Toll-Like Receptors (TLRs) are a primary mean whereby the innate immune system recognizes and rapidly responds to microbes. Studies employing the mouse models of toxoplasmosis indicate that the Myeloid Differentiation Factor 88 (MyD88), an adaptor-signaling molecule for the TLRs, is critical for initiation of early inflammatory responses and host resistance to infection with T. gondii. At least three TLRs (i.e. TLR2, TLR4 and TLR11) are involved in activation of the innate immune system and host resistance during T. gondii infection in mice. Human TLR 11 has a stop codon making this protein apparently nonfunctional. The main goal of our project is to characterize mechanisms whereby the human innate immune system responds to infection with T. gondii. Specifically, we will test the hypotheses that in humans, TLRs are key cognate receptors involved in the innate immune response to T. gondii tachyzoites, influence development of cell- mediated immunity, and that polymorphisms in TLRs related molecules affects human susceptibility to T. gondii infection. We will characterize the ability of tachyzoites, including their glycosylphospatidylinositol (GPI) and glycosylinositolphospholipids (GIPLs) or other glycolipids, as determined by a lipidomic approach, to bind and signal human cells via TLRs. Our focus will be on TLR2 and TLR4. Using single nucleotide polymorphisms (SNPs) we will look for allelic variation in the genes encoding the relevant TLRs as well as proteins in the signaling pathways that are critical for the functions triggered by TLRs. To determine whether there are associations with disease due to T. gondii in humans, we will characterize TLRs in patients with congenital toxoplasmosis and their parents, and in patients with ocular toxoplasmosis that remains stable or that recurs frequently. We will also evaluate whether allelic variations in TLR genes influence innate and acquired immunologic responses elicited by T. gondii in asymptomatic as well as patients with congenital disease, or acquired ocular toxoplasmosis. T. gondii causes eye disease and neurologic damage in congenitally infected individuals;in addition it affects immunocompromised persons and eye disease in a proportion of those who acquire T. gondii postnatally. Identification of the mechanisms of innate immunity involved in parasite recognition and that influence immune response during T. gondii infection will provide important information about new-strategies that may be applicable in vaccine development and therapy of human toxoplasmosis that maybe used to control parasite transmission, lessen the pathologies mentioned above and to improve the prognosis of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071319-05
Application #
7918923
Study Section
Special Emphasis Panel (ZAI1-AR-I (M2))
Program Officer
Palker, Thomas J
Project Start
2006-09-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2010
Total Cost
$596,019
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Ngô, Huân M; Zhou, Ying; Lorenzi, Hernan et al. (2017) Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer. Sci Rep 7:11496
Pena, Geórgia G; Martinez-Perez, Angel; Dutra, Míriam Santos et al. (2016) Genetic determinants of cardiometabolic risk factors in rural families in Brazil. Am J Hum Biol 28:619-26
Witola, William H; Liu, Susan Ruosu; Montpetit, Alexandre et al. (2014) ALOX12 in human toxoplasmosis. Infect Immun 82:2670-9
Gazzinelli, Ricardo T; Mendonça-Neto, Rondon; Lilue, Jingtao et al. (2014) Innate resistance against Toxoplasma gondii: an evolutionary tale of mice, cats, and men. Cell Host Microbe 15:132-8
Stahl, Philipp; Ruppert, Volker; Meyer, Thomas et al. (2013) Trypomastigotes and amastigotes of Trypanosoma cruzi induce apoptosis and STAT3 activation in cardiomyocytes in vitro. Apoptosis 18:653-63
Dutra, Míriam S; Béla, Samantha R; Peixoto-Rangel, Alba L et al. (2013) Association of a NOD2 gene polymorphism and T-helper 17 cells with presumed ocular toxoplasmosis. J Infect Dis 207:152-63
Andrade, Warrison A; Souza, Maria do Carmo; Ramos-Martinez, Espiridion et al. (2013) Combined action of nucleic acid-sensing Toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to Toxoplasma gondii in mice. Cell Host Microbe 13:42-53
Schamber-Reis, Bruno Luiz Fonseca; Petritus, Patricia M; Caetano, Braulia C et al. (2013) UNC93B1 and nucleic acid-sensing Toll-like receptors mediate host resistance to infection with Leishmania major. J Biol Chem 288:7127-36
Bela, Samantha R; Dutra, Miriam S; Mui, Ernest et al. (2012) Impaired innate immunity in mice deficient in interleukin-1 receptor-associated kinase 4 leads to defective type 1 T cell responses, B cell expansion, and enhanced susceptibility to infection with Toxoplasma gondii. Infect Immun 80:4298-308
Cong, Hua; Mui, Ernest J; Witola, William H et al. (2011) Towards an immunosense vaccine to prevent toxoplasmosis: protective Toxoplasma gondii epitopes restricted by HLA-A*0201. Vaccine 29:754-62

Showing the most recent 10 out of 25 publications