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How to make S. neurona resistant to treatment

Mantra: EPM is a syndrome that has two components that are protozoa and inflammation. The inflammatory pathway, used by the host to fight infection, is a common host response to infectious organisms (bacteria, virus, parasites, and protozoa). Sarcocystis neurona can manipulate the inflammatory pathway near its origin favoring the growth of protozoa in the horse. By manipulating the host responses, and quelling the neuroinflammation at the origin, we can alleviate disease.

Based on our view of the pathogenesis of disease:

Significance of the presence of antibodies against S. neurona in normal horses:

None! Normal horses, horses without clinical signs, don’t have equine protozoal myeloencephalitis (EPM). There are no licensed treatments for normal horses with or without antibodies to S. neurona.

Significance of the presence of antibody against Sarcocystis in normal horses treated for EPM:

None! However, after treatment of EPM, when the horse is normal, there may be some information that is useful from obtaining an antibody titer if the Sarcocystis was neurona.

Significance of antibody titer against S. neurona in ataxic horses:

The host responds to the mere presence of infectious invaders by directing the innate molecules down an inflammatory path (we suggest the pathway is IL6). The prior experience of the host will change the type and duration of the antibodies. Antibodies appear at an average of 17 days post-challenge (determined by experimental infections) in naïve horses. Antibodies will appear sooner than 17 days in horses that experienced past infections. A four fold increase in titer indicates active infection. Antibodies will decline faster in a naïve horse when compared to experienced horses.

Treatment with antiprotozoal drugs can change the detection of antibodies…duration and levels (titer). Antibodies are delayed in horses that are treated with antiprotozoal drugs before challenge (determined by experimental infections). Horses may be exposed to antiprotozoal drugs if they share the environment with a horse treated with some antiprotozoal drugs. If horses can be exposed by environmental challenge, then other animals (opossums) can be exposed as well. Environmental exposure of animals (that support sexual development of parasites) favors selection of resistant strains. Don’t indiscriminately treat horses that do not have clinical signs of EPM—resistance will condemn future horses to ineffective treatments-indiscriminate use of antibiotics led to super bugs, we don’t want super protozoa! There are specific situations that require preventing the development of parasitic protozoa in the gut of horses, make sure the drug you are using 1) has been shown experimentally to prevent development of protozoa in the gut of animals and 2) does not contaminate the environment.

Significance of phenotype:

Our research focus is the association of encephalomyelitis in disease conditions that stimulate inflammation. The syndrome we study is EPM, the most common etiology is the organism is S. neurona, and the disease is encephalomyelitis. We’ve identified conditions that don’t have an etiology of S. neurona that are often thought to be EPM, until there is a diagnosis we lump non-S. neurona encephalomyelitis into the category Idiopathic Encephalomyelitis. The definition of idiopathic is “arising from an obscure or unknown cause”…so it is quite fitting and descriptive for our uses. Until the cause is known it is idiopathic. We also focus on phenotypes of S. neurona.

Testing serum with the SAG 1, 5, 6 ELISA is unique because it ensures that all phenotypes of S. neurona are screened. Other tests use S. neurona SAG 1 strains for their tests. It is impossible to detect antibodies against S. neurona SAG 5 or S. neurona 6 using a S. neurona SAG 1 strain for antigens. And that is important because ataxic horses most commonly have multiple infections. The only way to detect a resistant strain (if clinical signs are observed in horses that have been treated with antiprotozoal drugs) is by examining the levels of phenotype antibodies. Detection of “common” antigens (IFAT, SAG 2, 3/4) won’t differentiate the resistant strain, untreated disease, or recurrent disease. Resistant strains are probable.

Producing resistant S. neurona

There are several ways to select for drug resistant protozoa. A selection strategy uses the definitive host, opossum, allowing genetic recombination in the sexual stages of S. neurona to produce a resistant or partially resistant protozoa. Allow the organism to prosper by continually using a specific anti-protozoal agent for selection pressure. This results in elimination non-resistant or partially resistant organisms that complete for space in the gut of the opossum. In this way, the opossum would shed many oocysts derived from the resistant strain into the environment and could cause disease in many horses on a local level.

In the field, using a drug to exert selection pressure on the asexual stage of the organism that is found in the horse is accomplished by using sub-optimal doses of drug over an extended time. Of course, for that horse, selecting a different effective drug would be critical to surviving EPM. Increasing the level of drug will adapt the organism to withstand levels that kill non-resistant organisms.

Significance of this blog

A recent short communication (Vet Rec. 2013 Sept 14 (173(10):249 concluded “that there was no difference in the decline in serum antibody titer to S. neurona (IFAT) in untreated versus ponazuril (Marquis) treated normal horses.” Their objective was to show antibodies in this group of horses declined very slowly. They identified re-exposure in 25% of the test group horses and exposure in 33% of the control negative group indicating that S. neurona (a strain that was detected by IFAT) was in the environment at sufficient levels to infect 28.5% of the animals used in their study. They showed that antibodies in this group of horses declined slowly when Sarcocystis remained in the environment. Infection (re-exposure determined by antibody titer) in at least one horse treated for 60 days with 5 mg/kg Marquis was identified in this study. Have these researchers identified a ponazuril (Marquis) resistant organism on this farm? Time will tell.

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