**3. The SARS-CoV-2 interactome and viral infection**

SARS-CoV-2 is an enveloped, positive-sense, single-stranded, RNA virus with a genome of 30 kb, encoding for 29 viral proteins. These proteins target about 332 human molecules, some of which are also involved in psychiatric disorders and the action mechanism of psychotropic drugs [24]. The virus accesses host cells via its spike (S) glycoprotein that attaches to the cell surface receptor ACE-2 [46]. Viral binding is mediated by TMPRSS2, a human protease, that cleaves S antigen into the S1 subunit, the receptor binding site, and S2, the mediator of viral fusion with host cell membranes [47]. Upon fusion the virus is internalized through the EP pits that join the early and late endosomes, reaching the lysosomes. The later, link the EP to autophagy via autolysosomes (autophagosomes fused with lysosomes) (**Figure 2**).

#### **Figure 2.**

*Upon receptor binding and fusion, SARS-CoV-2/ACE-2 complexes enter human cells through the endocytic pathway (EP) pits early and late endosomes that subsequently join the lysosomes. Lysosomes link the EP to autophagy as authophagosomes (that can also carry the virus) fuse with the lysosomes, engendering the autolysosomes. Viruses are released from the endoplasmic reticulum - Golgi intermediate compartment (ERGIC)(not shown) to the cell surface, either individually or packed in extracellular vesicles (EVs). Viruses connected to ACE-2 receptors that are not endocytosed are shed by ADAM17. Both endocytosis and shedding contribute to ACE-2 downregulation, a marker of COVID-19 critical illness.*

*COVID-19: A Catalyst for Novel Psychiatric Paradigms - Part 1 DOI: http://dx.doi.org/10.5772/intechopen.96940*

The SARS-CoV-2 protein–protein interaction studies have reported that 40% of viral proteins interact with human EP, indicating that vesicular trafficking plays a crucial role in COVID-19 pathogenesis [24]. In addition, several viral proteins usurp mitochondria and autophagy, cellular systems associated with host antiviral defenses [48]. Indeed, the SARS-CoV-2 interactome revealed that the virus hijacks both the mammalian target of rapamycin complex 1 (mTORC1), the master regulator of autophagy, and the E3 ubiquitin ligases in the outer mitochondrial membrane [24].

Upon release from EP into the cytosol, the SARS-CoV-2 virus replicates and assembles in the endoplasmic reticulum - Golgi intermediate compartment (ERGIC) from which the viral progeny is released at the cell surface [49].

## **4. The SARS-CoV-2/ACE-2 attachment**

Novel studies have reported that the S antigen of SARS-CoV-2 virus attaches with high affinity to ACE-2 receptors, promoting oxidative stress by several mechanisms, including ANG 1–7 downregulation, ANG II accumulation and NMDRs or AT-1Rs overstimulation (**Figure 1**) [49–54].

Aside from the S antigen, several other SARS-CoV-2 proteins interact directly with the human molecules, disrupting numerous pathways, including EP, epigenome, mitochondria and autophagy (**Table 2**).


**Table 2.**

*The SARS-CoV-2 non-S antigen interactions with human proteins.*

Both the S antigen and non-S-induced molecular changes affect molecular pathways previously associated with schizophrenia and autism. For example, excessive NMDAR activation and externalization of phosphatidylserine (PS) on the outer leaflet of plasma membrane was documented in both COVID-19 critical illness and schizophrenia [60]. This is relevant because PS exposure has been linked to dysregulated immunosuppression and the activation of coagulation cascade, changes associated with severe COVID-19 and some psychiatric disorders [61, 62]. With the same token, NMDAR/PS exposure facilitates SARS-CoV-2 endocytosis via the EP [63–65]. Interestingly, PS externalization was associated with schizophrenia as it inhibits monoamine oxidase B (MAO-B), a dopamine (DA) metabolizing enzyme [66]. Loss of MAO-B with subsequent DA upregulation is believed to trigger psychosis, linking PS exposure to severe psychiatric conditions. Furthermore, other studies have associated normal aging with EP upregulation, likely explaining the increased risk of COVID-19 complications in elderly [67].
