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Innate triggering and antiviral effector functions of activin A

View ORCID ProfileK. Al-Hourani, N Ramamurthy, E Marchi, RM Eichinger, LN Lee, P Fabris, P Klenerman, H. Drakesmith
doi: https://doi.org/10.1101/2021.03.23.436626
K. Al-Hourani
University of Oxford
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N Ramamurthy
University of Oxford
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E Marchi
University of Oxford
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RM Eichinger
University of Oxford
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LN Lee
University of Oxford
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P Fabris
University of Oxford
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P Klenerman
University of Oxford
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  • For correspondence: paul.klenerman@ndm.ox.ac.uk
H. Drakesmith
University of Oxford
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Abstract

First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by germline-encoded pattern recognition receptors, followed by activation of the type I IFN system and establishment of an intracellular antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. Activin A mediates multiple innate and adaptive immune functions – including antiviral effects. However, how such effects are mediated and how activin might be triggered by viral infection have not been defined. Here we addressed this in vivo and in vitro, in humans and mice.

Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant activin A and IFNα in vitro. Activin A mRNA, encoded by INHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and in human peripheral blood mononuclear cells. In vivo, infection of mice with influenza A also upregulated Inhba mRNA in the lung; this local upregulation of Inhba is retained in MAVS knockout mice, indicating a role for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis.

Together, these data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions. This model has implications for the development of targeted antiviral therapies, in addition to revealing novel facets of activin biology.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 23, 2021.
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Innate triggering and antiviral effector functions of activin A
K. Al-Hourani, N Ramamurthy, E Marchi, RM Eichinger, LN Lee, P Fabris, P Klenerman, H. Drakesmith
bioRxiv 2021.03.23.436626; doi: https://doi.org/10.1101/2021.03.23.436626
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Innate triggering and antiviral effector functions of activin A
K. Al-Hourani, N Ramamurthy, E Marchi, RM Eichinger, LN Lee, P Fabris, P Klenerman, H. Drakesmith
bioRxiv 2021.03.23.436626; doi: https://doi.org/10.1101/2021.03.23.436626

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