SARS-CoV-2 Dissemination Through Peripheral Nerves Explains Multiple Organ Injury

Abstract

Coronavirus disease (CoVID-19), caused by recently identified severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2), is characterized by inconsistent clinical presentations. While many infected individuals remain asymptomatic or show mild respiratory symptoms, others develop severe pneumonia or even respiratory distress syndrome. SARS-CoV-2 is reported to be able to infect the lungs, the intestines, blood vessels, the bile ducts, the conjunctiva, macrophages, T lymphocytes, the heart, liver, kidneys, and brain. More than a third of cases displayed neurological involvement, and many severely ill patients developed multiple organ infection and injury. However, less than 1% of patients had a detectable level of SARS-CoV-2 in the blood, raising a question of how the virus spreads throughout the body. We propose that nerve terminals in the orofacial mucosa, eyes, and olfactory neuroepithelium act as entry points for the brain invasion, allowing SARS-CoV-2 to infect the brainstem. By exploiting the subcellular membrane compartments of infected cells, a feature common to all coronaviruses, SARS-CoV-2 is capable to disseminate from the brain to periphery via vesicular axonal transport and passive diffusion through axonal endoplasmic reticula, causing multiple organ injury independently of an underlying respiratory infection. The proposed model clarifies a wide range of clinically observed phenomena in CoVID-19 patients, such as neurological symptoms unassociated with lung pathology, protracted presence of the virus in samples obtained from recovered patients, exaggerated immune response, and multiple organ failure in severe cases with variable course and dynamics of the disease. We believe that this model can provide novel insights into CoVID-19 and its long-term sequelae, and establish a framework for further research.

COVID-19 sequelae in adults aged less than 50 years: A systematic review

“…There is an ever-expanding body of knowledge regarding the acute effects of a SARS-CoV-2 infection on several organs. So far, it is known that SARS-CoV-2 can infect lung, heart, liver and kidney tissue, gastrointestinal mucosa, vascular endothelium, macrophages, T-lymphocytes and neurons [ 38 ]. In addition to the direct damage through the viral infection, in some patients the infection leads to a massive release of cytokines, a cytokine storm, which indirectly results in extensive tissue damage [ 39 ].…”

“…Radiologically, there seem to be distinct changes in cerebral micro-structure, especially in those areas related to memory and smell loss, compared to healthy controls [ 29 ]. However, there is widespread speculation concerning neurological long-term consequences [ 38 , [44] , [45] , [46] ]. Several authors speculate that SARS-CoV-2 might trigger neurodegenerative diseases like multiple sclerosis, Parkinson’s disease and narcolepsy in predisposed individuals in the long-term [ [44] , [45] , [46] ].…”

Neurological Consequences of SARS-CoV-2 Infection and Concurrence of Treatment-Induced Neuropsychiatric Adverse Events in COVID-19 Patients: Navigating the Uncharted

“…Additionally, the SARS-CoV-2 is also assumed to spread to the brainstem via olfactory bulb (direct route) or orofacial sensory fibers (alternate route) via cranial ganglia. The direct olfactory route involves the dissemination of SARS-CoV-2 to the amygdala and piriform cortex through the medial forebrain bundle that projects caudally to the dorsal vagal nuclei and solitary tract ( Fenrich et al, 2020 ). Importantly, the COVID-19 associated dysgeusia may be explained by the viral replication in the solitary tract neurons.…”

“…Generally, kinesin-mediated anterograde axonal transport allows the trafficking of vesicles from the soma to the axon or axonal ends ( Berth et al, 2009 ). As SARS-CoV-2 also forms ERGIC, it could manipulate the kinesin-mediated anterograde route to disseminate along the axons ( Fenrich et al, 2020 ). Also, lateral transfections, either cell to- cell or axo-axonal spreading could be possible.…”

“…Although the exact time required for viral invasion is not determined well, it is certainly dependent on the route of virus entry and viral load. Based on the axonal transport dynamics via active and passive processes, the CNS infection may develop within a week after the virus exposure ( Fenrich et al, 2020 ).…”