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Organotypic brain explants reveal an interleukin-12 / interferon-γ / T-cell dependent clearance of measles virus infection

Stubblefield Park, Samantha Renee
http://rave.ohiolink.edu/etdc/view?acc_num=case1297280439

Abstract Details

2011, Doctor of Philosophy, Case Western Reserve University, Molecular Biology and Microbiology.
Genetic studies in immunocompetent mice have shown the importance of both T cells and interferon (IFN)-γ for animal survival of MV challenge; however, the direct role of T cells and IFN-γ within MV-infected brain has not been addressed. Organotypic brain explants represent an effective ex vivo system to define CNS-specific mechanisms of leukocyte migration, activation, and MV clearance and have allowed the visualization of intimate interactions between infected neurons and CD4 T cells, but not CD8 T cells. Additionally, brain explants can be used to determine the antiviral capacity of exogenous leukocytes. Within the heterogeneous brain-derived leukocyte population, which reduces MV RNA levels in brain explants by 60%, CD3 T cells are the active antiviral cells, as CD3+ cells are highly antiviral and CD3-depleted leukocytes are unable to reduce viral load. Neutralization of CCL5 and CXCL10 decreases leukocyte migration to areas of infection up to 70%. However, despite directed migration of T cells to infected neurons, chemokine neutralization revealed that migration is not required for viral clearance, suggesting a cytokine-mediated antiviral mechanism. In accordance with our hypothesis, the ability of leukocytes to clear virus was abrogated when explants were treated with IFN-γ neutralizing antibodies. IFN-γ applied to infected slices reduces viral load by more than 80%; therefore, in brain tissue, IFN-γ is both necessary and sufficient to clear MV from neurons. Jak signaling is required for IFN-γ function indicating that IFN-γ signals through the Jak/STAT pathway. Secretion of IFN-γ is stimulated by IL-12 in the brain explant, as neutralization of IL-12 results in a loss of antiviral activity and stimulation of leukocytes with IL-12/IL-18 enhances their immune effector function. These results reveal that primed T cells directly act to clear MV infection of the brain, using a noncytolytic IL-12- and IFN-γ-dependent mechanism in the CNS.
Alan Levine (Advisor)
Catherine Patterson (Advisor)
Jo Ann Wise (Committee Chair)
Gary Landreth (Committee Member)
Richard Ransohoff (Committee Member)
Amiya Banerjee (Committee Member)
176 p.
Virology
viral immunology; measles virus; T cell, interferon-&947; ; antiviral; CNS

Recommended Citations

Citations

  • Stubblefield Park, S. R. (2011). Organotypic brain explants reveal an interleukin-12 / interferon-γ / T-cell dependent clearance of measles virus infection [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1297280439

    APA Style (7th edition)

  • Stubblefield Park, Samantha. Organotypic brain explants reveal an interleukin-12 / interferon-γ / T-cell dependent clearance of measles virus infection. 2011. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1297280439.

    MLA Style (8th edition)

  • Stubblefield Park, Samantha. "Organotypic brain explants reveal an interleukin-12 / interferon-γ / T-cell dependent clearance of measles virus infection." Doctoral dissertation, Case Western Reserve University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1297280439

    Chicago Manual of Style (17th edition)

case1297280439
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© 2011, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.