Virus Sars-CoV-2 as a Neuroinvasive Agent

The nervous system is involved in different vital functions that guarantee the survival of the individual. Covid-19 infection is a multisystemic and multi organic disease that disrupts homeostasis and endangers the infected individual’s life. It leads to neurological manifestations of varying intensity. However, the nervous system as a target of CoV-2 virus infection must be clarified. In this review we examine the expression of ACE-2 receptor and the interaction of Co-2 virus with nerve cells, describing some findings in nerve cells of different organs. Additionally, a CoV-2 dissemination map is postulated, with emphasis on the nervous functions at the somatic and autonomic levels .


Entrance door to the brain
The presence of SARS-CoV-2 RNA for the virus has been demonstrated in the olfactory bulb and in the olfactory tubercle, a sensory processing center, already housed in the cerebral cortex itself. The viral proteins detected in the respiratory center of the medulla oblongata [5] and the cranial nerves glossopharyngeal (pairs IX) and vagus nerve (pairs X), that converge in the medulla oblongata [6], seem to be responsible for the autonomic disfunction and problems with breathing, cardiac arrhythmia and abnormal blood gas levels, that contribute to the need of assisted ventilation in seriously infected patients [7].

Transsynaptic pathway brain dissemination
Taking advantage of the polarization of neurons and the machinery responsible for anterograde (from the soma) and retrograde (towards the soma) transport, CoV-2 and virions travel by neural circuits through synaptic clefts [8]. Infected neural cells were evidenced near the olfactory bulb, in brain structures such as the frontal lobe [9], thalamus [5], basal ganglia, brainstem, cerebellum, hippocampus [6] and midbrain [10]. The infected structures include activated microglial cells, the innate antigen presenting cells (APC) of the. central nervous system (CNS). This is evidenced by the expression of MHC-1: histocompatibility HLA-DR antigen, the lectin IBa1 and the protein TMEM119. The presence of reactive astrocytes is evidenced by their morphological change and their overexpressing glial fibrillary acidic protein (GFAP). The activation of the acquired immune response is evidenced by the presence of cytotoxic, CD8 positive lymphocytes [6].

Brain dissemination by disruption of the blood-brainbarrier
Vascular pericytes express high levels of ACE-2 receptors and are infected by CoV-2 [4]. Electron microscopy permits visualizing cells of the vascular epithelium with basement membrane and the formation of shoots with virions fusing with the neuronal membrane. This fusion is postulated to induce the production of molecules with a chemoattractant effect for effector cells, such as macrophages [9] that affect BBB permeability. Vasogenic edema, due to the passage of fluid from the intravascular to the extracellular space, is common in the white matter. Extravasation hemorrhage and vessels with increased perimetral space are also evidenced. Histopathology and confocal microscopy images show blood vessels and brain thrombi infested by CoV-2 viruses [11].

Spinal cord infection
Most of somatic and autonomic nerve endings in tissues (Peripheral Nervous System) are communicated with ganglia, which are groups of neurons outside the CNS. Their axons communicate at various metameric levels with the spinal cord [12,13] reaching the brain in an organized or somatotopic manner. ACE-2 receptor is expressed in the spinal cord and angiotensin, a neuropeptide involved in nociception [14]. It is postulated that CoV-2 uses this pathway to infect sensory neurons of the anterior horn and motor neurons of the ventral horn [15].

Infection of the gut neural environment
The throat is a reservoir of CoV-2. The swallowed virus evades digestive defense mechanisms and invade the digestive tract and intestine. CoV-2 may gain access to the CNS through the glossopharyngeal and vagus nerve. The terminals of the vagus nerve are located along oral and gastrointestinal tracts and afferents to intramural neuronal cells are grouped mainly in two plexuses: the submucosal and the myenteric. Neuronal plexuses expressing ACE-2 receptor and markers such as PGP 9.5 and HuC of intermediate filaments of the neuronal cytoskeleton [16] may be targets for CoV-2 invasion. On the other hand, based on single-cell transcriptomic analysis, ACE2 and TMPRSS2 are also co expressed in both upper epithelial and gland cells from esophagus and absorptive enterocytes from ileum and colon [17]. In the intestine, neuroenteroendocrine cells (NEEC) emit projections to the lumen of the intestine and interact with microbiota and mucus. These local nerve cells produce classic neurotransmitters, neuropeptides and neurohormones, stored separately in different subcellular compartments [18] that are targeted by the CoV2 virus. The electron microscopy shows hair cells with ultrastructural features compatible with NEEC, infected by CoV-2, and virions released from the villi into the intestinal lumen. Goblet cells are not infected. The virus is excreted with the feces [19]. Figure 1: A pathway for neuronal dissemination of CoV-2 through the neural environment is postulated in COVID-19 disease, including some of the most affected organs.