resistant oocysts derived from cat feces and is able to spread transplacentally from mother to fetus. Furthermore, another special feature of this evolutionarily successful parasite is the fact that it usually causes asymptomatic infections and in most cases does not kill immunocompetent hosts. However, without sufficient therapy, reactivation of T. gondii in immunocompromised individuals frequently results in death of the host (31, 26, 18).In 1984 a T. gondii-like parasite was found in the cerebral tissue of dogs and described (5). This parasite was later detected in brain tissue from dogs which had clinical signs of neuromuscular disease and was named Neospora caninum (15). It took until 1998 to discover that dogs are not only intermediate hosts but also one of the definitive hosts of this parasite (29). In nature, dogs are frequently intermediate hosts of N. caninum, although canine neosporosis seems to be rare (2). N. caninum can also be isolated from cattle, and vertically transmitted N. caninum infection is considered an important cause of bovine abortion worldwide (17). In sheep N. caninum-associated abortion seems to be rare (16). This is in contrast to infections with T. gondii, which often cause abortion in sheep but seldom in cattle (14). Furthermore, so far, there is no evidence that N. caninum infection is zoonotic (16). It has been shown that under experimental conditions N. caninum is able to infect rhesus monkeys, indicating the zoonotic potential of this parasite. However, serologic studies with humans have shown that no or only small amounts of N. caninum-specific antibodies are detectable in some human sera, even sera from high-risk groups like farm workers (30, 16, 22). Despite the high levels of homology between T. gondii and N. caninum, many differences have also been detected. Both parasites can be transmitted via food, via oocysts in soil, and also transplacentally (23). Several species have been successfully infected experimentally with N. caninum, and in vitro N. caninum is capable of replicating in different types of cells derived from various animal species or humans.The variability in the susceptibility to natural T. gondii or N. caninum infection among various host species might be due to differences in the immune responses. Different antiparasite effector mechanisms might, at least in part, be involved in the evolutionary success of both parasites. In support of this, workers have obtained some data showing that experimental infection with attenuated or apathogenic N. caninum strains can induce immunity to this parasite in mice and cattle (3). Furthermore, a lot of data indicate that the cellular immune response is necessary to control infection with N. caninum. In addition, it was found that gamma interferon (IFN-γ), a product of activated T cells and natural killer (NK) cells, is one of the main cytokines conferring resistance to N. caninum (21). So far, the IFN-γ-induced effector mechanism that is active against N. caninum in cattle has not been defined.In this paper we provide evidence that induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO), which is the most prominent antiparasite effector mechanism active against T. gondii in human cells (28), is also effective for inhibiting N. caninum growth in tissue cells from humans and cattle.