Abstract
ABSTRACTWhen viruses infect their host cells, they can make defective virus-like particles along with intact virus. Cells coinfected with virus and defective particles often exhibit interference with virus growth caused by the competition for resources by defective genomes. Recent reports of the coexistence and cotransmission of such defective interfering particles (DIPs) in vivo, across epidemiological length and time scales, suggest a role in viral pathogenesis, but it is not known how DIPs impact infection spread, even under controlled culture conditions. Using fluorescence microscopy, we quantified coinfections of vesicular stomatitis virus (VSV) expressing a fluorescent reporter protein and its DIPs on BHK-21 host cell monolayers. We found that viral gene expression was more delayed, infections spread more slowly, and patterns of spread became more “patchy” with higher DIP inputs to the initial cell. To examine how infection spread might depend on the behavior of the initial coinfected cell, we built a computational model, adapting a cellular automaton (CA) approach to incorporate kinetic data on virus growth for the first time. Specifically, changes in observed patterns of infection spread could be directly linked to previous high-throughput single-cell measures of virus-DIP coinfection. The CA model also provided testable hypotheses on the spatial-temporal distribution of the DIPs, which remain governed by their predator-prey interaction. More generally, this work offers a data-driven computational modeling approach for better understanding of how single infected cells impact the multiround spread of virus infections across cell populations. IMPORTANCE Defective interfering particles (DIPs) compete with intact virus, depleting host cell resources that are essential for virus growth and infection spread. However, it is not known how such competition, strong or weak, ultimately affects the way in which infections spread and cause disease. In this study, we address this unmet need by developing an integrated experimental-computational approach, which sheds new light on how infections spread. We anticipate that our approach will also be useful in the development of DIPs as therapeutic agents to manage the spread of viral infections.
Highlights
When viruses infect their host cells, they can make defective virus-like particles along with intact virus
Defective interfering particles (DIPs) compete with intact virus, depleting host cell resources that are essential for virus growth and infection spread
Inhibition of Infection Spread by DI Particles simpler agent-based cellular automaton (CA) models that enable the reproduction of the discrete nature of biological systems and link intracellular and extracellular components of virus infections have been developed [12,13,14,15,16]
Summary
When viruses infect their host cells, they can make defective virus-like particles along with intact virus. While the study of the interactions at each scale can provide valuable data about virus infections, it is becoming increasingly clear that a comprehensive picture of virus infections that accounts for and incorporates virus-host interactions across multiple length scales (from the molecular to the cell and tissue levels, as well as the systemic level) and across multiple time scales (from minutes to hours to days) will be needed to frame in an appropriate context the major challenges facing molecular and cell scientists, clinical virologists, and epidemiologists [1,2,3] Such perspectives may enable the identification and development of new approaches toward the design of antiviral strategies, strategies for preventing viral escape [4,5,6,7]. Such behaviors have yet to inform PDE or CA models of infection spread
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