THE ROAD LESS TAKEN: CHARACTERIZING THE TRIGEMINAL NERVE ROUTE OF NEUROINVASION BY RESPIRATORY SARS-COV-2

COVID-19, while primarily recognized as a respiratory disease, also presents with a wide range of neurological symptoms, including seizures, anxiety, depression, amnesia, attention deficits, and alterations in consciousness. Although the olfactory nerve is widely accepted as the primary route of neuroinvasion by which the etiological agent SARS-CoV-2 invades the brain, the trigeminal nerve may serve as an additional, yet often overlooked, neuroinvasive route. We initially conducted a pilot study using AC70 human ACE2 transgenic mice, which were subjected to intranasal inoculation of SARS-CoV-2, to investigate the olfactory nerve route of neuroinvasion. We incidentally found the trigeminal ganglion is an additional extrapulmonary, peripheral nervous site of viral infection akin to the well-known olfactory epithelium. To explore the possibility of the trigeminal nerve as a route of neuroinvasion by SARS-CoV-2, we then conducted a more detailed study using the same mouse model to characterize the route and found the trigeminal ganglion is an early and highly efficient site of viral replication which then rapidly spread throughout the brain and appearing to primarily target neurons. Despite the extensive spread of virus within the brain, we did not consistently observe significant tissue pathology, such as inflammatory infiltration, glial activation, or apoptotic cell deaths, which are typically associated with neuroinvasive viral infections. However, our findings indicated a significant induction of inflammatory cytokines, suggesting an active immune response. Additionally, we observed alterations in the expression levels of several genes related to neuronal function, including those involved in the dopamine neurotransmitter pathway, synaptic function, and markers of neuronal damage, when compared to control mice. These findings suggest that the trigeminal nerve may act as a complementary route to the olfactory nerve for SARS-CoV-2 neuroinvasion, leading to a distinct neuropathological profile. Our study provides valuable insights into the potential mechanisms of coronavirus-induced neuropathogenesis and underscores the importance of further research into the neurological impacts of COVID-19.

Name thesis:degree_name

Biochemistry and Molecular Biology (Doctoral)

Discipline thesis:degree_discipline

VIROLOGY

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2024

Author dc:creator

• HSU, JASON CHENG-CHIEH 1995-

Advisor dc:contributor.advisor

• TSENG, CHIEN-TE (SKTSENG@utmb.edu)

Committee members dc:contributor.committeemember

• FREIBERG, ALEX (anfreibe@utmb.edu)
• LAZARTIGUES, ERIC (elazar@lsuhsc.edu)
• PENG, BI-HUNG (bpeng@utmb.edu)
• WU, PING (piwu@utmb.edu)

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12738

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12738