Antiviral responses are shaped by heterogeneity in viral replication dynamics

Lucas J M Bruurs; Micha Müller; Jelle G Schipper; Huib H Rabouw; Sanne Boersma; Frank J M van Kuppeveld; Marvin E Tanenbaum

doi:10.1038/s41564-023-01501-z

Antiviral responses are shaped by heterogeneity in viral replication dynamics

Lucas J M Bruurs
, Micha Müller
, Jelle G Schipper
, Huib H Rabouw
, Sanne Boersma
, Frank J M van Kuppeveld
, Marvin E Tanenbaum^*

^*Corresponding author for this work

Hubrecht Institute

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Antiviral signalling, which can be activated in host cells upon virus infection, restricts virus replication and communicates infection status to neighbouring cells. The antiviral response is heterogeneous, both quantitatively (efficiency of response activation) and qualitatively (transcribed antiviral gene set). To investigate the basis of this heterogeneity, we combined Virus Infection Real-time IMaging (VIRIM), a live-cell single-molecule imaging method, with real-time readouts of the dsRNA sensing pathway to analyse the response of human cells to encephalomyocarditis virus (EMCV) infection. We find that cell-to-cell heterogeneity in viral replication rates early in infection affect the efficiency of antiviral response activation, with lower replication rates leading to more antiviral response activation. Furthermore, we show that qualitatively distinct antiviral responses can be linked to the strength of the antiviral signalling pathway. Our analyses identify variation in early viral replication rates as an important parameter contributing to heterogeneity in antiviral response activation.

Original language	English
Pages (from-to)	2115-2129
Number of pages	15
Journal	Nature Reviews Microbiology
Volume	8
Issue number	11
Early online date	9 Oct 2023
DOIs	https://doi.org/10.1038/s41564-023-01501-z
Publication status	Published - Nov 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

We thank T. Hoek for help with the logistic growth model simulations, and members of the Tanenbaum lab and van Kuppeveld lab for helpful discussions. This work was financially supported by an ERC starting grant to M.E.T. (EU/ERC-677936 RNAREG), an NWO klein-2 grant (OCENW.KLEIN.344) to M.E.T. and F.J.M.v.K, the Howard Hughes Medical Institute through an international research scholar grant to M.E.T. (HHMI/IRS 55008747), and an NWO VICI grant to F.J.M.v.K. (91812628). We also thank the Friends of the Hubrecht Institute for financial support. L.J.M.B., M.M., H.H.R., S.B. and M.E.T. were supported by the Oncode Institute, which is partly funded by the Dutch Cancer Society (KWF).

Funders	Funder number
Howard Hughes Medical Institute	HHMI/IRS 55008747, 91812628
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	OCENW.KLEIN.344
KWF Kankerbestrijding
Hubrecht Institute
Oncode Institute

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s41564-023-01501-zFinal published version, 6.13 MBLicence: CC BY

Cite this

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title = "Antiviral responses are shaped by heterogeneity in viral replication dynamics",

abstract = "Antiviral signalling, which can be activated in host cells upon virus infection, restricts virus replication and communicates infection status to neighbouring cells. The antiviral response is heterogeneous, both quantitatively (efficiency of response activation) and qualitatively (transcribed antiviral gene set). To investigate the basis of this heterogeneity, we combined Virus Infection Real-time IMaging (VIRIM), a live-cell single-molecule imaging method, with real-time readouts of the dsRNA sensing pathway to analyse the response of human cells to encephalomyocarditis virus (EMCV) infection. We find that cell-to-cell heterogeneity in viral replication rates early in infection affect the efficiency of antiviral response activation, with lower replication rates leading to more antiviral response activation. Furthermore, we show that qualitatively distinct antiviral responses can be linked to the strength of the antiviral signalling pathway. Our analyses identify variation in early viral replication rates as an important parameter contributing to heterogeneity in antiviral response activation.",

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AU - Müller, Micha

AU - Schipper, Jelle G

AU - Rabouw, Huib H

AU - Boersma, Sanne

AU - van Kuppeveld, Frank J M

AU - Tanenbaum, Marvin E

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Antiviral responses are shaped by heterogeneity in viral replication dynamics

Abstract

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Funding

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