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Kristopher D Parker, Jason P Gigley, Naomi L Ward
No abstract text is available yet for this article.
September 2016: Cellular and Molecular Gastroenterology and Hepatology
Daria L Ivanova, Rida Fatima, Jason P Gigley
Conventional natural killer (cNK) cells, members of group 1 innate lymphoid cells, are a diverse cell subpopulation based on surface receptor expression, maturation, and functional potential. cNK cells are critical for early immunity to Toxoplasma gondii via IFNγ production. Acute cNK cell responses to infection with different strains of T. gondii have not yet been characterized in detail. Here, we comprehensively performed this analysis with Type I virulent RH, Type II avirulent ME49, and fully attenuated Type I cps1-1 strains...
2016: Frontiers in Immunology
David W Donley, Andrew R Olson, Merl F Raisbeck, Jonathan H Fox, Jason P Gigley
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals...
2016: PloS One
Jason P Gigley
No abstract text is available yet for this article.
February 2016: PLoS Pathogens
Daria Ivanova, Ryan Krempels, Jennyfer Ryfe, Kaitlyn Weitzman, David Stephenson, Jason P Gigley
Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined...
2014: BioMed Research International
Jason P Gigley, Rajarshi Bhadra, Magali M Moretto, Imtiaz A Khan
Protozoan parasites cause severe morbidity and mortality in humans worldwide, especially in developing countries where access to chemotherapeutic agents is limited. Although parasites initially evoke a robust immune response, subsequent immunity fails to clear infection, ultimately leading to the chronic stage. This enigmatic situation was initially addressed in chronic viral models, where T cells lose their function, a phenomenon referred to as 'exhaustion'. However, recent studies demonstrate that this paradigm can be extended to protozoan diseases as well, although with notable differences...
September 2012: Trends in Parasitology
Rajarshi Bhadra, Jason P Gigley, Imtiaz A Khan
We reported earlier that during chronic toxoplasmosis CD8(+) T cells become functionally exhausted with concomitant PD-1 upregulation, leading to eventual host mortality. However, how immune exhaustion specifically mediates attrition of CD8 polyfunctionality, a hallmark of potent T-cell response, during persistent infections has not been addressed. In this study, we demonstrate that PD-1 is preferentially expressed on polyfunctional memory CD8(+) T cells, which renders them susceptible to apoptosis. In vitro blockade of the PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and interferon γ(+)/granzyme B(-) memory but not effector CD8(+) T cells...
July 1, 2012: Journal of Infectious Diseases
Rajarshi Bhadra, Jason P Gigley, Imtiaz A Khan
CD8 exhaustion mediated by an inhibitory programmed death-1-programmed death ligand-1 (PD-L1) pathway occurs in several chronic infections, including toxoplasmosis. Although blockade of the programmed death-1-PD-L1 pathway revives this response, the role of costimulatory receptors involved in this rescue has not been ascertained in any model of CD8 exhaustion. This report demonstrates that one such costimulatory pathway, CD40-CD40L, plays a critical role during rescue of exhausted CD8 T cells. Blockade of this pathway abrogates the ameliorative effects of anti-PD-L1 treatment on CD8 T cells...
November 1, 2011: Journal of Immunology: Official Journal of the American Association of Immunologists
Jason P Gigley, Imtiaz A Khan
Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected...
2011: PloS One
Jason P Gigley, Rajarshi Bhadra, Imtiaz A Khan
CD8 T cells are essential for control of Toxoplasma gondii infection. Once activated they undergo differentiation into short-lived effector and memory precursor effector cells. As effector cells, CD8 T cells exert immune pressure on the parasite via production of inflammatory cytokines and through their cytolytic activity. Once immune control has been established, the parasite encysts and develops into chronic infection regulated by the memory CD8 T-cell population. Several signals are needed for this process to be initiated and for development of fully differentiated memory CD8 T cells...
2011: Journal of Parasitology Research
Rajarshi Bhadra, Jason P Gigley, Imtiaz A Khan
Toxoplasma gondii infection induces a robust CD8 T-cell immunity that is critical for keeping chronic infection under control. In studies using animal models, it has been demonstrated that the absence of this response can compromise the host ability to keep chronic infection under check. Therapeutic agents that facilitate the induction and maintenance of CD8 T-cell response against the pathogen need to be developed. In the last decade, major strides in understanding the development of effector and memory response, particularly in viral and tumor models, have been made...
June 2011: Immunotherapy
Rajarshi Bhadra, Jason P Gigley, Louis M Weiss, Imtiaz A Khan
In this study, we document that Toxoplasma gondii differentiation and reactivation are mediated by systemic CD8 T-cell dysfunction during chronic infection. We demonstrate that CD8(+) T-cell exhaustion occurs despite control of parasitemia during early-chronic toxoplasmosis. During later phases, these cells become exhausted, leading to parasite reactivation and mortality. Concomitant with increased CD8(+) T-cell apoptosis and decreased effector response, this dysfunction is characterized by a graded elevation in expression of inhibitory receptor PD-1 on these cells in both lymphoid and nonlymphoid tissue...
