Table 2.
Direct of routes of entry by SARS-CoV-2 into the autonomic nervous system. Different cranial nerves can act as access points by SARS-CoV-2 to reach the hypothalamus or brainstem. The virus can reach the autonomic nervous system through the blood by crossing the blood-brain-barrier or the circumventricular organs. Abbreviations: ANS: autonomic nervous system; ACE-2: angiotensin-converting enzyme type 2; BBB: blood-brain barrier; CVOs: circumventricular organs; MFB: medial forebrain bundle; NTS: nucleus tractus solitarius; NRP1: neuropillin 1; PVN: paraventricular nucleus; TMPRSS2: transmembrane serine protease 2.
| Route of entry | Anatomical site of entry | Findings suggesting entry through the route | Reference | Suggested pathway to ANS invasion |
|---|---|---|---|---|
| Neuronal | Olfactory nerve | Autopsy of patients with COVID-19 showed viral RNA of SARS-CoV-2 in the olfactory mucosa and olfactory bulb. Spike protein was colocalized with neuronal cells In macaques, SARS-CoV-2 was detected in the olfactory cortex preferentially in neurons |
Meinhardt et al., 2021 Beckman et al., 2022 |
Olfactory epithelium → olfactory nerve → olfactory cortex → MFB → brainstem |
| Ocular nerve | In patients with COVID-19, SARS-CoV-2 was detected in the retina Patients with COVID-19 had increased retinal nerve fiber layer thickness |
Casagrande et al., 2020 Burgos-Blasco et al., 2021 |
Retina → ocular nerve → retinohypothalamic tract → suprachiasmatic nucleus of the hypothalamus | |
| Trigeminal nerve | Oral mucosa, taste buds, salivary gland, and trigeminal ganglion express ACE-2 receptors and TMPRSS2 | Park et al., 2022 | Nociceptors in the oral cavity → trigeminal nerve → trigeminal ganglia → trigeminal spinal nucleus caudalis in the medulla | |
| Glossopharyngeal and vagus, nerves | High expression of ACE-2, NRP1, and TMPRSS2, in the vagus and the glossopharyngeal nerves | Vitale-Cross et al., 2022 | Taste sensory fibers in oral cavity → glossopharyngeal and vagus nerves → NTS Respiratory tract epithelium → vagus nerve → vagal ganglia → NTS and the nucleus ambiguous |
|
| Hematogenous | BBB | Postmortem examination of a COVID-19 patient showed viral-like particles in the capillary endothelium of the frontal lobe | Paniz-Mondolfi et al., 2020 | Viral hijacked leukocytes or transcellular/paracellular migration across BBB → hypothalamus and brainstem |
| CVOs | High expression of ACE-2 in CVOs and PVN | Ong et al., 2022 | Subfornical zone, organum vasculosum, median eminence, and area postrema → PVN of hypothalamus |