Cerebellum, and brainstem [74]. Yet another autopsy study revealed occasional presence of viral N- or S-protein in individual cells of unknown identity inside the CNS but found no 20(S)-Hydroxycholesterol Autophagy direct relation in the cellular infection to key CNS pathological modifications [83]. Pathological findings from COVID-19 autopsies incorporate in depth inflammation, microglia activation, astrogliosis (specifically in OB and medulla oblongata), perivascular infiltration of cytotoxic T lymphocytes or leukocytes, intravascular microthrombi [74,75,83,92], and hypoxia-associated alterations [93]. Brain imaging abnormalities, indicative of edema, injury, and microbleeding, have also been reported inside the olfactory bulb of COVID-19 sufferers [946]. In experimental animals, irrespective of SARS-CoV-2 infection on the RE and OE, there has been no report of substantial invasion on the virus in to the CNS neurons or glia (like the OB) [10,760,979], with a handful of exceptions (see below). SARS-CoV-2 nucleoprotein-positive myeloid cells were occasionally observed within the OB, but the precise identity (blood monocytes, macrophages, or CNS microglia) and locations (intravascular or PHA-543613 Membrane Transporter/Ion Channel extravascular) of these cells remained uncertain [23]. Likewise, though mainly undetectable in neurons or glia within the brain (including the OB), SARS-CoV-2 could at times be recovered from brain samples of infected animals, in all probability from infected blood or vascular endothelial cells [23,78]. Neuropathological alterations after SARS-CoV-2 infection of susceptible experimental animals ranged from absence of clear modifications to inflammation, microglia activation, and infiltration of macrophages, comparable to autopsy findings in human COVID-19 [76,77]. One exception could be the K18-hACE2 transgenic mice that overexpress human ACE2 transgene (hACE2) beneath human K-18 promotor handle and show unusually high sensitivity to SARS-CoV-2. Intranasal infection of K18-hACE2 transgenic mice could lead to not merely viral invasion with the OE, RE, and lungs, but also substantial virus spread into CNS regions for example the OB, anterior olfactory nucleus, thalamus, hypothalamus, and cerebral cortices [100,101]. In contrast, a further line of transgenic mice that overexpresses hACE2 beneath the mouse ACE2 promotor handle also suffers from SARS-CoV-2 infection and illness but did not show prominent virus spread towards the CNS [102]. Although seemingly unrepresentative, the K18-hACE2 transgenic mouse model appears appropriate for therapeutic screening, as evidenced by the effectiveness of COVID-19 convalescent antisera in stopping disease or mortality by SARS-CoV-2 in these mice [101].Viruses 2021, 13, x FOR PEER REVIEW7 ofViruses 2021, 13,seems appropriate for therapeutic screening, as evidenced by the effectiveness of COVID7 of 15 19 convalescent antisera in preventing disease or mortality by SARS-CoV-2 in these mice [101]. COVID-19 four. Olfactory Neuropathogenesis in COVID-19 4.1. Pathogenesis inside the OE upon SARS-CoV-2 Infection four.1. Pathogenesis in the OE upon SARS-CoV-2 InfectionIn summary, SARS-CoV-2 at the OE primarily infects the olfactory sustentacular cells In summary, SARS-CoV-2 in the OE primarily infects the olfactory sustentacular cells (Figure 2A,B). While OE horizontal basal cells have already been shown to express moderate (Figure 2A,B). Despite the fact that OE horizontal basal cells have been shown to express moderate ACE2, these cells are commonly not exposed for the nasal cavity and mucus, and as a result may ACE2, these cells are normally not exposed towards the nasal c.