This project is directed at defining intercellular communication pathways critical for host defense to a persistent pathogen. The TNF related cytokines, Lymphotoxin-ap and LIGHT form an integrated communication network between lymphocytes, dendritic cells and stromal cells that is specifically targeted by herpesviruses. We uncovered a molecular pathway of mutual cooperation between these cytokines and the viral pathogen, human cytomegalovirus. Signaling by the Lymphotoxin (LT)-p receptor inhibited cytopathic effects and replication of human CMV that depended on cooperative induction of interferon-p (IFNp). In the mouse, the LTap-IFNp pathway is required for controlling mouse CMV in part by providing critical survival signals for T and B lymphocytes. However, the cell-to-cell networks that form the LTap-IFNp defense mechanism are not defined. We recently identified an inhibitory cosignaling pathway that regulates T cell proliferation. The herpesyirus entry mediator (HVEM) acts as a dual switch by propagating positive signals from LIGHT and activating inhibitory signals through the Ig-family member, B T lymphocyte attenuator (BTLA). BTLA contains an ITIM motif that when activated by HVEM inhibits T cell signaling. Human CMV may usurp the HVEM-BTLA inhibitory cosignaling pathway through the UL144 orf. UL144 is an ortholog of HVEM that binds BTLA, but not LIGHT, and thus may attenuate T cell activation. The experiments proposed for this project are designed to identify genetic and molecular mechanisms of how LTap/LIGHT-related cytokines coordinate cell-to-cell communication that orchestrate host defense to cytomegalovirus.
Three aims are proposed to address these questions.
In aim 1 the cellular source of LTap required to induce IFNp during MCMV infection will be addressed using mice with conditional deletion of LTp in T or B cells. The cells producing IFNp in response to LTap signaling will be defined using an IFNp knockin reporter mouse. The role of HVEM-BTLA system in resistance to MCMV will be tested in HVEM and BTLA deficient mice. The mouse CMV model provides genetic and physiological context in which to view intercellular interactions mediated by these cytokines.
In aim 2 the role of UL144 as coreceptor for BTLA will be addressed by mutagenesis to define the binding interactions and determine if UL144 mimics or antagonizes BTLA cosignaling activity in human T cells. We developed a cervical tissue explant model in which to study HCMV pathogenesis that will be applied in Aim 3 to evaluate the LTap-IFNp and UL144-BTLA pathways in human CMV pathogenesis. Lay summary: This project investigates how lymphoid cells communicate with each other to defend against a persistent virus. We discovered several tricks used by herpesviruses that thwart the immune system that may prevent clearance of the virus from the body. The experiments here will provide a comprehensive investigation with mouse and humans that may reveal new approaches to altering immune responses to a persistent pathogen.
|Šedý, John R; Balmert, M Olivia; Ware, Brian C et al. (2017) A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem 292:21060-21070|
|Ward-Kavanagh, Lindsay K; Lin, Wai Wai; Šedý, John R et al. (2016) The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44:1005-19|
|Šedý, John; Bekiaris, Vasileios; Ware, Carl F (2015) Tumor necrosis factor superfamily in innate immunity and inflammation. Cold Spring Harb Perspect Biol 7:a016279|
|Lau, E; Sedy, J; Sander, C et al. (2015) Transcriptional repression of IFN?1 by ATF2 confers melanoma resistance to therapy. Oncogene 34:5739-48|
|Li, Hao; Fu, Yang-Xin; Wu, Qi et al. (2015) Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus. J Clin Invest 125:2877-90|
|Bekiaris, Vasileios; Šedý, John R; Ware, Carl F (2014) Mixing Signals: Molecular Turn Ons and Turn Offs for Innate ?? T-Cells. Front Immunol 5:654|
|Gommerman, Jennifer L; Browning, Jeffrey L; Ware, Carl F (2014) The Lymphotoxin Network: orchestrating a type I interferon response to optimize adaptive immunity. Cytokine Growth Factor Rev 25:139-45|
|Allen, Sariah J; Rhode-Kurnow, Antje; Mott, Kevin R et al. (2014) Interactions between herpesvirus entry mediator (TNFRSF14) and latency-associated transcript during herpes simplex virus 1 latency. J Virol 88:1961-71|
|Ware, Carl F (2013) Protein therapeutics targeted at the TNF superfamily. Adv Pharmacol 66:51-80|
|Šedý, John R; Bjordahl, Ryan L; Bekiaris, Vasileios et al. (2013) CD160 activation by herpesvirus entry mediator augments inflammatory cytokine production and cytolytic function by NK cells. J Immunol 191:828-36|
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