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Nothing remains quite the same

Like Jimmy Buffett says: changes in latitudes, changes in attitudes, nothing remains quite the same.  And nothing is truer than for the SarcocystisSarcocystidae have been around a long time giving them plenty of time to hone their skills as very successful parasites. The parasites strategy is change.  Toxoplasma and Sarcocystis are closely related and use similar infection strategies, that by design, make them very selective for the hosts they infect. These parasites display different surface proteins (SAG’s), during different parts of the infection cycle, that keeps the parasite ahead of protective responses that may be mounted by the host. Stage related protein expression is thought to maintain host specificity and also allow the parasite to manipulate the host’s immune system.

Sarcocystis fayeri infects horses and, unless the horse is debilitated, little pathology results because the horse is a natural intermediate host. Horses have adapted to this species and not surprisingly, horses don’t produce measurable antibodies to the S. fayeri  parasites. Sometimes SAG proteins aren’t abundant enough for laboratory detection, but are important in the animal’s response to infection. Undetectable (laboratory) levels of a parasite protein trigger mechanisms that allow the host to tolerate the parasite.  It is surprising that parasitic protozoa prominently display some SAG’s that become the dominant target of antibody production. This recognition must give some advantage to the parasites.  The resulting serum antibodies are instrumental in controlling infections and that can also favor the ultimate survival of the parasite.

Examples of dominant Sarcocystis neurona SAG’s are SAG 1, 5, and 6.  These SAG’s are detected by day 14-17 of infection, the levels of antibodies rise as the duration of unresolved infection continues. An example of SAG’s that do not induce a measureable antibody response are SAG 3 and 4, as was shown in a horse experiment run at the University of Kentucky.  Variable expression was shown by SAG 2 in the Kentucky experiment, initially measured SAG 2 antibody resolved before the end of the experiment.

In some cases the parasite proteins initiate pathological host immune responses.  These harmful responses can be in full force before other SAG’s are recognized by the host.  This is by parasite design.  For example, in early infections of Toxoplasma gondii, the most successful pathogenic protozoa on the planet, responses to TgSAG1 induce local pathological inflammation.  Experimentally deleting this SAG from the surface of the Toxo also eliminates the pathological immune response.  Likewise, in Sarcocystis neurona, we believe SnSAG1 recruits these adaptive immune responsive cells and these cells may provide the parasite a ride into the central nervous system: inside a host cell.

A large conundrum in Toxoplasmosis is why the intestinal stages of the parasite don’t induce an immune response in the (intermediate) host.  The same proteins displayed on these infectious organisms will induce good immune responses when given as adjuvanted vaccines, proving that they can induce an immune response.  As the infection progresses the parasites display SAG’s that make them recognizable to the host-- eliciting their own demise.  Controlling an infection may benefit Toxo because limiting the infection can ensure the hosts survival.

The horse is an aberrant host for S. neurona, the parasite-horse relationship evolved to limit infections. Some of these adaptive proteins, in some horses, stimulate pathological inflammation.This is perhaps why inflammation persists long after parasite elimination. And a reason why parasites are rarely found in the CNS of experimentally infected horses.  Testing for parasite antibodies can distinguish between animals with inflammatory pathology and those that need an anti-parasitic agent.

It is suggested that the lack of TgSAG1 compromises the ability of the parasite to persist in the brain tissues of mice.  Perhaps the lack of TgSAG1 changes the surface structure of the parasites and hinders its ability to enter host cells. Or it is possible that eliminating the pathological inflammatory process somehow hinders infections in mice. Also, again using Toxoplasma as an example, dendritic cells that are present in the intestinal tissue can extend across the intestinal epithelium and this may be an important mechanism used by parasites to disseminate in the body.

It is our hypothesis that S. neurona also uses dendritic cells to modulate IL6 inflammation. Currently under investigation at Virginia Tech University is the ability of levamisole to regulate the dendritic cells  response in regulating equine leukocytes.  We can provide circumstantial evidence of mechanisms of action of a drug if we can selectively block the action.  Parasites up-regulate IL6 in a detrimental fashion while levamisole turns off the inflammatory component of the IL6 response.  Decreasing the IL6 response by levamisole has been shown in mice and the IL6 response was implicated in dogs with visceral leishmaniasis.  Leishmania is a pathogenic protozoa and stimulates inflammatory molecules to invade the CNS causing signs of disease.  The parasites don’t need to enter the CNS to cause disese, just the cytokine.  If we can turn off the cytokine responses we can alleviate clinical signs of disease.

Part of our work is  to establish the mechanism of action of the drugs used to fight sarcocystosis.  Minor modifications of drugs can make them more efficient or render them ineffective.  For example, the efficacy decoquinate is 15 fold greater, due to increased bioavailability, when smaller particles are used in the formulation.  These effects are demonstrated in PK (pharmakokinetic) studies. Other changes are seen with levamisole.  Levamisole phosphate is toxic while the hydrochloride molecule is not.  And levamisole HCl breaks down very quickly, in just days if it is diluted in water.  That is why levamisole solutions can’t be prepared ahead of time and stored, these solutions won’t work properly.  It doesn’t remain quite the same.

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