Toxoplasma gondii is an intracellular protozoan parasite that has a worldwide distribution. Depending on the geographic area, 30-70% of the human population is infected with this parasite, and essentially the entire human population is at risk of infection. This obligate parasite is usually responsible for multi-organ failure only in immunocompromised individuals, especially those afflicted with AIDS, but if infection with T. gondii occurs during pregnancy, abortion or fetal abnormalities often occur. The combined efforts of IL-12 and IFN- are central to resistance to T. gondii. We have recently established that TLR11 plays a dominant role in sensing T. gondii, regulating IL-12 production, and activating T cell-mediated responses to the parasite. Concomitantly, TLR11 is represented in humans only by a non-functional pseudogene, and the major question of how human innate and adaptive immune responses occur in the absence of TLR11 remains unanswered. The overall goals of this project are 1) to determine the roles of neutrophils, macrophages, and DCs in the regulation of TLR11-independent induction of IL-12;2) to determine the roles of NK, CD4, and CD8 T cells in IFN--dependent host resistance to T. gondii in the absence of TLR11;and 3) to identify similarities and differences during systemic and mucosal TLR11-independent immune responses to T. gondii. These studies are expected to identify mechanisms of TLR11-independent host resistance to T. gondii. In addition, these studies are essential for establishing animal models suitable for the design of protective vaccines against T. gondii, and possibly against other apicomplexan parasites.

Public Health Relevance

The protozoan parasite Toxoplasma gondii is a universally-distributed pathogen that infects over 1 billion people world-wide. The goal of this proposal is to determine how innate and adaptive immunity to T. gondii are induced and regulated in the absence of TLR11 (a situation relevant to human toxoplasmosis). Through the experiments described in this proposal, we expect to obtain the knowledge needed to develop strategies for safe and efficient vaccines against T. gondii and other protozoan parasites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085263-03
Application #
8212630
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Wali, Tonu M
Project Start
2010-02-15
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$392,803
Indirect Cost
$145,303
Name
University of Texas Sw Medical Center Dallas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Song, Jeongmin; Wilhelm, Cara L; Wangdi, Tamding et al. (2016) Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell 164:827-8
Sturge, Carolyn R; Burger, Elise; Raetz, Megan et al. (2015) Cutting Edge: Developmental Regulation of IFN-γ Production by Mouse Neutrophil Precursor Cells. J Immunol 195:36-40
Yarovinsky, Felix (2014) Innate immunity to Toxoplasma gondii infection. Nat Rev Immunol 14:109-21
Oh, Jason Z; Ravindran, Rajesh; Chassaing, Benoit et al. (2014) TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41:478-92
Raetz, Megan; Hwang, Sun-Hee; Wilhelm, Cara L et al. (2013) Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells. Nat Immunol 14:136-42
Raetz, Megan; Kibardin, Alexey; Sturge, Carolyn R et al. (2013) Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin. J Immunol 191:4818-27
Benson, Alicia; Murray, Sean; Divakar, Prashanthi et al. (2012) Microbial infection-induced expansion of effector T cells overcomes the suppressive effects of regulatory T cells via an IL-2 deprivation mechanism. J Immunol 188:800-10
Hwang, Sun-Hee; Lee, Huiyin; Yamamoto, Miwako et al. (2012) B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice. J Immunol 189:5786-96
Kirkland, Donna; Benson, Alicia; Mirpuri, Julie et al. (2012) B cell-intrinsic MyD88 signaling prevents the lethal dissemination of commensal bacteria during colonic damage. Immunity 36:228-38
Hou, Baidong; Benson, Alicia; Kuzmich, Lili et al. (2011) Critical coordination of innate immune defense against Toxoplasma gondii by dendritic cells responding via their Toll-like receptors. Proc Natl Acad Sci U S A 108:278-83

Showing the most recent 10 out of 12 publications