Host response against SARS-CoV-2 infection is impacted by allosteric modulation of cholinergic and purinergic receptors
- 1Institut Pasteur
Abstract
The COVID-19 pandemic has caused nearly 8 million deaths and a broad spectrum of clinical manifestations driven by dysregulated host inflammation, notably involving key signalling proteins IL-6, CXCL10, and CXCL5. We previously demonstrated that ivermectin (IVM) improves clinical outcomes and reduces the IL-6/IL-10 ratio in the lungs of SARS-CoV-2-infected hamsters. Here, combining high-throughput confocal microscopy and transcriptomics in human cell co-cultures and a hamster model, we dissected how IVM modulates host cells responses via 7nAChR and purinergic receptors. In vitro, IVM acted independently of 7nAChR, instead triggering a P2X4-dependent drop in intracellular ATP, rapidly upregulating CXCL10 in macrophages, and suppressing CXCL5 and IL-6. In vivo, however, 7nAChR antagonists abolished IVMs clinical benefit, as did the P2X4 blocker BX430; moreover, whereas the orthosteric agonist EVP-6124 was ineffective, the positive allosteric modulators (PAMs) IVM and GAT-107 reduced lung pathology and anosmia. Thus, IVM operates through a dynamic, context-dependent interplay: P2X4 drives early innate responses in cellular systems including macrophages, whereas the situation in vivo is more complex with 7nAChR being essential for tissue protection. These data position selective PAMs and the CXCL10/CXCL5 axis as promising targets for host-directed therapy in COVID-19.
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BibTeX
@misc{perraud2026host,
title = {{Host response against SARS-CoV-2 infection is impacted by allosteric modulation of cholinergic and purinergic receptors}},
author = {V. Perraud and G. Dias de Melo and M. Cecchini and L. Kergoat and J. Lannoy and J.-P. Changeux and H. Bourhy and F. Larrous},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.761280},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.761280v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Host response against SARS-CoV-2 infection is impacted by allosteric modulation of cholinergic and purinergic receptors
AU - V. Perraud
AU - G. Dias de Melo
AU - M. Cecchini
AU - L. Kergoat
AU - J. Lannoy
AU - J.-P. Changeux
AU - H. Bourhy
AU - F. Larrous
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.761280
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.761280v1
AB - The COVID-19 pandemic has caused nearly 8 million deaths and a broad spectrum of clinical manifestations driven by dysregulated host inflammation, notably involving key signalling proteins IL-6, CXCL10, and CXCL5. We previously demonstrated that ivermectin (IVM) improves clinical outcomes and reduces the IL-6/IL-10 ratio in the lungs of SARS-CoV-2-infected hamsters. Here, combining high-throughput confocal microscopy and transcriptomics in human cell co-cultures and a hamster model, we dissected how IVM modulates host cells responses via 7nAChR and purinergic receptors. In vitro, IVM acted independently of 7nAChR, instead triggering a P2X4-dependent drop in intracellular ATP, rapidly upregulating CXCL10 in macrophages, and suppressing CXCL5 and IL-6. In vivo, however, 7nAChR antagonists abolished IVMs clinical benefit, as did the P2X4 blocker BX430; moreover, whereas the orthosteric agonist EVP-6124 was ineffective, the positive allosteric modulators (PAMs) IVM and GAT-107 reduced lung pathology and anosmia. Thus, IVM operates through a dynamic, context-dependent interplay: P2X4 drives early innate responses in cellular systems including macrophages, whereas the situation in vivo is more complex with 7nAChR being essential for tissue protection. These data position selective PAMs and the CXCL10/CXCL5 axis as promising targets for host-directed therapy in COVID-19.
ER -