Tunicamycins, a class of nucleoside antibiotics similar to corynetoxins of the Rathayibacter toxicus, increase susceptibility of mice to Neospora caninum

Neosporosis is the leading cause of abortion in cattle. Neospora caninum-associated abortion may exhibit both endemic and epidemic patterns. It was reported that the epidemic outbreaks took place in the form of "abortion storms" and were not significantly correlated with seasonal changes or consumption of any particular feeds; and thus, the mechanisms by which the epidemic "abortion storms" are triggered remain unclear. Annual ryegrass toxicity (ARGT) is a severe or fatal neurological disorder of livestock of Australia and South Africa. This disorder is caused by the ingestion of several plant genera (Lolium, Polypogon, and Agrostis) colonized by a nematode (Anguina sp.) and a bacterium, Rathayibacter toxicus. Corynetoxins (CTs) produced by R. toxicus contaminate plants which are in turn ingested by sheep and cattle, causing severe or often fatal hepatocerebral disorders in affected animals. We hypothesize that N. caninum-associated fetal deaths and abortions in cattle may be potentiated by pre-exposure of sublethal levels of CT-contaminated plants prior to N. caninum infection or reactivation of a latent infection. The exposure of sublethal CTs may not cause clinical diseases, but may increase susceptibility to pathogens such as N. caninum. Indeed, CT poisoning surviving pregnant sheep can have up to 10% abortions. The present study investigated whether animals pre-exposed to tunicamycins (TMs), a functional substitute for CTs, had a lowered resistance to sublethal experimental infection by N. caninum tachyzoites in mice. The results showed that sublethal doses of TMs or N. caninum alone did not cause significant deaths. Sublethal doses of N. caninum induced high mortality in TM-treated mice in a dose dependent manner. When mice were treated with a low dose of TMs (5 μg/mouse), as few as 2.5 × 10(6) tachyzoites were needed to induce more than 30% of mortality which is equivalent to the mortality rate caused by 40 × 10(6) tachyzoites. Spleen cells of mice treated with TMs had reduced (p<0.05) Neospora antigen-induced interferon-gamma (IFN-g) production and Con A-stimulated proliferation. The results suggest that CT contaminated plants, when exposed to animals under natural conditions, may contribute to lowered host resistance and increased N. caninum-associated fetal morbidity and mortality in affected animals.