Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). To improve prevention and management of TE, it is important to understand the immunopathogenesis of the disease. The murine models of TE that we developed provide an excellent opportunity to critically analyze the mechanisms of host defense in the brain. It is well documented that T cells recruited into the brain are an essential source of IFN-3 for prevention of TE. However, it is not known how the host defense functions during the early stage of reactivation of infection before large numbers of T cells enter the brain. This early defense system could be crucial for limiting tachyzoite growth and initiating T cell immunity to prevent TE. We recently found that microglia, which are resident macrophages in the brain parenchyma, produce IFN-3 during the early stage of reactivation. Our studies also suggest that production of IFN-3 by brain-specific cells, in addition to T cells, is required for prevention of TE. Therefore, IFN-3 production by microglia appears to be a novel early defense mechanism essential for prevention of the disease.
The specific aims i n this proposal are designed to define the role of IFN-3 produced by microglia in inhibition of tachyzoites growth, induction of T cell immunity, and prevention of TE. In the first aim, we will examine the inhibitory effects of IFN-3 produced by microglia on tachyzoite proliferation in the brain after reactivation of infection using mice that have IFN-3 production only by microglia.
The second aim i s to determine if IFN-3 production by microglia induces expression of mediators that recruit T cells into the brain. We will examine whether IFN-3 production by microglia induces expression of chemokines in brain cells and adhesion molecules on cerebrovascular endothelial cells. We will then use in vivo T cell migration assays to determine whether IFN-3 production by microglia facilitates infiltration of immune T cells into the brain.
The third aim i s to determine if IFN-3 production by microglia induces expression of MHC molecules for activation of T cells in the brain. In the fourth aim, we will determine the requirement of IFN-3 production by microglia and T cells for prevention of TE. For this purpose, we will purify immune T cells from infected wild-type or IFN-3-deficient mice and transfer these T cells into infected mice that express IFN-3 only by microglia or lack expression of this cytokine. Host mice will be followed for development of TE. We will also examine the role of IFN-3-dependent mediators of T cell recruitment determined in Specific Aim 2 for prevention of TE. The studies in these four specific aims will provide novel and crucial information that allows us to understand how IFN-3-production by microglia enables the host defense system in the brain to prevent TE.

Public Health Relevance

Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). The proposed studies are to analyze how brain cells (microglia) inhibit parasite growth and induce the immune responses to prevent TE. This information will contribute to better understanding of the immunopathogenesis of TE and to improved prevention and management of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078756-06
Application #
8294972
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
2008-07-03
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$358,538
Indirect Cost
$113,513
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Ochiai, Eri; Sa, Qila; Perkins, Sara et al. (2016) CD8(+) T cells remove cysts of Toxoplasma gondii from the brain mostly by recognizing epitopes commonly expressed by or cross-reactive between type II and type III strains of the parasite. Microbes Infect 18:517-22
Sa, Qila; Ochiai, Eri; Tiwari, Ashish et al. (2015) Cutting Edge: IFN-γ Produced by Brain-Resident Cells Is Crucial To Control Cerebral Infection with Toxoplasma gondii. J Immunol 195:796-800
Ochiai, Eri; Sa, Qila; Brogli, Morgan et al. (2015) CXCL9 is important for recruiting immune T cells into the brain and inducing an accumulation of the T cells to the areas of tachyzoite proliferation to prevent reactivation of chronic cerebral infection with Toxoplasma gondii. Am J Pathol 185:314-24
Sa, Qila; Ochiai, Eri; Sengoku, Tomoko et al. (2014) VCAM-1/α4β1 integrin interaction is crucial for prompt recruitment of immune T cells into the brain during the early stage of reactivation of chronic infection with Toxoplasma gondii to prevent toxoplasmic encephalitis. Infect Immun 82:2826-39
Sa, Qila; Woodward, Jerold; Suzuki, Yasuhiro (2013) IL-2 produced by CD8+ immune T cells can augment their IFN-ýý production independently from their proliferation in the secondary response to an intracellular pathogen. J Immunol 190:2199-207
Sullivan, Adam M; Zhao, Xiaopeng; Suzuki, Yasuhiro et al. (2013) Evidence for finely-regulated asynchronous growth of Toxoplasma gondii cysts based on data-driven model selection. PLoS Comput Biol 9:e1003283
Hester, James; Mullins, Jeremi; Sa, Qila et al. (2012) Toxoplasma gondii antigens recognized by IgG antibodies differ between mice with and without active proliferation of tachyzoites in the brain during the chronic stage of infection. Infect Immun 80:3611-20
Suzuki, Yasuhiro; Sa, Qila; Gehman, Marie et al. (2011) Interferon-gamma- and perforin-mediated immune responses for resistance against Toxoplasma gondii in the brain. Expert Rev Mol Med 13:e31
Singh, Jatinder; Graniello, Carmine; Ni, Yanyan et al. (2010) Toxoplasma IgG and IgA, but not IgM, antibody titers increase in sera of immunocompetent mice in association with proliferation of tachyzoites in the brain during the chronic stage of infection. Microbes Infect 12:1252-7
Wen, Xiangshu; Kudo, Tomoya; Payne, Laura et al. (2010) Predominant interferon-γ-mediated expression of CXCL9, CXCL10, and CCL5 proteins in the brain during chronic infection with Toxoplasma gondii in BALB/c mice resistant to development of toxoplasmic encephalitis. J Interferon Cytokine Res 30:653-60

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