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Evaluating CP inhibitor use for T. foetus in cats

Tolbert MK, Brand MD, Gould EN. In vitro effects of cysteine protease inhibitors on  Tritrichomonas foetus-induced cytopathic changes in porcine intestinal epithelial cells.  Am J Vet Res. 2016 Aug;77(8):890-897.

One of the major causes of infectious diarrhea in cats is a flagellated intestinal dwelling protozoan named Tritrichomonas foetus. Cats infected with T foetus have a waxing and waning diarrhea that can endure for the life of the cat, some cats becoming subclinical carriers.  The reported prevalence of T foetus infection is as high as 30% in dense housing environments, and the infection is found worldwide.

Currently the drug recommended for treatment of T foetus is ronidazole, which is associated with the risk of some adverse effects, including neurotoxic effects. Resistance to this drug is also rapidly developing; therefore, safe and effective treatments are of considerable interest.

The authors have previously demonstrated that adhesion and elaboration of cellular proteases (CPs) produced by T foetus in cats are an important part in the induction of intestinal cytopathic effects. A targeted inhibition of T foetus CPs could be a different approach to the treatment of trichomonosis in cats. Yet, cats also produce CPs that are part of life-critical systems and broad inhibition of CPs would be damaging to cats. The development of protease inhibitors that target specific families of CPs is considered an important step. This has led the way for safe and specific treatments for many protozoal diseases.

In this study, the investigators used T foetus isolates from four naturally infected cats.  The isolates were treated with or without 0.1 to 1.0mM of one of six CP inhibitors antipain, cystatin, leupeptin, and chymostatin and the vinyl sulphone inhibitors WRR-483 and KII777. Each treated or untreated isolate was also co-cultured on nontransformed porcine intestinal epithelial cells for 24 hours. The cytopathic effects of T foetus were then evaluated.

The results suggested an ability of WRR-483, KII777 and cystatin to target specific zones of CP activity of the isolates. The cytopathic changes to the intestinal epithelium induce by all of the isolates were significantly reduced. This is the first time noted for the efficacy of cystatin against trichomonad-induced cytopathic effects. This particular inhibitor may have the potential for treatment in cats and other species for trichomonosis. More study is needed to determine the safety and efficacy of these three protease inhibitors. (VT)

See also:
Tolbert MK, Stauffer SH, Brand MD, Gookin JL. Cysteine protease activity of feline Tritrochomonas foetus promotes adhesion-dependent cytotoxicity to intestinal epithelial cells. Infect Immun. 2014 Jul; 82(7):2851-2859.