Effectors, mechanisms and consequences of sphingomyelinase-dependent regulation of actin dynamics in measles virus induced T cell paralysis

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T cell paralysis is a major hallmark of measles virus (MV)-induced immunosuppression which is reflected by a loss of proliferative responses to mitogenic signals. At a cellular level, this has been related to abrogation of activation of its downstream effectors also including those regulating actin cytoskeletal dynamics. We have recently attributed T cell cytoskeletal paralysis as reflected by the loss of actin based protrusions, actin and receptor polarization, and activation of cytoskeletal linker proteins to activation of cellular sphingomyelinases (SMase) and subsequent accumulation of membrane ceramides in response to interaction of the MV glycoprotein complex with an as yet unknown receptor. The current application now aims on 1) identification of the receptor used by MV to cause T cell paralysis and characterization of its coupling to signaling also including SMase pathways, 2) characterizing the molecular mechanisms underlying MV-induced ceramide accumulation and evaluating consequences on lateral segregation of surface receptors, and actin dynamic dependent motility and its regulation, and lastly, as a follow up ot these studies, 3) the potential of ceramide elevation to regulate threshold levels of T cell activation. Using MV surface interaction with T cells as a model system, these studies will highlight the impact of receptor-dependent SMase activation on regulating T cell responses by targeting actin dynamic activation processes.