Infections of the central nervous system may result in viral meningitis or encephalitis. HSV-1 infections are often asymptomatic, but re-entry to a productive replication cycle after reactivation can result in blisters or sores, typically in oral, perioral and ocular sites. Primary infection of epithelial cells starts a lytic replication cycle of HSV-1 and is followed by life-long latency in peripheral neurons and periodic reactivation. Based on the sequential expression, the >80 known HSV-1 genes are classified into immediate-early, early, and late 10. During a lytic infection, the viral nucleocapsid enters the cytoplasm and is transported to the nuclear pores where the double-stranded DNA genome is released into the nucleus, transcribed, and replicated. As a model virus, we used herpes simplex virus type 1 (HSV-1) that is a highly prevalent human pathogen 9. We explored the possibility that the infection heterogeneity is connected to how the virus is able to alter the cellular state consisting of the physicochemical status and neighborhood of individual cells. Thus, single-cell studies indicate that infection heterogeneity is a result of a combined action of viral, cellular, and environmental factors. It is also known that cell cycle, size, and neighborhood affect cell-to-cell variation in infections 7, 8. Kinetics of poliovirus infections suggest that cellular and viral factors determine heterogeneity at different infection stages 6. Genetic diversity in virus populations only partially explains variation in influenza virus infections 5. Importantly, the source of cell-to-cell variability in virus infections remains unclear. For example in several life-threatening viral infections immune responses of single cells correlate with disease progression 1, 2, 3, 4. Single-cell heterogeneity in virus infections involves diverse cellular responses to infections as well as variable infection progressions, which together determine disease outcomes. Our data show that multiplexed quantification of responses at the single-cell level, across thousands of cells helps predict infections and identify new targets for antivirals. The multiplexed imaging of HSV-1-induced cellular modifications links infection progression to changes in signaling responses, transcriptional activity, and processing bodies. Spatial information reveals that infection changes the cellular state of both infected cells and of their neighbors. Here we show that the high-dimensional cellular state scape can predict heterogenous infections, and cells move through the cellular state landscape according to infection progression. To study the multimodal response of single human cells to herpes simplex virus type 1 (HSV-1) infection, we mapped high-dimensional viral and cellular state spaces throughout the infection using multiplexed imaging and quantitative single-cell measurements of viral and cellular mRNAs and proteins. Prediction, prevention and treatment of virus infections require understanding of cell-to-cell variability that leads to heterogenous disease outcomes, but the source of this heterogeneity has yet to be clarified.
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