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Principal Investigator: YASUHIRO SUZUKI
Organization: UNIVERSITY OF KENTUCKY
Fiscal Year: 2022
Award: $459,000
Funding agency: National Institute of Allergy and Infectious Diseases
Chronic infection with Toxoplasma gondii can reactivate and cause life-threatening toxoplasmic encephalitis in
AIDS patients and other immunocompromised individuals. The basis of persistence of this chronic infection is
the tissue cyst. Thus, eliminating T. gondii cysts from chronically infected individuals before they become
severely immunosuppressed will be able to prevent this serious disease. However, there are currently no
drugs effective against the cysts. Our recent studies using a murine model uncovered that CD8+ immune T
cells have a potent activity to directly penetrate into the cysts and induce their elimination through perforin-
mediated mechanisms. We also identified that the N-terminal region (amino acids 41-152) of dense granule
protein (GRA) 6 (GRA6Nt) of the parasite presented by the H-2Ld molecule is a key antigen to activate the anti-
cyst CD8+ T cells. Our studies also identified that Iba1+ microglia and Ly6C+ macrophages accumulate to the
cysts during the T cell-initiated immune process, and that these phagocytes kill T. gondii bradyzoites within the
cysts, at least in part, by phagolysosome acidification. Based on these observations, the proposed studies are
designed to obtain the information required for proceeding towards development of a vaccine to activate CD8+
T cells capable of targeting T. gondii cysts and eradicate chronic infection with this parasite in humans. For
this purpose, we need to determine whether GRA6Nt activates anti-cyst CD8+ T cells through human MHC
class I molecules, since the MHC class I molecules present antigens to activate CD8+ T cells. Aim 1 will
address this point by employing three transgenic mouse strains expressing either of the three major MHC class
I supermotifs that cover 90% of human population. Once the anti-cyst T cells are primed, these T cells need to
be recruited to cyst-containing cells and activated not only by recognizing T. gondii antigens but also by
appropriate costimulatory molecules expressed on the cyst-containing cells. Our recent studies suggested an
involvement of CXCL10 chemokine and inducible constimulator ligand (ICOSL) in these processes. Thus, Aim
2 will determine the roles of CXCL10 and ICOSL in recruitment and activation of anti-cyst CD8+ T cells,
respectively. Another critical but unsolved issue is that small numbers of cysts persist in the brains of infected
mice even in the presence of anti-cyst CD8+ T cells. Our recent study revealed that these persisting cysts
express significantly greater levels of mRNA for selected GRA and rhoptry (ROP) proteins when compared to
the overall cyst population that exists in the absence of the T cells. Since GRAs and ROPs are secreted from
the parasite into infected cells, upregulated secretion of these selected GRAs and ROPs could play crucial
roles in manipulating the functions of cyst-containing cells to prevent the attack by CD8+ T cells. Thus, Aim 3
focuses to determine whether these GRAs and ROPs play key roles in the evasion of the cysts from the T cell
attack. We will also address the molecular mechanisms underlying this evasion process. The information from
these studies will establish the basis for developing a novel method to eradicate chronic T. gondii infection.
Terms: <AIDS><Abscission><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunologic Deficiency Syndrome><Acute><Address><Amino Acids><Antigenic Determinants><Antigens><Binding Determinants><Body Tissues><Brain><Brain Nervous System><CD183><CD28><CD28 gene><CD8><CD8 Antigens><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8 molecule><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD86><CD86 gene><CD8B><CD8B1><CD8B1 gene><CKR-L2><CMKAR3><CRG-2><CXCL10><CXCL10 gene><CXCR3><CXCR3 gene><Cell Body><Cell surface><Cells><Chemokine (C-X-C Motif) Receptor 3><Chemotactic Cytokines><Chronic><Class I Antigens><Class I Genes><Class I Major Histocompatibility Antigens><Co-Stimulator><Combination Vaccines><Combined Vaccines><Complex Class 1><Costimulator><Cyst><Cytoplasmic Granules><Disease><Disorder><Drugs><Encephalon><Epidermal Thymocyte Activating Factor><Epitopes><Excision><Extirpation><Funding><G Protein-Coupled Receptor 9><GPR9><HLA Class I Histocompatibility Antigen, A-2 Alpha Chain><HLA-A Class I Antigen 2><HLA-A Histocompatibility Type Antigen 2><HLA-A2><HLA-A2 Antigen><Histocompatibility Antigens Class I><Homologous Chemotactic Cytokines><Hortega cell><Human><IFI10><IL-2><IL2 Protein><INP10><IP-10><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><Immune><Immune Evasion><Immunes><Immunity><Immunize><Immunochemical Immunologic><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunologic><Immunological><Immunologically><Immunologics><Immunosuppressed Host><Individual><Intercrines><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><KO mice><Knock-out Mice><Knockout Mice><LYT3><Leu-2 Antigens><Life><Ligands><Lymphocyte Mitogenic Factor><MHC Class I><MHC Class I Genes><MHC Class I Molecule><MHC Class I Protein><MHC class I antigen><MOB-1><Major Histocompatibility Complex Class 1><Major Histocompatibility Complex, Class I, A2 Antigen><Mediating><Medication><Messenger RNA><Methods><Mice><Mice Mammals><Microglia><Mig Receptor><Mig-R><MigR><Mitogenic Factor><Modern Man><Molecular><Mouse Strains><Murine><Mus><Mφ><N-terminal><NH2-terminal><Null Mouse><OKT8 antigen><Parasites><Patients><Phagocytes><Phagocytic Cell><Phagocytosis><Phagolysosome><Pharmaceutic Preparations><Pharmaceutical Preparations><Play><Population><Process><Proteins><Removal><Role><SCYB10><SIS cytokines><Surgical Removal><System><T cell growth factor><T gondii><T gondii infection><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cell T8 Antigens><T-Cells><T-Lymphocyte><T-Stage><T. gondii><T. gondii infection><T44><T8 Cells><T8 Lymphocytes><T8 molecule><Thymocyte Stimulating Factor><Tissues><Toxoplasma><Toxoplasma gondii><Toxoplasma gondii Infection><Toxoplasmosis><Transgenic Mice><Tumor stage><Vaccines><amebocyte><aminoacid><base><chemoattractant cytokine><chemokine><chronic infection><design><designing><develop a vaccine><develop vaccines><development of a vaccine><drug/agent><gIP-10><gitter cell><granule><immune modulatory intervention><immunogen><immunointervention><immunological intervention><immunosuppressed><immunosuppressed patient><improved><lymphocyte pore-forming protein><mRNA><macrophage><mesoglia><microglial cell><microgliocyte><mouse model><murine model><novel><pathogen><perforin><perivascular glial cell><persistent infection><prevent><preventing><rab G-Proteins><rab GTP-Binding Proteins><rab GTPases><recruit><resection><rhoptry><social role><suppressor T lymphocyte marker><thymus derived lymphocyte><toxoplasma encephalitis><toxoplasmic encephalitis><vaccine development>