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Sarcocystis fayeri produces a toxin that may cause weakness in horses

Sarcocystis spp. are prevalent in the muscles of horses in various regions of the United States and Europe, as many as 30% of the population are infected. There are four species that infect the muscles of horses, S. asinus, S. bertrami, S. equicanis, and S. fayeri. All of these species use canids as a definitive host and trans-placental infection can occur. The pathogenicity of the four species is variable.

Sarcocystosis can be mild or severe. Signs include fever, apathy, anorexia, myositis, muscle weakness, autoimmune disease, or hair loss. In chronic disease signs include weight loss, difficulty in chewing and swallowing, depression, ataxia, emaciation, and generalized weakness. Generally, the mild histological lesions of myositis don’t correlate with the profound muscular weakness seen in afflicted horses. The role of toxins associated with bradyzoites from sarcocysts is not defined, but may be associated with lost strength.

The pathway to chronic inflammation in horses is unknown. Evidently there is a prepatent period of greater than 79 days in naive horses because three S. neurona seronegative ponies that were fed S. fayeri oocysts remained clinically normal at day 79 when the experiment was terminated. Sarcocystis fayeri sarcocysts were found in striated muscles of all inoculated ponies. Perhaps degenerating cysts release toxin-producing bradyzoites. This pathway may explain profound muscle weakness in debilitated or chronically infected horses. The toxin presumably sensitizes CD4+ T cells. Upon re-exposure to S. fayeri in the gut inflammation may ensue. Inflammation may be measured by serum C-reactive protein (CRP) levels. Serum antibodies against S. fayeri toxin are detectable in horses.

The S. fayeri toxin, called sarcocystine, was first associated with sarcocysts in 1899. There is occasional mild interest in Sarcocystis toxins. In 1997 sarcocystine drew interest, there was an association between human sarcocystosis and multiple sclerosis. Sarcocysts, identified as S. gigantea and S. cruzi, produce a small, heat labile protein-toxin that causes increased respiration, depression, ascending paralysis, even death, in rats and rabbits. Last year severe food poisoning was reported in people eating raw horse meat.

Food poisoning was documented in up to 78% of people consuming contaminated raw horsemeat. Sarcocystis fayeri caused enteritis in people that ingested the muscle cysts. Sarcocysts in the meat were identified by morphology and completing the parasite lifecycle in dogs. The enterotoxin was isolated and characterized. Toxicity was confirmed in rabbits receiving 15 µg of S. fayeri sarcocystine. Molecular analysis indicated the toxin is 15kDa and has homology with virulence and cell-invasion factors of Toxoplasma gondii.

Toxoplasma-induced inflammatory bowel disease is studied in a pathogen-driven mouse model. Acute, lethal ileitis is induced in susceptible mice by single antigen of T. gondii. The susceptible mouse required antigen specific CD4+ effector cells and these cells could transfer susceptibility to resistant mice. The intestinal pathology induced by T. gondii required the induction of proinflammatory cytokines that included INF-γ and TNF-α. Neutralization of INF-γ or CD4+ T cells prevented necrosis of the ilea and prevented acute mortality. This model demonstrated that disease requires the production of chemokines that elicit a proinflammatory responses from CD4+ cells by transferring disease susceptibility to mice using these cells.

After S. fayeri infection, serum antibodies against S. neurona are detected by IFAT.* Sarcocystis fayeri infections may be misdiagnosed as being S. neurona infections using IFAT tests. Treatment for S. fayeri cysts in muscles may differ from treatments for S. neurona merozoites. It is important to determine the effects EPM treatments on S. fayeri cysts. Toxin-specific assays may associate degenerating S. fayeri sarcocysts to muscle weakness in some horses. We developed a serum ELISA to detect S. fayeri toxin-specific antibodies in equine serum. Unlike IFAT, tests the S. fayeri toxin antibodies do not cross-react on SAG 1, 5, or 6 ELISA tests.

*Saville, Dubey, Oglesbee, Sofaly, Marsh, Elitsur, Vianna, Lindsay, Reed 2004

S. neurona, electron micrograph

Apicomplexan parasites are intracellular protozoa that are responsible for a great range of diseases in man and animals. The family Sarcocystidae contain the cyst-forming coccidia, cysts form in muscle tissues of the prey-host. Carnivores (prey) eat the infected muscle tissue and that completes the parasites lifecycle. It is generally thought that muscle cysts (sarcocysts) cause no pathology in the prey-host, except perhaps in debilitated animals. A compromised host may lack a robust immune response that can limit the infection. Exposure to protozoa, and the resulting immunity, builds resistance to infections. It is well known that overuse of antimicrobials and antiparasitic agents was an unwise strategy, it is no different in the fight against Sarcocystis. An unintended consequence of chemical prophylaxis is an animal with no natural immunity.

