Toxoplasma gondii is a significant opportunistic infection of AIDS. T. gondii causes a common infection that develops into chronic life-long infection. Reactivated infection during immune suppression causes a difficult to treat and life-threatening Toxoplasmic encephalitis in AIDS. New strategies are needed to more effectively prevent and treat recurrent infections in AIDS. There is no vaccine or immunotherapy approved for use in humans and current drug treatments are suboptimal. Furthermore, T. gondii infection may influence the outcome of HIV infection and progression to AIDS. Eradicating chronic T. gondii infection is an excellent approach to control/prevent infection in AIDS, however, due to a lack of knowledge about T. gondii infection and host response no strategy is available today to achieve this goal. Immune control of acute and chronic T. gondii infection depends on the development of a protective CD8+ T cell response. We currently have limited knowledge of parasite and host mechanisms that determine priming of the protective CD8+ T cell response. T. gondii infected host cells, particularly infected antigen presenting cell types, such as dendritic cells and macrophages, play a major role in priming the protective CD8+ T cell response. Emerging evidence also points to parasite-secreted proteins as being central to mechanisms of host interaction and host cell manipulation by T. gondii. These observations lead us to hypothesize that parasite secreted proteins play a central role in controlling the priming of CD8+ T cell responses by infected antigen presenting cells. Consequently, we propose to examine the role of specific parasite secreted proteins from virulent type I strains (Aim 1) and chronic type II strains (Aim 2) in priming CD8+ T cells in vitro. Our model predicts that parasite-secreted proteins manipulate the ability of infected cells to prime CD8+ T cell responses. To test this hypothesis, we will measure the ability of host cells infected with type I or type II mutants that lack a specific secreted proein to prime CD8+ T cells.
Aim 3 of this innovative R21 proposal will further examine the role of specific secreted proteins identified in Aim 1 and Aim 2 in ex vivo assays to further understand the mechanisms used by parasite secreted proteins to regulate the priming of natural CD8+ T cell populations during T. gondii infection. Collectively, these Aims will functionally identify parasite-secreted proteins that determine the protective host response and control or loss of control of infection, and will thus identify new targets as well as new strategies for therapeutic intervention. This innovative and exploratory R21 project will also illuminate fundamental aspects of parasite vacuole biology, host-parasite interactions, host cell manipulation, and host response during T. gondii infection.
There is no current treatment to either prevent or eradicate chronic Toxoplasma gondii infection that affects approximately one-third of the population in the USA. Effective control and eradication of this parasite and associated disease in AIDS and immune suppression requires better understanding of how the parasite controls the development of effective CD8+ T cell immunity. This proposal will identify parasite-secreted molecules that control priming of CD8+ T cells and development of immunity, and will thus identify novel aspects of parasite biology and host cell interaction that can be applied to the development of improved therapeutics and vaccines.
|Fox, Barbara A; Rommereim, Leah M; Guevara, Rebekah B et al. (2016) The Toxoplasma gondii Rhoptry Kinome Is Essential for Chronic Infection. MBio 7:|
|Fox, Barbara A; Sanders, Kiah L; Rommereim, Leah M et al. (2016) Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity. PLoS Genet 12:e1006189|
|Rommereim, Leah M; Bellini, Valeria; Fox, Barbara A et al. (2016) Phenotypes Associated with Knockouts of Eight Dense Granule Gene Loci (GRA2-9) in Virulent Toxoplasma gondii. PLoS One 11:e0159306|
|Leroux, Louis-Philippe; Dasanayake, Dayal; Rommereim, Leah M et al. (2015) Secreted Toxoplasma gondii molecules interfere with expression of MHC-II in interferon gamma-activated macrophages. Int J Parasitol 45:319-32|
|Zhao, Yanlin; Marple, Andrew H; Ferguson, David J P et al. (2014) Avirulent strains of Toxoplasma gondii infect macrophages by active invasion from the phagosome. Proc Natl Acad Sci U S A 111:6437-42|
|Patil, Veerupaxagouda; Zhao, Yanlin; Shah, Suhagi et al. (2014) Co-existence of classical and alternative activation programs in macrophages responding to Toxoplasma gondii. Int J Parasitol 44:161-4|
|Mouveaux, Thomas; Oria, Gabrielle; Werkmeister, Elisabeth et al. (2014) Nuclear glycolytic enzyme enolase of Toxoplasma gondii functions as a transcriptional regulator. PLoS One 9:e105820|
|Fox, Barbara A; Sanders, Kiah L; Chen, Shan et al. (2013) Targeting tumors with nonreplicating Toxoplasma gondii uracil auxotroph vaccines. Trends Parasitol 29:431-7|
|Rommereim, Leah M; Hortua Triana, Miryam A; Falla, Alejandra et al. (2013) Genetic manipulation in ?ku80 strains for functional genomic analysis of Toxoplasma gondii. J Vis Exp :e50598|
|Fox, Barbara A; Sanders, Kiah L; Bzik, David J (2013) Non-replicating Toxoplasma gondii reverses tumor-associated immunosuppression. Oncoimmunology 2:e26296|
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