**3.3 Evidences of SARS CoV-2 tropism beyond neurons: the other side of the coin**

Conflicting results paired with the promiscuous entry routes of the virus stirs the ongoing debate on the neuronal vs. non-neuronal routes of invasion and tropism of SARS-CoV-2 virus. Those who are opposing the axonal hopping of the virus primarily point to the technical limitations of the studies *per se*. Meinhardt and colleagues critically evaluated the imaging data of virus nucleoproteins found at the OE, between the olfactory nerve layer and OB [3]. The axons of OSNs reaching to OB are highly entwined with the ACE2-expressing supporting cells processes, and they reasoned that the immunolabeled imaging may not convincingly reveal whether the virus is present in OSNs or in the wrappings of the sustentacular cells. Nevertheless, ultrastructural assessment using electron microscopy (EM) has also been done both in autoptic human samples and the animal models. Virus-like particles were detected in the cortex of K18-hACE2 mice, and pyknotic cells and abnormal mitochondrial ultra-structures in infected hamsters were observed using Transmission EM (TEM) [79]. A virus cytoplasmic inclusion body was also identified in the OB of an autotoptic patient sample observed using TEM [74]. However, TEM investigations are also subject to aberrant observations as virion-like vesicular bodies can act as decoys for pathologists and that direct neuronal infections cannot be confirmed by using this technique [80]. Post CoV-2 inoculation in rhesus monkey, one group carried out the transcriptomic profiling of the infected cells. Downregulation of genes involved in mitochondrial dysfunctions (ND3, ATP6, and COX3) was observed in the mature neurons, hippocampal microglia, endothelial vascular cells, and oligodendrocytes [81]. This is suggestive of dysfunctions happening in various cell types of the brain, which are collectively leading to CNS abnormalities. Hijacking the lipoprotein metabolism of susceptible cells of the brain barriers (BBB and BSCFB) suggests hematogenous route of entry [82]. Firstly, transcellular route, i.e., entering via ACE2 receptors of the choroid plexus epithelial cells, pericytes, astrocytes lining the endothelial cells followed by weakening of the tight junctions between the vascular endothelial cells of the BBB (called the paracellular modes) and finally utilizing the lipid vesicles and exosomes as the "Trojan horses" to breach the barrier while escaping the host's immune oversight constitutes the non-neuronal mode of entry of the virus [82].