Sarcocystis fayeri produces sarcocysts in horse muscles and like most Sarcocystis infections, this finding is considered incidental. Early research dismissed S. fayeri as a factor in equine protozoal myeloencephalitis (EPM). Experimentally infecting ponies with S. fayeri and evaluating the immune responses convinced the researchers that infections by two species neurona and fayeri, were indistinguishable using the IFAT test. Important molecular tests identifying S. neurona resulted in 22,076 nucleotide sequences. In contrast, S. fayeri has 15 reported sequences-all are the small subunit ribosomal RNA gene. Variability in the small subunit ribosomal gene is useful to identify Sarcocystis species. Incorrectly, S. neurona and S. falcatula were reported as the same organism based on synonymous regions of this gene.

Our investigations reveal the need for a reassessment of the pathogenesis of S. neurona infections in horses and a need evaluating the role of the immune responses in equine disease. There are reasons that S. fayeri should get a more serious look.

Sarcocystis neurona causes muscle weakness in horses but the parasite isn’t thought to develop cysts in horses. There are four horse-related species that develop cysts in horses: S. asinus, S. bertrami, S. equicanis, and S. fayeri. Canids, including dogs, are the reported definitive hosts for these organisms.

Generally sarcocysts are not associated with inflammation in horse muscles (examined by histopathology), although in some debilitated horses, muscle degeneration is reported. Equine sarcocystosis, considered a mild disease, but can cause fever, apathy, anorexia, myositis, difficulty chewing, muscle weakness, autoimmune disease and sometimes hair loss. Surprisingly the profound muscle weakness exhibited clinically doesn’t correlate with the mild lesions observed by histopathology. And this leads some to hypothesize that there is a toxin associated with muscle infections.

The toxin idea isn’t new. There were reports of Sarcocystis-cyst toxins, called sarcocystine, in 1899. A toxin was isolated from cattle muscle cysts and characterized one hundred years later. Yet the possibility of muscle toxins causing disease in horses hasn’t been evaluated. Sarcocystine causes disease in people. A toxin found in raw horsemeat was associated with human food poisoning. The toxin was isolated from S. fayeri sarcocysts and toxic effects were evaluated in rabbits. The protein toxin, histopathological lesions, animal feeding experiments, rabbit enterotoxin assays, enzymatic digestion experiments, and heat/acid lability assays are similar between S. cruzi and S. fayeri-cyst toxins.

So far, initial research on the enterotoxin from S. fayeri sarcocysts is in humans. It would be interesting to explore a relationship between a S. fayeri sarcocystine and myositis in horses.

There is enough molecular information to investigate sarcocystine as a cause of muscle weakness in horses. The proteomics suggest the S. fayeri sarcocystine is homologous to proteins of Eimeria tenella and Toxoplasma gondii. Protein similarity, if high enough, would indicate conservation of the protein and a role in parasite survival. Protein similarity between organisms would also sink the protein as a good diagnostic to implicate an organism. The best it could be is a diagnostic for protozoal myositis.

It is possible that detecting the sarcocystine would benefit the treatment of sarcocystosis in horses.

Coccidiosis in horses is complicated. It is important to examine many factors before initiating practices that have unintended consequences. It took many animal infection studies to correct the false claim that S. neurona and S. falcatula were synonymous. False assumptions have plagued EPM research for 25 years. This has cost many horses their lives. Studies that examine the effect of equine coccidial infections and the immune response to infection should dominate the conversation. Initially clarifying the definition of EPM and the pathogenesis of disease are important.

Recent attention to daily prophylaxis to reduce antibodies against S. neurona may have unintended consequences in the disease EPM. One must weigh the need for antibody prevention (the consequence of prophylaxis) against the risk of neurologic disease and the consequences to the reduction of natural protective immunity against coccidiosis in the horse. Natural immunity holds S. fayeri in check and probably minimizes the effect of cyst toxins on the infected horse.

Overuse of antimicrobials led to superbugs. The human pharmaceutical industry will spend the many millions of dollars to develop new antimicrobials—if they can. The animal pharmaceutical industry will not spend any dollars on developing new anti-protozoals for the treatment of EPM, especially if there is a resistant superbug. Unintended consequences of prophylaxis may be the release of toxins from S. fayeri cysts. A veterinarian may misdiagnose a toxic event for an active infection—how can one distinguish these cases?