Variant-specific nucleocapsid mutations shape host innate immune trajectories during SARS-CoV-2 infection
- 1CSSB Centre for Structural Systems Biology, DESY, LIV, University of Luebeck
Abstract
The SARS-CoV-2 nucleocapsid (N) protein is one of the most highly expressed proteins during infection and plays crucial roles in the protection and packaging of viral RNA, replication, suppression of the immune response and virus assembly. The N gene and the overlapping accessory open reading frame ORF9b have continually evolved throughout the circulation of the virus, likely due to ongoing adaptation to the human host. This genetic variability influences the interplay of the N protein and its interactors. Yet, little is known about how specific mutations within the N/ORF9b locus of Variants of Concern (VOCs) shape the progression and outcome of infection. Here, we use a multi-omics approach to decipher how these genetic alterations reprogram the host cell by creating Wuhan-Hu-1-based recombinant viruses carrying an isogenic backbone with respective N mutations from the VOCs (called rNs) and comparing their effects at the transcriptome and proteome levels. We found that the mutations induce distinct transcriptional and translational alterations: rN-Alpha drives a stealth-like infection characterized by sustained translation efficiency and specific evasion of the 2'-5'-oligoadenylate synthetase (OAS) innate immune sensor, whereas rN-Delta and rN-BA.2 trigger a highly elevated inflammatory response. For rN-Delta, hyperphosphorylation of the N-protein drives cellular stress culminating in necroptotic cell death. Because these viruses differ only within the N/ORF9b locus, N sequence variation emerges as a determinant of infection outcome in its own right, warranting increased surveillance attention.
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BibTeX
@misc{berger2026variantspecific,
title = {{Variant-specific nucleocapsid mutations shape host innate immune trajectories during SARS-CoV-2 infection}},
author = {J. M. Berger and J. M. Schroeder and T. K. Soh and N. Pekarek and L.-M. Breul and S. Doerner and P. Bluemke and J. Huang and J. B. Bosse and S. Pfefferle and C. Uetrecht},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749134},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749134v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Variant-specific nucleocapsid mutations shape host innate immune trajectories during SARS-CoV-2 infection
AU - J. M. Berger
AU - J. M. Schroeder
AU - T. K. Soh
AU - N. Pekarek
AU - L.-M. Breul
AU - S. Doerner
AU - P. Bluemke
AU - J. Huang
AU - J. B. Bosse
AU - S. Pfefferle
AU - C. Uetrecht
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749134
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749134v1
AB - The SARS-CoV-2 nucleocapsid (N) protein is one of the most highly expressed proteins during infection and plays crucial roles in the protection and packaging of viral RNA, replication, suppression of the immune response and virus assembly. The N gene and the overlapping accessory open reading frame ORF9b have continually evolved throughout the circulation of the virus, likely due to ongoing adaptation to the human host. This genetic variability influences the interplay of the N protein and its interactors. Yet, little is known about how specific mutations within the N/ORF9b locus of Variants of Concern (VOCs) shape the progression and outcome of infection. Here, we use a multi-omics approach to decipher how these genetic alterations reprogram the host cell by creating Wuhan-Hu-1-based recombinant viruses carrying an isogenic backbone with respective N mutations from the VOCs (called rNs) and comparing their effects at the transcriptome and proteome levels. We found that the mutations induce distinct transcriptional and translational alterations: rN-Alpha drives a stealth-like infection characterized by sustained translation efficiency and specific evasion of the 2'-5'-oligoadenylate synthetase (OAS) innate immune sensor, whereas rN-Delta and rN-BA.2 trigger a highly elevated inflammatory response. For rN-Delta, hyperphosphorylation of the N-protein drives cellular stress culminating in necroptotic cell death. Because these viruses differ only within the N/ORF9b locus, N sequence variation emerges as a determinant of infection outcome in its own right, warranting increased surveillance attention.
ER -