The VALIDATE Network - Vaccine development for complex intracellular neglected pathogens
Identification and Characterization of Persistence Mechanisms of Select Protozoan Pathogens
Deadline 22 February 2022
The purpose of this Funding Opportunity Announcement (FOA) is to expand our understanding of protozoan parasite persistence mechanisms and provide research tools and strategies to enable identification and credentialing of novel treatments for persistent protozoan pathogens.
Various parasitic protozoa establish long-term infections, often in the face of apparently effective treatment. The basis for the establishment of such infections is not well understood but appears to be linked to a subpopulation of parasites that is capable of limiting the impact of host defenses and antiparasitic therapy. Indeed, a subpopulation of parasites, known as persisters, appears to be capable of entering into a metabolically quiescent state that is distinct from that of the parent population and renders them refractory to specific drugs. The mechanisms driving this persistence in protozoa remain largely unknown and potentially serve as an untapped source of potential targets for intervention. Major gaps in our knowledge of the basic biology of these populations include host environmental conditions that drive a subset of the population to enter a persistent state, signaling mechanisms used by the parasite to enter and exit the persistent state, and a lack of appropriate in vitro and in vivo models and diagnostics for persister phenotypes. While major strides have recently been made in the understanding and control of these pathogens, the inability to easily detect, prevent, or treat persistent parasites limits efforts to rid the human host of these pathogens, resulting in continued pathology and transmission. Consequently, successful efforts to control and eliminate these pathogens in the future must also address the persister stages.
Parasitic protozoa, such as Plasmodium species that cause malaria, Toxoplasma gondii, kinetoplastid protozoa including Trypanosoma cruzi and Leishmania spp, and Trichomonas vaginalis, are responsible for substantial morbidity and mortality globally each year. These pathogens are known to establish long-lived infections, sometimes even in the face of seemingly appropriate therapy, and, in part due to the complex lifecycles of these pathogens, the mechanisms utilized by them to establish persistent states have proven quite difficult to identify and dissect. Of particular interest to this initiative are the following pathogens and lifecycle stages:
Hypnozoite stage of Plasmodium vivax, P. ovale, and P. cynomolgi: this parasitic stage is responsible for relapsing malaria infections but is difficult to study due the rarity of hypnozoites within host hepatocytes and a lack of appropriate rodent modeling or robust in vitro culture methodology.
Bradyzoite stage of Toxoplasma gondii: the signals and molecular pathways driving the transition from tachyzoite to bradyzoite, and back again, in toxoplasmosis are still poorly understood and remain an impediment in the development of appropriate treatment therapies.
Amastigote stages of Trypanosoma cruzi and Leishmania spp.: the spontaneously occurring intracellular-amastigote stage of T. cruzi allows the parasite to transiently evade multiple forms of drug treatment before returning to an actively replicating trypomastigote stage; similarly, Leishmania spp, are known to develop a semi-quiescent amastigote stage with reduced metabolic activity that provides a treatment avoidance capability.
Pseudocyst stage of Trichomonas vaginalis: the recent discovery of the pseudocyst form of T. vaginalis has highlighted yet another protozoan parasite with the ability to evade conventional antimicrobial treatment.
This initiative will support basic and preclinical research to characterize persister stages in selected protozoan infections (i.e., relapsing malaria, Chagas’ Disease, leishmaniasis, toxoplasmosis, and trichomoniasis). For each pathogen, priority research areas include but are not limited to:
Identification of host environmental signals or triggers for protozoan entry into or exit from metabolically quiescent states.
Identification of the parasitic mechanisms for entry into, maintenance of, and exit from metabolically quiescent states.
Discovery of diagnostics and biomarkers for persister stages.
Development of appropriate, experimentally tractable in vitro and in vivo models of persister infection.
Identification of potential druggable targets during quiescent states or approaches to break dormancy.
Applications proposing the following topic will be considered non-responsive and will not be reviewed.
Applications focused on parasites and/or parasite developmental stages other than those identified above.