Infections of the brain with herpes simplex virus type 1 (HSV-1) cause life-threatening
Herpes simplex encephalitis (HSE) characterized by viral replication in neurons and neuro-
inflammation including an infiltration of peripheral immune cells. HSV-1 reprograms host cells to foster its own replication and for immune evasion, but eventually the immune responses clear the
infection in most patients. However, many survivors suffer from long-term neuronal damage and cannot regenerate all brain functions. HSV-1 influences the physiology of neurons, astrocytes, oligodendrocytes and microglia, and significantly changes their
protein expression and secretion pattern. To characterize temporal changes upon HSV-1
infection in detail, we inoculated mixed primary cultures of the murine brain cortex, and performed quantitative mass spectrometry analyses of the cell-associated
proteome and the secretome. We identified 28 differentially regulated host
proteins influencing
inflammasome formation and intracellular vesicle trafficking during endocytosis and secretion. The
NIMA-related kinase 7 (NEK7), a critical component of the
inflammasome, and ArfGap1, a regulator of endocytosis, were significantly up-regulated upon HSV-1
infection. In the secretome, we identified 71
proteins including guidance cues regulating axonal regeneration, such as semaphorin6D, which were enriched in the
conditioned media of HSV-1 infected cells. Modulation of
inflammasome activity and intracellular membrane traffic are critical for HSV-1 cell entry, virus assembly, and intracellular spread. Our
proteome analysis provides first clues on host factors that might dampen the
inflammasome response and modulate intracellular vesicle transport to promote HSV
infection of the brain. Furthermore, our secretome analysis revealed a set of
proteins involved in neuroregeneration that might foster neuronal repair processes to restore brain functions after clearance of an HSV-1
infection.