The SARS-CoV-2 S protein must be primed by host proteases before it can bind to host receptors and infect cells. The host proteases that have been identified in helping aid in the binding of the S protein to host receptors include TMPRSS2, ADAM10/17, and Furin (Hussain et al., 2020). TMPRSS2 was found to increase viral entry into host cells significantly and is expressed in astrocytes and oligodendrocytes (Heurich et al., 2014; Dong et al., 2020). Previous work has demonstrated that camostat mesylate, a TMPRSS2 inhibitor, resulted in the blockage of SARS-CoV-2 into TMPRSS2⁺ cells (Hoffmann et al., 2020). ADAM-10/17 (A disintegrin and metalloprotease 10 and 17) are proteases that cleave the extracellular domain of ACE2. However, they are reportedly less efficient than TMPRSS2 (Heurich et al., 2014; Aljohmani and Yildiz, 2020). FURIN also aids SARS-CoV-2 entry. The FURIN protein is an endoprotease and is expressed in hippocampal and cortical neurons (Yang et al., 2018). FURIN cleaves proteins within a specific motif (R/K)-(2X) n-(R/K) and plays a role in priming the SARS-CoV at the S1/S2 site (Coutard et al., 2020). This cleavage allows the virus to shed the spike protein and enter the host cell. The use of the protease is thought to be a key component of the pathogenicity of many viruses, including SARS-CoV-2 infection (Coutard et al., 2020; Fitzgerald, 2020). Of the known pathogenic beta coronaviruses, only the SARS-CoV2, MERS-CoV, and HCoV-OC43 viruses possess the FURIN cleavage complex motif. This protease also plays a role in apoptosis, inflammation of the vasculature, and lipid metabolism (Liu et al., 2020).

ACE2 is a part of the renin-angiotensin-aldosterone system (RAAS), and it is the principal host receptor used by SARS-CoV-2 (Motaghinejad and Gholami, 2020). The RAAS functions to maintain blood pressure by regulating fluid and electrolyte balance and vascular diameter (Wiese et al., 2020). The SARS-CoV-2 infection leads to the downregulation of ACE2, leading to what is referred to as Angiotensin II intoxication (Sfera et al., 2020; Wiese et al., 2020). ACE2 is expressed throughout the epithelia of the respiratory tract. However, the expression of ACE2 can be described as a gradient, where it is highest in the proximal nasal epithelia and attenuates as one proceeds to the epithelia of the lower respiratory tract (Hou et al., 2020). Within the central nervous system, the ACE2 receptor is expressed in both neurons and glial cells (Venkatakrishnan et al., 2020). It is also important to note that the expression of ACE2 and TMPRSS2 also increases with age, according to an investigation of temporal expression profiles in mice at ages 2 months and 2 years (Bilinska et al., 2020).

DPP4 is a ubiquitously expressed serine protease that plays a role in inflammation energy metabolism and has also been reported as a marker of senescence (Klemann et al., 2016; Kim et al., 2017; Shao et al., 2020; Rohmann et al., 2021). The DPP4 protein is widely expressed in many cell types throughout the CNS, including dopaminergic neurons, macrophages, and glia (Venkatakrishnan et al., 2020). Although it is primarily known as the host receptor utilized by the MERS-CoV virus, previous work has shown that SARS-CoV-2 may also use as a point of entry. A protein docking simulation and subsequent analysis of free energy binding found that SARS-CoV2 bound firmly to DPP4 (Li et al., 2020). It is worth noting that the RAAS system and the DPP4 receptor are dysregulated in diabetes, a risk factor in severe COVID illness (Valencia et al., 2020).

Lymphopenia is one of the symptoms seen in patients with COVID-19. This observation has led to the notion that SARS-CoV-2 might also utilize other receptors, like XCR1, to facilitate T-Cell entry (Mobini et al., 2021). A structural study of binding affinity found that XCR1, in addition to several chemokine and immune receptors, had a higher binding affinity for the SARS-CoV-2 S protein than ACE2. XCR1 and other chemokine receptors are present in many types of immune cells. The XCR1 gene is upregulated in response to traumatic brain injury (Mobini et al., 2021). Several other chemokines, as well as their receptors, have been linked to prognostic outcomes in SARS-CoV and MERS-CoV infection (Khalil et al., 2021).

Neuropilin is a host receptor that concretizes the overlapping impacts of SARS-CoV-2 infection as it plays a role in the inflammatory response, angiogenesis, and nerve growth, as well as synaptogenesis (Cai and Reed, 1999; Mayi et al., 2021). Investigators who used x-ray crystallography were able to demonstrate that SARS-CoV-2 spike protein cleaved at the furin site was able to bind with neuropilin (NRP1) (Daly et al., 2020). Neuropilin is known to bind proteins cleaved by FURIN protease. In an investigation of host cell entry, the authors used HEK-293 T cells transfected with plasmids to permit the expression of ACE2 and NRP1 (Cantuti-Castelvetri et al., 2020). Furthermore, comparative analysis of postmortem olfactory epithelium from COVID-19 patients and uninfected controls showed that SARS-CoV-2 could infect NRP1 positive cells of the olfactory epithelium (Cantuti-Castelvetri et al., 2020). Although the levels of ACE2 in the cells of the olfactory epithelium were relatively low, the authors found that expression levels of high levels of NRP1 and oligodendrocyte transcription factor (OLIG2), a marker for neuronal progenitors of the olfactory tract, were higher by comparison (Cantuti-Castelvetri et al., 2020).

