Inhibition of infection spread by co-transmitted defective interfering particles.

Ashley Baltes,Fulya Akpinar,Bahar Inankur,John Yin,Stefan Pöhlmann

doi:10.1371/journal.pone.0184029

Ashley Baltes, Fulya Akpinar + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0184029

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Abstract

Although virus release from host cells and tissues propels the spread of many infectious diseases, most virus particles are not infectious; many are defective, lacking essential genetic information needed for replication. When defective and viable particles enter the same cell, the defective particles can multiply while interfering with viable particle production. Defective interfering particles (DIPs) occur in nature, but their role in disease pathogenesis and spread is not known. Here, we engineered an RNA virus and its DIPs to express different fluorescent reporters, and we observed how DIPs impact viral gene expression and infection spread. Across thousands of host cells, co-infected with infectious virus and DIPs, gene expression was highly variable, but average levels of viral reporter expression fell at higher DIP doses. In cell populations spatial patterns of infection spread provided the first direct evidence for the co-transmission of DIPs with infectious virus. Patterns of spread were highly sensitive to the behavior of initial or early co-infected cells, with slower overall spread stemming from higher early DIP doses. Under such conditions striking patterns of patchy gene expression reflected localized regions of DIP or virus enrichment. From a broader perspective, these results suggest DIPs contribute to the ecological and evolutionary persistence of viruses in nature.

Highlights

When a virus infects a host cell, it can produce many thousands of virus particles, but most are non-infectious [1], with the ratio of total particles-to-infectious units spanning from 10-to-1 to 100,000-to-1 for diverse RNA and DNA viruses [2]
The red fluorescent protein (RFP)-expressing infectious virus was previously found to grow like wild-type virus, where RFP expression correlated with the production of virus particles [34, 36]
The Inhibition of infection spread by co-transmitted defective interfering particles dual reporters provided detectable measures of both viral and Defective interfering particles (DIPs) gene expression from the same co-infected cells

Summary

Introduction

When a virus infects a host cell, it can produce many thousands of virus particles, but most are non-infectious [1], with the ratio of total particles-to-infectious units spanning from 10-to-1 to 100,000-to-1 for diverse RNA and DNA viruses [2]. Defective interfering particles (DIPs) were discovered more than 70 years ago by von Magnus, who found that serial passage of allantoic fluid containing influenza A virus produced a large increase in material that, like virus, agglutinated red blood cells, but failed to cause infection [3, 4]. DIPs have been found in laboratory cultures of most classes of RNA and DNA viruses [5,6,7]. They have been isolated from patients infected with hepatitis B [8], hepatitis C [9, 10], influenza A [11], and dengue.

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