Mini viral RNAs act as innate immune agonists during influenza virus infection

Aartjan J.W. te Velthuis; Joshua C. Long; David L.V. Bauer; Rebecca L.Y. Fan; Hui Ling Yen; Jane Sharps; Jurre Y. Siegers; Marian J. Killip; Hollie French; Maria José Oliva-Martín; Richard E. Randall; Emmie de Wit; Debby van Riel; Leo L.M. Poon; Ervin Fodor

doi:10.1038/s41564-018-0240-5

Mini viral RNAs act as innate immune agonists during influenza virus infection

Aartjan J.W. te Velthuis^*, Joshua C. Long, David L.V. Bauer, Rebecca L.Y. Fan, Hui Ling Yen, Jane Sharps, Jurre Y. Siegers, Marian J. Killip, Hollie French, Maria José Oliva-Martín, Richard E. Randall, Emmie de Wit, Debby van Riel, Leo L.M. Poon, Ervin Fodor

^*Corresponding author for this work

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

Abstract

The molecular processes that determine the outcome of influenza virus infection in humans are multifactorial and involve a complex interplay between host, viral and bacterial factors¹. However, it is generally accepted that a strong innate immune dysregulation known as ‘cytokine storm’ contributes to the pathology of infections with the 1918 H1N1 pandemic or the highly pathogenic avian influenza viruses of the H5N1 subtype^2,3,4. The RNA sensor retinoic acid-inducible gene I (RIG-I) plays an important role in sensing viral infection and initiating a signalling cascade that leads to interferon expression⁵. Here, we show that short aberrant RNAs (mini viral RNAs (mvRNAs)), produced by the viral RNA polymerase during the replication of the viral RNA genome, bind to and activate RIG-I and lead to the expression of interferon-β. We find that erroneous polymerase activity, dysregulation of viral RNA replication or the presence of avian-specific amino acids underlie mvRNA generation and cytokine expression in mammalian cells. By deep sequencing RNA samples from the lungs of ferrets infected with influenza viruses, we show that mvRNAs are generated during infection in vivo. We propose that mvRNAs act as the main agonists of RIG-I during influenza virus infection.

Original language	English
Pages (from-to)	1234–1242
Journal	Nature Microbiology
Volume	3
Early online date	17 Sept 2018
DOIs	https://doi.org/10.1038/s41564-018-0240-5
Publication status	Published - Nov 2018

Access to Document

10.1038/s41564-018-0240-5

Randall_2018_MicroBio_MiniViralRNAs_AAM
©2020 Macmillan Publishers Limited. All Rights Reserved. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1038/s41564-018-0240-5
Accepted author manuscript, 1.38 MB

https://www.repository.cam.ac.uk/handle/1810/279913

Cite this

te Velthuis, A. J. W., Long, J. C., Bauer, D. L. V., Fan, R. L. Y., Yen, H. L., Sharps, J., Siegers, J. Y., Killip, M. J., French, H., Oliva-Martín, M. J., Randall, R. E., de Wit, E., van Riel, D., Poon, L. L. M., & Fodor, E. (2018). Mini viral RNAs act as innate immune agonists during influenza virus infection. Nature Microbiology, 3, 1234–1242. https://doi.org/10.1038/s41564-018-0240-5

@article{062a7e7297774ea6acc3d32304cd47a4,

title = "Mini viral RNAs act as innate immune agonists during influenza virus infection",

abstract = "The molecular processes that determine the outcome of influenza virus infection in humans are multifactorial and involve a complex interplay between host, viral and bacterial factors1. However, it is generally accepted that a strong innate immune dysregulation known as {\textquoteleft}cytokine storm{\textquoteright} contributes to the pathology of infections with the 1918 H1N1 pandemic or the highly pathogenic avian influenza viruses of the H5N1 subtype2,3,4. The RNA sensor retinoic acid-inducible gene I (RIG-I) plays an important role in sensing viral infection and initiating a signalling cascade that leads to interferon expression5. Here, we show that short aberrant RNAs (mini viral RNAs (mvRNAs)), produced by the viral RNA polymerase during the replication of the viral RNA genome, bind to and activate RIG-I and lead to the expression of interferon-β. We find that erroneous polymerase activity, dysregulation of viral RNA replication or the presence of avian-specific amino acids underlie mvRNA generation and cytokine expression in mammalian cells. By deep sequencing RNA samples from the lungs of ferrets infected with influenza viruses, we show that mvRNAs are generated during infection in vivo. We propose that mvRNAs act as the main agonists of RIG-I during influenza virus infection.",

author = "{te Velthuis}, {Aartjan J.W.} and Long, {Joshua C.} and Bauer, {David L.V.} and Fan, {Rebecca L.Y.} and Yen, {Hui Ling} and Jane Sharps and Siegers, {Jurre Y.} and Killip, {Marian J.} and Hollie French and Oliva-Mart{\'i}n, {Maria Jos{\'e}} and Randall, {Richard E.} and {de Wit}, Emmie and {van Riel}, Debby and Poon, {Leo L.M.} and Ervin Fodor",