May 31, 2011: Proceedings of the National Academy of Sciences of the United States of America
Barbara A Fox, Alejandra Falla, Leah M Rommereim, Tadakimi Tomita, Jason P Gigley, Corinne Mercier, Marie-France Cesbron-Delauw, Louis M Weiss, David J Bzik
Type II Toxoplasma gondii KU80 knockouts (Δku80) deficient in nonhomologous end joining were developed to delete the dominant pathway mediating random integration of targeting episomes. Gene targeting frequency in the type II Δku80 Δhxgprt strain measured at the orotate (OPRT) and the uracil (UPRT) phosphoribosyltransferase loci was highly efficient. To assess the potential of the type II Δku80 Δhxgprt strain to examine gene function affecting cyst biology and latent stages of infection, we targeted the deletion of four parasite antigen genes (GRA4, GRA6, ROP7, and tgd057) that encode characterized CD8(+) T cell epitopes that elicit corresponding antigen-specific CD8(+) T cell populations associated with control of infection...
September 2011: Eukaryotic Cell
Molly A Balsley, Miroslav Malesevic, Erik J Stemmy, Jason Gigley, Rosalyn A Jurjus, Dallen Herzog, Michael I Bukrinsky, Gunter Fischer, Stephanie L Constant
Although the main regulators of leukocyte trafficking are chemokines, another family of chemotactic agents is cyclophilins. Intracellular cyclophilins function as peptidyl-prolyl cis-trans isomerases and are targets of the immunosuppressive drug cyclosporine A (CsA). Cyclophilins can also be secreted in response to stress factors, with elevated levels of extracellular cyclophilins detected in several inflammatory diseases. Extracellular cyclophilins are known to have potent chemotactic properties, suggesting that they might contribute to inflammatory responses by recruiting leukocytes into tissues...
December 15, 2010: Journal of Immunology: Official Journal of the American Association of Immunologists
Jason P Gigley, Barbara A Fox, David J Bzik
C57BL/6 (B6) mice are genetically highly susceptible to chronic type II Toxoplasma gondii infections that invariably cause lethal toxoplasmic encephalitis. We examined the ability of an attenuated type I vaccine strain to elicit long-term immunity to lethal acute or chronic type II infections in susceptible B6 mice. Mice immunized with the type I cps1-1 vaccine strain were not susceptible to a lethal (100-cyst) challenge with the type II strain ME49. Immunized mice challenged with 10 ME49 cysts exhibited significant reductions in brain cyst and parasite burdens compared to naive mice, regardless of the route of challenge infection...
December 2009: Infection and Immunity
Barbara A Fox, Jessica G Ristuccia, Jason P Gigley, David J Bzik
A high frequency of nonhomologous recombination has hampered gene targeting approaches in the model apicomplexan parasite Toxoplasma gondii. To address whether the nonhomologous end-joining (NHEJ) DNA repair pathway could be disrupted in this obligate intracellular parasite, putative KU proteins were identified and a predicted KU80 gene was deleted. The efficiency of gene targeting via double-crossover homologous recombination at several genetic loci was found to be greater than 97% of the total transformants in KU80 knockouts...
April 2009: Eukaryotic Cell
Jason P Gigley, Barbara A Fox, David J Bzik
A single inoculation of mice with the live, attenuated Toxoplasma gondii uracil auxotroph strain cps1-1 induces long-lasting immunity against lethal challenge with hypervirulent strain RH. The mechanism for this robust immunity in the absence of parasite replication has not been addressed. The mechanism of long-lasting immunity, the importance of route of immunization, cellular recruitment to the site of infection, and local and systemic inflammation were evaluated. Our results show that infection with cps1-1 elicits long-lasting CD8+ T cell- mediated immunity...
January 15, 2009: Journal of Immunology: Official Journal of the American Association of Immunologists
Laura M Beaver, Erik J Stemmy, Stephanie L Constant, Arnold Schwartz, Laura G Little, Jason P Gigley, Gina Chun, Kent D Sugden, Susan M Ceryak, Steven R Patierno
Certain particulate hexavalent chromium [Cr(VI)] compounds are human respiratory carcinogens that release genotoxic soluble chromate, and are associated with fibrosis, fibrosarcomas, adenocarcinomas and squamous cell carcinomas of the lung. We postulate that inflammatory processes and mediators may contribute to the etiology of Cr(VI) carcinogenesis, however the immediate (0-24 h) pathologic injury and immune responses after exposure to particulate chromates have not been adequately investigated. Our aim was to determine the nature of the lung injury, inflammatory response, and survival signaling responses following intranasal exposure of BALB/c mice to particulate basic zinc chromate...
February 15, 2009: Toxicology and Applied Pharmacology
Hongbing Guan, Magali Moretto, David J Bzik, Jason Gigley, Imtiaz A Khan
Recent studies have shown that NK-dendritic cell (DC) interaction plays an important role in the induction of immune response against tumors and certain viruses. Although the effect of this interaction is bidirectional, the mechanism or molecules involved in this cross-talk have not been identified. In this study, we report that coculture with NK cells causes several fold increase in IL-12 production by Toxoplasma gondii lysate Ag-pulsed DC. This interaction also leads to stronger priming of Ag-specific CD8+ T cell response by these cells...
July 1, 2007: Journal of Immunology: Official Journal of the American Association of Immunologists
Crescent L Combe, Magali M Moretto, Joseph D Schwartzman, Jason P Gigley, David J Bzik, Imtiaz A Khan
IFN-gamma-producing CD4+ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-gamma-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4+ T cells from WT to IL-15-/- mice reversed inhibition of gut pathology and caused mortality equivalent to levels of parental WT mice...
April 25, 2006: Proceedings of the National Academy of Sciences of the United States of America
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