Comparative and functional genomics of Toxoplasma and Hammondia hammondi

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Principal Investigator: Jon P Boyle
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $387,539
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT:
Toxoplasma gondii is an important opportunistic pathogen of humans where it can cause severe disease in the
developing fetus and those with HIV/AIDS. Parasite development is critical for its ability to cause severe
disease, yet the precise mechanisms for how it does this are poorly understood. T. gondii is also modulates the
cell that in infects via secretion of a multitude of effectors. Much of the work aimed at understanding how T.
gondii is able to cause disease has focused exclusively on T. gondii itself. An innovative alternative to this
approach is to perform functional and genetic comparisons between T. gondii and its near relatives to reveal
previously unknown mechanisms of parasite virulence and developmental regulation. The parasite Hammondia
hammondi is one such relative, and our work in the prior funding period has developed this organism into a
powerful comparative model for probing T. gondii biology from an evolutionary context. In this renewal we
follow up on two observations from the prior funding period: 1) that T. gondii is unique in its ability to
facultatively regulate its conversion to the quiescent cyst stage and 2) that T. gondii is unique in its ability to
alter the host cell cycle and that this may be linked to suppression of host anti-parasitic responses. In Aim 1 we
use a focused RNAseq screen to identify new regulators of T. gondii development, using H. hammondi as a
natural filter to focus on relevant candidate genes. Success of this Aim is facilitated by the use of new
transgenic approaches for H. hammondi and preliminary data supporting the premise of our candidate based
approach. In Aim 2 we determine how T. gondii and H. hammondi differentially regulate changes in the
infected host cell, with a focus on underappreciated host pathways including DNA damage responses and
cellular senescence. Success of this aim is facilitated by our extensive experience with T. gondii and H.
hammondi sporozoites and in vitro assays, as well as transgenic approaches in H. hammondi that will permit
us to perform the first ever cross-species complementation experiments in this organism. Overall these studies
build on work during the prior funding period aimed at identifying important phenotypic differences between
these closely related parasite species and then determining their molecular mechanisms. We expect these
studies to result in new discoveries of how T. gondii regulates in growth and development and how it is able to
suppress a wide variety of host defenses. Both of these lines of inquiry will identify new avenues for
therapeutic intervention, whether they target the parasite itself or host responses found to be critical for its
survival.

Terms: <0-11 years old><21+ years old><AIDS/HIV><Active Follow-up><Acute><Adopted><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Animals><Antiparasitic Agents><Antiparasitic Drugs><Antiparasitics><Automobile Driving><Biology><Candidate Disease Gene><Candidate Gene><Cell Aging><Cell Body><Cell Cycle><Cell Division Cycle><Cell Senescence><Cells><Cells Placenta-Tissue><Cellular Aging><Cellular Senescence><Child><Child Youth><Children (0-21)><Complement><Complement Proteins><Cyst><DNA Damage><DNA Injury><Data><Developing fetus><Development><Developmental Gene><Disease><Disorder><Fetal Development><Foundations><Funding><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Generalized Growth><Genes><Genetic><Goals><Growth><Growth and Development><Growth and Development function><HIV/AIDS><Host Defense><Immune response><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infection><Inflammatory><Inflammatory Response><Innate Immune Response><Life Cycle><Life Cycle Stages><Link><Masks><Modeling><Molecular><Normal Placentoma><Organism><Outcome><Parasites><Parasiticides><Pathogenesis><Pathogenicity Factors><Pathway interactions><Patients><Persons><Phenotype><Placenta><Placenta Embryonic Tissue><Placentome><Predisposition><RNA Seq><RNA sequencing><RNAseq><Refractory><Regulation><Regulatory Pathway><Replicative Senescence><Signal Pathway><Sporozoites><Stress><Susceptibility><Syntenic Homology><Synteny><System><T gondii><T gondii infection><T. gondii><T. gondii infection><Testing><Therapeutic Intervention><Tissue Growth><Toxoplasma><Toxoplasma gondii><Toxoplasma gondii Infection><Toxoplasmosis><Transgenic Organisms><Virulence><Virulence Factors><Work><active followup><adulthood><comparative><comparative genomics><complementation><developmental><driving><epigenomics><experience><experiment><experimental research><experimental study><experiments><follow up><follow-up><followed up><followup><functional genomics><genetic approach><genetic strategy><host response><human disease><human pathogen><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vitro Assay><innovate><innovation><innovative><intervention therapy><kids><knockout gene><life course><living system><model of animal><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><nucleic acid binding protein><obligate intracellular parasite><ontogeny><opportunistic pathogen><pathogenicity gene><pathway><prevent><preventing><response><success><trait><transcriptome sequencing><transcriptomic sequencing><transcriptomics><transgenic><virulence gene><virulent gene><youngster>