note = "We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant 090532/Z/09/Z) for the generation of adapter-ligated mvRNA sequencing data. This work was supported by the Wellcome Trust grant 098721/Z/12/Z, the joint Wellcome Trust and Royal Society grant 206579/Z/17/Z and a Netherlands Organization for Scientific Research (NWO) grant 825.11.029 to A.J.W.t.V.; EPA Cephalosporin Junior Research Fellowship to D.L.V.B.; support by the Intramural Research Program of NIAID, NIH, to E.d.W.; Research Grants Council of the Hong Kong Special Administrative Region, China, project no. T11-705/14N and a Croucher Senior Research Fellowship to L.L.M.P.; and Medical Research Council (MRC) programme grants MR/K000241/1 and MR/R009945/1 to E.F. and studentship to J.C.L.",

year = "2018",

month = nov,

doi = "10.1038/s41564-018-0240-5",

language = "English",

volume = "3",

pages = "1234–1242",

journal = "Nature Microbiology",

issn = "2058-5276",

publisher = "Nature publishing group",

}

TY - JOUR

T1 - Mini viral RNAs act as innate immune agonists during influenza virus infection

AU - te Velthuis, Aartjan J.W.

AU - Long, Joshua C.

AU - Bauer, David L.V.

AU - Fan, Rebecca L.Y.

AU - Yen, Hui Ling

AU - Sharps, Jane

AU - Siegers, Jurre Y.

AU - Killip, Marian J.

AU - French, Hollie

AU - Oliva-Martín, Maria José

AU - Randall, Richard E.

AU - de Wit, Emmie

AU - van Riel, Debby

AU - Poon, Leo L.M.

AU - Fodor, Ervin

N1 - We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant 090532/Z/09/Z) for the generation of adapter-ligated mvRNA sequencing data. This work was supported by the Wellcome Trust grant 098721/Z/12/Z, the joint Wellcome Trust and Royal Society grant 206579/Z/17/Z and a Netherlands Organization for Scientific Research (NWO) grant 825.11.029 to A.J.W.t.V.; EPA Cephalosporin Junior Research Fellowship to D.L.V.B.; support by the Intramural Research Program of NIAID, NIH, to E.d.W.; Research Grants Council of the Hong Kong Special Administrative Region, China, project no. T11-705/14N and a Croucher Senior Research Fellowship to L.L.M.P.; and Medical Research Council (MRC) programme grants MR/K000241/1 and MR/R009945/1 to E.F. and studentship to J.C.L.

PY - 2018/11

Y1 - 2018/11

N2 - The molecular processes that determine the outcome of influenza virus infection in humans are multifactorial and involve a complex interplay between host, viral and bacterial factors1. However, it is generally accepted that a strong innate immune dysregulation known as ‘cytokine storm’ contributes to the pathology of infections with the 1918 H1N1 pandemic or the highly pathogenic avian influenza viruses of the H5N1 subtype2,3,4. The RNA sensor retinoic acid-inducible gene I (RIG-I) plays an important role in sensing viral infection and initiating a signalling cascade that leads to interferon expression5. Here, we show that short aberrant RNAs (mini viral RNAs (mvRNAs)), produced by the viral RNA polymerase during the replication of the viral RNA genome, bind to and activate RIG-I and lead to the expression of interferon-β. We find that erroneous polymerase activity, dysregulation of viral RNA replication or the presence of avian-specific amino acids underlie mvRNA generation and cytokine expression in mammalian cells. By deep sequencing RNA samples from the lungs of ferrets infected with influenza viruses, we show that mvRNAs are generated during infection in vivo. We propose that mvRNAs act as the main agonists of RIG-I during influenza virus infection.

AB - The molecular processes that determine the outcome of influenza virus infection in humans are multifactorial and involve a complex interplay between host, viral and bacterial factors1. However, it is generally accepted that a strong innate immune dysregulation known as ‘cytokine storm’ contributes to the pathology of infections with the 1918 H1N1 pandemic or the highly pathogenic avian influenza viruses of the H5N1 subtype2,3,4. The RNA sensor retinoic acid-inducible gene I (RIG-I) plays an important role in sensing viral infection and initiating a signalling cascade that leads to interferon expression5. Here, we show that short aberrant RNAs (mini viral RNAs (mvRNAs)), produced by the viral RNA polymerase during the replication of the viral RNA genome, bind to and activate RIG-I and lead to the expression of interferon-β. We find that erroneous polymerase activity, dysregulation of viral RNA replication or the presence of avian-specific amino acids underlie mvRNA generation and cytokine expression in mammalian cells. By deep sequencing RNA samples from the lungs of ferrets infected with influenza viruses, we show that mvRNAs are generated during infection in vivo. We propose that mvRNAs act as the main agonists of RIG-I during influenza virus infection.

UR - https://doi.org/10.1101/385716

U2 - 10.1038/s41564-018-0240-5

DO - 10.1038/s41564-018-0240-5

M3 - Article

AN - SCOPUS:85053552716

SN - 2058-5276

VL - 3

SP - 1234

EP - 1242

JO - Nature Microbiology

JF - Nature Microbiology

ER -

Mini viral RNAs act as innate immune agonists during influenza virus infection

Abstract

Access to Document

Other files and links

Fingerprint

Richard Edward Randall