Intranasal delivery of SARS-CoV-2 triggers cellular and molecular alterations in the mouse trigeminal ganglion and brainstem: focus on the nociceptive pathways related to migraine

In the TG, SARS-CoV-2 proteins S and N were detected in nerve fibers as well as in transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) nociceptive neurons. Transcriptomics analysis of the TG from infected K18-hACE2 have revealed significant changes in gene expression, including Ccl2, Atf3, Cxcl10, Saa3, Plin4 genes. Additionally, increased immunoreactivity for ATF3 and Iba1 has been detected in the TG of these mice post-infection.

In the brainstem, SARS-CoV-2 protein was exclusively found in neurons, with no detection in astrocytes or microglial cells, the latter exhibiting an activated form in K18-hACE2 infected mice. Bulk RNA-Seq analysis clearly confirmed a cytokine and chemokine storms, inflammasome activation (Gsdmd, Casp4/1, Nlrp3), molecular markers of neuronal activation (Jun, Fos, Fosb), neuronal injury (Atf3) and pain markers (Gfra1, Ntrk1, Ptgs2).

We also shown that a significant number of infected neurons were found within, or in close contact to a dense network of CGRP-positive nociceptive nerve fibers in the trigeminal brainstem. Finally, we provided gene interaction networks and identified specific SARS-CoV-2 biomarkers Saa3, Cxcl10, Ccl2, Atf3 and Plin4 in TG and brainstem which could serve as potential indicators of disease severity. In conclusion, this study reports a robust set of transcriptomic and cellular changes triggered by SARS-CoV-2 in the TG and brainstem, offering a potential mechanistic explanation for sensory abnormalities, such as migraine, observed in COVID-19 patients.