(A) CT imaging suggesting that SARS-CoV-2 infection may cause inflammation that is localized to the olfactory clefts. 
- the inflammation will block the path of olfactory bulb to nasal cavity

A. Nasal inflammation in the olfactory clefts caused by SARS-CoV-2 infection

(E) Immunostaining for ACE2 protein in the mouse olfactory bulb suggests that  vascular pericytes express high level of ACE2 protein 
- Pericytes are critical for maintaining the blood-brain barrier, defining local blood pressure, mediating neuroimmune responses 
- SARS-CoV-2 attaching vascular pericytes  may cause perfusion changes or  inflammation that affect chemosensory perception in the brain


E. ACE2 expression in vascular pericytes may  affect chemosensory perception causing the loss of smell

(B) Sustentacular cells, Bowman’s gland cells, and microvillar cells in the olfactory epithelium express both ACE2 and TMPRSS2 and may be directly infected by SARS-CoV-2. 
- Support cell infection may cause changes in the olfactory mucus or ion imbalances that can inhibit olfactory signaling; such changes may be rapidly reversible. 
- The loss of these support cells in animal models can also result in the death of olfactory sensory neurons; such changes may be irreversible

B. Infection of support cells may inhibit olfactory signaling causing OSN death

(C) Inflammatory cytokines may also directly or indirectly inhibit olfactory sensory neuron function. 

C. Inflammatory cytokines may also directly or indirectly cause loss of smell

(D) Although current data suggest that sustentacular and other support cells are the primary targets of SARS-CoV-2, a remaining possibility is that SARS-CoV-2 directly infects OSNs. 

D. SARS-CoV-2 directly infects OSNs causing loss of smell

- 5 hypothesized mechanisms 
- detailed summaries in child nodes
- 1 for taste and chemesthesis (included after node: SARS-CoV-2 Targets Taste and Chemesthesis)


Smith College

- SARS-CoV-2 infects cells through interactions between its S protein and the ACE2 receptor on target cells
- recent work in macaques, ferrets, and cats identifies the nasal epithelium as a major source of viral RNA after SARS-CoV-2 infection 

Human Olfactory Epithelium 
- Olfactory Sensory Neurons do not express ACE2 
- ACE2 expressed in key support cells (including sustentacular, Bowman’s gland, and microvillar cells) 


Underlying Mechanism of SARS-CoV-2 targeting chemical senses--Olfaction

Cooper, K. W., Brann, D. H., Farruggia, M. C., Bhutani, S., Pellegrino, R., Tsukahara, T., ... & Albers, M. W. (2020). COVID-19 and the chemical senses: supporting players take center stage. Neuron.
https://doi.org/10.1016/j.neuron.2020.06.032
https://www.sciencedirect.com/science/article/pii/S0896627320304864

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