Evolution of SARS-CoV-2 in the murine central nervous system drives viral diversification

Jacob Class; Lacy M. Simons; Ramon Lorenzo-Redondo; Jazmin Galván Achi; Laura Cooper; Tanushree Dangi; Pablo Penaloza-MacMaster; Egon A. Ozer; Sarah E. Lutz; Lijun Rong; Judd F. Hultquist; Justin M. Richner

doi:10.1038/s41564-024-01786-8

Evolution of SARS-CoV-2 in the murine central nervous system drives viral diversification

Jacob Class, Lacy M. Simons, Ramon Lorenzo-Redondo, Jazmin Galván Achi, Laura Cooper, Tanushree Dangi, Pablo Penaloza-MacMaster, Egon A. Ozer, Sarah E. Lutz, Lijun Rong, Judd F. Hultquist^*, Justin M. Richner^*

^*Corresponding author for this work

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

Abstract

Severe coronavirus disease 2019 and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are associated with neurological complications that may be linked to direct infection of the central nervous system (CNS), but the selective pressures ruling neuroinvasion are poorly defined. Here we assessed SARS-CoV-2 evolution in the lung versus CNS of infected mice. Higher levels of viral divergence were observed in the CNS than the lung after intranasal challenge with a high frequency of mutations in the spike furin cleavage site (FCS). Deletion of the FCS significantly attenuated virulence after intranasal challenge, with lower viral titres and decreased morbidity compared with the wild-type virus. Intracranial inoculation of the FCS-deleted virus, however, was sufficient to restore virulence. After intracranial inoculation, both viruses established infection in the lung, but dissemination from the CNS to the lung required the intact FCS. Cumulatively, these data suggest a critical role for the FCS in determining SARS-CoV-2 tropism and compartmentalization.

Original language	English (US)
Pages (from-to)	2383-2394
Number of pages	12
Journal	Nature Microbiology
Volume	9
Issue number	9
DOIs	https://doi.org/10.1038/s41564-024-01786-8
State	Published - Sep 2024

Funding

Infectious clones provided by the Vineet Menachery lab from University of Texas Medical Branch. This research was supported, in part, through the computational resources and staff contributions provided by the Quest high-performance computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research and Northwestern University Information Technology. Tissue embedding and imaging was performed by the Research Histology and Tissue Imaging Core at UIC Research Resources Center. Funding for this work was provided by: NIH grants R01 AI150672 and R56 DE033249 (J.M.R.), DOD grant MS200290 (S.E.L.), NIH grant R21 AI163912 (J.F.H.), NIH grant U19 AI135964 (J.F.H., E.A.O. and R.L.R.), and through institutional support for the Center for Pathogen Genomics and Microbial Evolution (J.F.H., E.A.O. and R.L.R.). The funding sources had no role in the study design, data collection, analysis, interpretation or writing of the report. Figures and were created with BioRender.com .

ASJC Scopus subject areas

Microbiology
Immunology
Applied Microbiology and Biotechnology
Genetics
Microbiology (medical)
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41564-024-01786-8

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abstract = "Severe coronavirus disease 2019 and post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are associated with neurological complications that may be linked to direct infection of the central nervous system (CNS), but the selective pressures ruling neuroinvasion are poorly defined. Here we assessed SARS-CoV-2 evolution in the lung versus CNS of infected mice. Higher levels of viral divergence were observed in the CNS than the lung after intranasal challenge with a high frequency of mutations in the spike furin cleavage site (FCS). Deletion of the FCS significantly attenuated virulence after intranasal challenge, with lower viral titres and decreased morbidity compared with the wild-type virus. Intracranial inoculation of the FCS-deleted virus, however, was sufficient to restore virulence. After intracranial inoculation, both viruses established infection in the lung, but dissemination from the CNS to the lung required the intact FCS. Cumulatively, these data suggest a critical role for the FCS in determining SARS-CoV-2 tropism and compartmentalization.",

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Evolution of SARS-CoV-2 in the murine central nervous system drives viral diversification

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UN SDGs

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