Edward S. Mocarski

Natural killer (NK) cells express inhibitory receptors for major histocompatibility complex (MHC) class I antigens, preventing attack against healthy cells. Mouse cytomegalovirus (MCMV) encodes an MHC-like protein (m157) that binds to an inhibitory NK cell receptor in certain MCMV-susceptible mice. In MCMV-resistant mice, this viral protein engages a related activating receptor (Ly49H) and confers host protection. These activating and inhibitory receptors are highly homologous, suggesting the possibility that one evolved from the other in response to selective pressure imposed by the pathogen.

Toll-like receptor (TLR) signaling is triggered by pathogen-associated molecular patterns that mediate well established cytokine-driven pathways, activating NF-κB together with IRF3/IRF7. In addition, TLR3 drives caspase 8-regulated programmed cell death pathways reminiscent of TNF family death receptor signaling. We find that inhibition or elimination of caspase 8 during stimulation of TLR2, TLR3, TLR4, TLR5, or TLR9 results in receptor interacting protein (RIP) 3 kinase-dependent programmed necrosis that occurs through either TIR domain-containing adapter-inducing interferon-β (TRIF) or MyD88 signal transduction. TLR3 or TLR4 directly activates programmed necrosis through a RIP homotypic interaction motif-dependent association of TRIF with RIP3 kinase (also called RIPK3). In fibroblasts, this pathway proceeds independent of RIP1 or its kinase activity, but it remains dependent on mixed lineage kinase domain-like protein (MLKL) downstream of RIP3 kinase. Here, we describe two small molecule RIP3 kinase inhibitors and employ them to demonstrate the common requirement for RIP3 kinase in programmed necrosis induced by RIP1-RIP3, DAI-RIP3, and TRIF-RIP3 complexes. Cell fate decisions following TLR signaling parallel death receptor signaling and rely on caspase 8 to suppress RIP3-dependent programmed necrosis whether initiated directly by a TRIF-RIP3-MLKL pathway or indirectly via TNF activation and the RIP1-RIP3-MLKL necroptosis pathway.

Part I. Introduction Part II. Basic Virology and Viral Gene Effects on Host Cell Functions Part II. Basic Virology and Viral Gene Effects on Host Cell Functions Part II. Basic Virology and Viral Gene Effects on Host Cell Functions Part III. Pathogenesis, Clinical Disease, Host Response, and Epidemiology Part III. Pathogenesis, Clinical Disease, Host Response, and Epidemiology Part III. Pathogenesis, Clinical Disease, Host Response, and Epidemiology Part III. HHV- 6a, 6b and 7 Ann Arvin and Richard Whitley Part III. Pathogenesis, Clinical Disease, Host Response, and Epidemiology Part IV. Non-Human Primate Herpesviruses Ann Arvin, Patrick Moore and Richard Whitley Part V. Subversion of Adaptive Immunity Richard Whitley and Ann Arvin Part VI. Antiviral Therapy Richard Whitley Part VII. Vaccines and Immunotherapy Ann Arvin and Koichi Yamanishi Part VIII. Herpes as Therapeutic Agents Richard Whitley and Bernard Roizman.