Abstract
Viral infection is usually studied at the population level by averaging over millions of cells. However, infection at the single-cell level is highly heterogeneous, with most infected cells giving rise to no or few viral progeny while some cells produce thousands. Analysis of Herpes Simplex virus 1 (HSV-1) infection by population-averaged measurements has taught us a lot about the course of viral infection, but has also produced contradictory results, such as the concurrent activation and inhibition of type I interferon signaling during infection. Here, we combine live-cell imaging and single-cell RNA sequencing to characterize viral and host transcriptional heterogeneity during HSV-1 infection of primary human cells. We find extreme variability in the level of viral gene expression among individually infected cells and show that these cells cluster into transcriptionally distinct sub-populations. We find that anti-viral signaling is initiated in a rare group of abortively infected cells, while highly infected cells undergo cellular reprogramming to an embryonic-like transcriptional state. This reprogramming involves the recruitment of β-catenin to the host nucleus and viral replication compartments, and is required for late viral gene expression and progeny production. These findings uncover the transcriptional differences in cells with variable infection outcomes and shed new light on the manipulation of host pathways by HSV-1.
Highlights
Viruses are obligatory intracellular parasites that rely on the biochemical functions of their hosts to carry out infection
A later study measured the burst size from individual HeLa cells infected with Herpes Simplex virus 1 (HSV-1) and found that many of the infected cells did not release viral progeny, that the variability between individual cells was high and that it did not correlate with the multiplicity of infection (MOI) used (Wildy et al, 1959)
We find that single cells that are infected by the virus show variability in all aspects of infection, starting from the initial phenotype, through the timing and rate of viral gene expression, and ending with the host cellular response
Summary
Viruses are obligatory intracellular parasites that rely on the biochemical functions of their hosts to carry out infection. The picture that emerges from population-level measurements is paradoxical, with wildtype HSV-1 infection both clearly activating (Gianni et al, 2013; Hu et al, 2016; Liu et al, 2016; Reinert et al, 2016) and clearly repressing (Lin et al, 2004; Johnson et al, 2008; Kew et al, 2013; Johnson and Knipe, 2010; Su et al, 2016; Christensen et al, 2016; Manivanh et al, 2017; Yuan et al, 2018; Chiang et al, 2018) the type I IFN pathway Such discrepancies might be resolved with the use of single-cell measurements. We focus on the viral activation of the WNT/b-catenin pathway and find that bcatenin is recruited to the cell nucleus and the viral RCs, and is required for viral gene expression and progeny production
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