De Neck, S. | Search bioRxiv

bioRxiv2026

The biodistribution and effect of post-exposure neutralising monoclonal antibody treatment in a mouse model of SARS-CoV-2 infection with viral spread to the brain

Ronapreve, a combination of two neutralising monoclonal antibodies, casirivimab and imdevimab, was amongst the authorised treatments against SARS-CoV-2 early in the COVID-19 pandemic. Ronapreve has lost some of its efficiency with the rise of new virus variants, however, it remains a valuable tool for experimental studies to gain insights into the mechanisms and effects of anti-viral drugs. In this study we combined morphological, pharmacokinetic and molecular approaches (including multiomics) to investigate the biodistribution of Ronapreve in the K18-hACE2 murine model of SARS-CoV-2 neuroinvasion, as well as possible consequences for the brain. We also investigated the effect of the treatment on the infection status. Our results showed that after intraperitoneal injection, Ronapreve accumulates in the serum and is unable to cross the blood-brain barrier, thus not reaching the brain parenchyma; treatment has only a minimal effect on the brain transcriptome, with no significant changes in the brain lipidome or metabolome. Nonetheless, post-exposure Ronapreve treatment resulted in reduced viral loads in the lung and, in particular, the brain, with markedly reduced tissue response in the brain, as shown by the transcriptomic analysis. The results suggest a peripheral mode of action of Ronapreve to block brain infection, possibly by lowering viral replication in the nasal epithelium, reducing a subsequent spread to the brain.

pathology↗

bioRxiv2025

SARS-CoV-2 infection of the brain: the K18-hACE2 mouse model to illustrate the role and response of the vasculature in neurotropic viral infection

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) primarily affects the respiratory tract and lungs; however, the associated disease, coronavirus disease 2019 (COVID-19), can involve the central nervous system (CNS) in both its acute and long-term (Long COVID) clinical manifestation. The pathomechanisms underlying neurological impairments in COVID-19 are not yet fully understood, hence experimental studies to clarify the direct effect of SARS-CoV-2 in the brain can provide further insight. In the present study we used the K18-hACE2 model, intranasally challenged with SARS-CoV-2 ancestral and Delta isolates at low or medium doses, to address the hypothesis that the inflammatory response raised in the brain of infected mice is secondary to neuronal infection. Our data confirmed that the virus reaches the brain even after low dose (102 PFU/mouse, Delta isolate) infection where it targets the neurons without overt neuropathic effect, sparing the blood vessels. In situ investigation of the resulting inflammatory response showed the recruitment of leukocytes via postcapillary venules, with their accumulation in the perivascular space and occasional migration into the neuroparenchyma, without targeting and/or damage to the vessel wall. These changes were reflected in the brain transcriptome and proteome which showed positive enrichment of pathways and up-regulation of genes involved in the inflammatory response including the recruitment (including adhesion and migration) and activity of leukocytes. Additionally, morphological and transcriptome/proteome changes suggest minimal associated blood-brain barrier dysfunction. The brain metabolome and lipidome showed minimal changes; these were consistent with oxidative stress and inflammatory and immune/antiviral responses. The results obtained from our model indicate that SARS-CoV-2 infection of the neurons can result in limited neuroinflammation. These data can help to understand more fully the reaction of the CNS in COVID-19 patients, and neurotropic virus infections in general.

pathology↗