Viral infection of human neurons triggers strain-specific differences in host neuronal and viral transcriptomes

Infection with herpes simplex virus 1 (HSV-1) occurs in over half the global population, causing recurrent orofacial and/or genital lesions. Individual strains of HSV-1 demonstrate differences in neurovirulence in vivo, suggesting that viral genetic differences may impact phenotype. Here differentiated SH-SY5Y human neuronal cells were infected with one of three HSV-1 strains known to differ in neurovirulence in vivo. Host and viral RNA were sequenced simultaneously, revealing strain-specific differences in both viral and host transcription in infected neurons. Neuronal morphology and immunofluorescence data highlight the pathological changes in neuronal cytoarchitecture induced by HSV-1 infection, which may reflect host transcriptional changes in pathways associated with adherens junctions, integrin signaling, and others. Comparison of viral protein levels in neurons and epithelial cells demonstrated that a number of differences were neuron-specific, suggesting that strain-to-strain variations in host and virus transcription are cell type-dependent. Together, these data demonstrate the importance of studying virus strain- and cell-type-specific factors that may contribute to neurovirulence in vivo, and highlight the specificity of HSV-1–host interactions.
Author summary Infection with herpes simplex virus 1 (HSV-1) affects a significant portion of the global population, and recent research has implicated persistent HSV-1 infection with the development of disease later in life, including neurodegenerative disease and cardiovascular disease. It is clear that individual strains of HSV-1 that exist within the circulating population exhibit specific genetic differences that affect their phenotypes in experimental settings. These differences in turn may contribute to the wide range of clinical outcomes observed between infected individuals. In this study, we sought to understand virus strain- and host-specific transcriptional changes during HSV-1 infection using an in vitro model of human neurons, a key cell type involved in HSV-1 persistence in humans. We show that different strains of HSV-1 demonstrate differences in viral gene expression and protein levels in infected human neuronal cells. These differences are not as pronounced in epithelial cells, suggesting that dissimilarities in viral gene expression and protein levels between strains may be cell-type specific. Infected neurons also exhibit unique transcriptional changes in response to specific HSV-1 strains, in pathways such as integrin signaling and remodeling of adherens junctions. Together, these data highlight the specificity of HSV-1 strain- and host-interactions, and the need to study the virus strain- and cell type-specific factors that contribute to HSV-1 pathogenesis.