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bioRxiv · 10.1101/2024.06.13.598936

Viral Insulin/IGF-like Peptides Selectively Activate Host Insulin/IGF Signaling pathways during Grouper Iridovirus Infection

CHUARD, A.·Nesarajah, K.·Danazumi, K.·Reiners, K.·Zhang, F.·Levintov, L.·Vashisth, H.·DiMarchi, R.·Altindis, E.
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Abstract

Until our recent discovery of viral insulin/IGF-1-like peptides (VILPs), examples of viral mimicry were mostly limited to immunomodulatory proteins and growth factors. We previously showed that six viruses in the Iridoviridae family encode genes mimicking insulin and IGF-1. While VILP-carrying viruses are isolated from fish, the role of VILPs in host-pathogen interactions remain elusive. In this study, we used the Grouper Iridovirus (GIV), one of the VILP-carrying viruses, to examine the impact of the GIV-VILPs on the host IGF-1R/IR system during infection. Our structural analysis revealed that GIV-VILP is 35% identical to both zebrafish insulin and 35 IGF-1. We also showed that GIV-VILPs are early viral transcripts and resulting peptides are secreted during viral infection. Both single-chain (sc, resembling IGF-1) and double chain (dc, resembling insulin) forms of chemically synthesized GIV-VILPs can stimulate insulin receptor (IR) and IGF-1 receptor (IGF1R) phosphorylation. They could also stimulatepost-receptor signaling in both grouper kidney (GK) and zebrafish AB.9 cells as potently as insulin. Notably, supernatants obtained from GIV-infected cells could stimulate insulin/IGF system in a dose dependent manner. Interestingly, GIV-VILP was able to selectively activate the Akt/PI3K pathway while had no or minimal effect on Erk/MAPK pathway. Using either IR, IGF1R or dual inhibitors, we illustrated that inhibition of IR signaling suppressed GIV viral replication while inhibition of IGF1R enhanced viral replication. Consistent with selective signaling action of PI3K/Akt pathway, inhibition of the Akt reduced GIV viral replication however Erk pathway inhibition did not affect it. In summary, GIV-VILP is produced during GIV infection and manipulates host insulin/IGF signaling in a selective manner. Our findings reveal a previously unknown viral strategy in which viruses mimic a host hormone to exploit the hosts endocrine system. This discovery unveils a novel viral pathogenesis mechanism, broadens our understanding of viral mimicry, and opens a new avenue to better understand viral strategies to manipulate the host.

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CHUARD, A., Nesarajah, K., Danazumi, K., Reiners, K., Zhang, F., Levintov, L., Vashisth, H., DiMarchi, R., Altindis, E.. 2024-06-14. Viral Insulin/IGF-like Peptides Selectively Activate Host Insulin/IGF Signaling pathways during Grouper Iridovirus Infection. https://doi.org/10.1101/2024.06.13.598936

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