Eradicating latent toxoplasmosis - Toxoplasma gondii is an intracellular protozoan parasite of warm-blooded animals, and has infected up to
one-third of the human population. The replicative stage (tachyzoite) develops into a latent stage (bradyzoite)
that resides inside host cells as cysts in brain, heart, and skeletal muscle tissues. These tissue cysts persist
within the host for life, as they are impervious to the immune response and currently approved anti-parasitic
drugs (e.g. antifolates). Tissue cysts give rise to recurrent reactivation of infection in immune compromised
patients, and some studies have correlated latent toxoplasmosis with various neurological disorders, including
schizophrenia. One of the most pressing needs in the field is the discovery of chemical entities possessing the
ability to attack and reduce tissue cysts. In recent studies, we demonstrated that guanabenz (GA), an old drug
used to treat hypertension, also has potent anti-parasitic activity against Toxoplasma through its ability to
interfere with parasite translational control. GA is already FDA-approved and can cross the blood-brain barrier,
making it an attractive candidate for repurposing as a drug to treat toxoplasmosis. In a mouse model of
infection, we showed that GA displayed modest activity against acute infection, but remarkable activity against
bradyzoite tissue cysts in latent toxoplasmosis, reducing the brain cyst burden 70-80% compared to vehicle
controls. GA thus represents one of the first drugs that demonstrates it is possible to reduce tissue cyst levels
in infected animals. In unrelated studies, our collaborator, Dr. Stone Doggett, found that endochin-like
quinolones (ELQs), which target the parasite's cytochrome bc1 complex, can reduce brain cyst burden up to
~85%. Intriguingly, these two drugs, which have differing mechanisms of action, each lacks the ability to fully
eradicate cysts. We hypothesize that these remaining cysts arise from residual tachyzoites that can be nullified
through the use of a drug combination. In this R21 application, we propose to address this hypothesis with two
specific aims: (i) after treating latently infected mice with GA or ELQ, we will examine specific brain regions to
determine where the intractable cysts remain, and determine whether other organs harbor parasites that evade
drug treatment; (ii) we will determine whether novel combinations of GA and ELQ, or co-administration of
antifolates, will reduce tissue cysts to undetectable levels. The identification of a pharmacological strategy that
reduces or eliminates Toxoplasma tissue cysts would be a significant advance towards a radical cure for
toxoplasmosis.
