Toxoplasma remains an important cause of congenital infection and a common opportunistic infection in patients with primary and acquired defects in T cell function. This parasite can also cause significant disease in immune competent individuals and has been classified as a category B agent of bioterrorism. Consequently, there has been a long standing interest in defining the immune mechanisms that control this organism. Studies using mouse and human cells have led to a model in which the innate immune system directs the development of protective T cells, characterized by the production of IFN-? which limits parasite replication. However, while T cells are required for the long-term control of T. gondii this same response can contribute to immune-pathology. Consequently, there are numerous regulatory networks that limit the pathological response and early studies identified IL-10 as a key cytokine to prevent immune hyper-reactivity. More recently, this laboratory identified a similar role for the heterodimeric cytokine IL-27 in limiting T cell responses during toxoplasmosis and defined a role for IL-27 in inhibiting multiple T helper cell responses during other parasitic infections. Subsequently we also showed that IL-27 induced the production of IL-10. This latter finding has led to competing models for how T cell sources of IL-10 are regulated. In addition, there remains a poor understanding of the cellular sources of IL-27, the stimuli that control its production during infection and whether it is a negative regulator of innate immunity to T. gondii. Moreover, our preliminary data indicate that different components of IL-27 have unique biological functions and this has raised questions about the role of the cytokine sub-units in promoting protective anti-parasite responses versus limiting infection-induced pathology. Based on these findings, complimentary SA have been developed with the overall goal of understanding the role o IL-27 in innate and adaptive responses to T. gondii.

Public Health Relevance

Toxoplasma is a common opportunistic infection in patients with defects in T cell function and can cause significant disease in immune competent individuals. Under certain circumstances the immune response to this microbe can be extremely violent and cause severe tissue damage. The overall goal of this proposal is to understand how the molecule IL-27 prevents the immune system from over reacting to this infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042334-14
Application #
8488389
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
1997-12-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
14
Fiscal Year
2013
Total Cost
$368,518
Indirect Cost
$138,194
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Harms Pritchard, Gretchen; Hall, Aisling O'Hara; Christian, David A et al. (2015) Diverse roles for T-bet in the effector responses required for resistance to infection. J Immunol 194:1131-40
Dupont, Christopher D; Harms Pritchard, Gretchen; Hidano, Shinya et al. (2015) Flt3 Ligand Is Essential for Survival and Protective Immune Responses during Toxoplasmosis. J Immunol 195:4369-77
Banigan, Edward J; Harris, Tajie H; Christian, David A et al. (2015) Heterogeneous CD8+ T cell migration in the lymph node in the absence of inflammation revealed by quantitative migration analysis. PLoS Comput Biol 11:e1004058
Wagage, Sagie; John, Beena; Krock, Bryan L et al. (2014) The aryl hydrocarbon receptor promotes IL-10 production by NK cells. J Immunol 192:1661-70
Glatman Zaretsky, Arielle; Engiles, Julie B; Hunter, Christopher A (2014) Infection-induced changes in hematopoiesis. J Immunol 192:27-33
Beiting, Daniel P; Peixoto, Lucia; Akopyants, Natalia S et al. (2014) Differential induction of TLR3-dependent innate immune signaling by closely related parasite species. PLoS One 9:e88398
Dupont, Christopher D; Christian, David A; Selleck, Elizabeth M et al. (2014) Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii. PLoS Pathog 10:e1004047
Christian, David A; Koshy, Anita A; Reuter, Morgan A et al. (2014) Use of transgenic parasites and host reporters to dissect events that promote interleukin-12 production during toxoplasmosis. Infect Immun 82:4056-67
Hall, Aisling O'Hara; Beiting, Daniel P; Tato, Cristina et al. (2012) The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37:511-23
Pszenny, Viviana; Davis, Paul H; Zhou, Xing W et al. (2012) Targeted disruption of Toxoplasma gondii serine protease inhibitor 1 increases bradyzoite cyst formation in vitro and parasite tissue burden in mice. Infect Immun 80:1156-65

Showing the most recent 10 out of 81 publications