The TLRs are molecular pattern recognition receptors that help to monitor the external cellular environment for pathogenic-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPS) (Lim and Staudt, 2013; Kumar, 2019; Liu et al., 2019a). The activation of TLRs following SARS-CoV-2 infection can incite a cytokine storm within the respiratory endothelia. However, it is also capable of activating glial cells of the CNS, releasing several inflammatory factors such as interleukin-1 (IL-1), IL-6, IL-12, C-X-C motif chemokine ligand 10 (CXCL10), C-C motif ligand 3 (CCL3), CCL5, CCL2, TNF-alpha, CXCR6, XCR1, and CCR1, causing chronic inflammation and brain damage (Bouças et al., 2020; Coperchini et al., 2020; Jakhmola et al., 2020; Wu et al., 2020b; Khanmohammadi and Rezaei, 2021). Several of these chemokines and inflammatory factors are expressed in astrocytes, glia, neurons, neural stem cells, and oligodendrocytes (Sowa and Tokarski, 2021). The cytokine storm, particularly the release of TNF-alpha, then leads to the suppression of B-cells and thus antibody production (Kumar et al., 2021). One host protein that is critically involved in the cytokine storm is GSK-3β.GSK-3β is a serine-threonine kinase involved in the inflammatory response to infectious disease and plays a role in the phosphorylation of the SARS-CoV-2 N-protein. Inhibition of GSK-3β by drugs such as lithium has been demonstrated to reduce viral replication and enhance immune response (Taylor et al., 2016; de Souza et al., 2020; Rana et al., 2021). Human Leukocyte Antigen (HLA) also plays a key role in genes regulating the immune response to pathogens through antigen presentation. However, the effect of HLA variants on susceptibility and resistance in coronavirus infection is less evident in the case of SAR-CoV-2 infection (Saulle et al., 2021). For example, the HLA-A*24:02 allele was reported to be both a contributing factor to susceptibility and resistance to SARS-CoV-2 infection in separate investigations (Saulle et al., 2021).

The pro-inflammatory High Mobility Group Box 1 (HMGB1) is a non-histone protein that also provides an entry point for SARS-CoV-2 (Andersson et al., 2020). HMGB1 is involved in organizing chromatin but acts as a damage signal when released by cells, such as neurons and glia, under conditions of stress or inflammation (Paudel et al., 2018). When necrotic cells release DAMP and PAMP molecules in the extracellular milieu, they can bind with HMGB1. These complexes of HMGB1 and DAMP and PAMP signals are then taken up by the cell through endocytosis and translocated to lysosomes. This activity leads to increased proinflammatory effects by breaking down the lysosomal membrane and releasing cytokines and other factors into the cytosol (Andersson et al., 2020). The extent to which chloroquine compounds may provide some benefit in COVID infections is that they might prevent the transfer of PAMPs and DAMPs containing SARS-CoV-2 RNA to the cytosol (Andersson et al., 2020).

Previous reports have demonstrated correlations between severe SARS-CoV-2 infection and cell cycle arrest in the S/G2 phase (Suryawanshi et al., 2021). For example, the C-terminus of the E-protein of the SARS-CoV and SARS-CoV-2 shares a very similar motif to the N-terminus of histone 3 (Gordon et al., 2020). Recently several proteins involved chromatin remodeling were identified in a genome-wide CRISPR screen in Vero-E6 cells infected with SARS-CoV-2, MERS-CoV, bat HKU5 expressing the SARS-CoV-1 S protein, and the vesicular stomatitis virus expressing the SARS-CoV-1 S protein. The authors found that AT-rich interactive domain-containing protein 1A (ARID1A) was a pro-viral gene in the case of infection by SARS-CoV-2 and MERS-CoV viruses (Wei et al., 2021). ARID1A/B is a component of the mammalian BRG1/BRM (BAF) complex, involved in chromatin remodeling and cell cycle arrest (Shigetomi et al., 2011; Pagliaroli and Trizzino, 2021). ARID1A is ubiquitously expressed in neural stem progenitor cells and throughout the brain (Liu et al., 2021). Another cellular component found to be perturbed by SARS-CoV-2 infection was the SWI/SNF (SWItch/Sucrose Non-Fermentable) complex, which is responsible for ATP-dependent chromatin remodeling. Interference with cell cycle progression allows the SARS-CoV-2 to hijack cellular machinery to increase viral replication (Kumar et al., 2021).

Bone-derived neurotrophic factor (BDNF) is a growth factor that plays a role in neurotransmission and neuroplasticity. It is expressed throughout the brain, including in astrocytes, Schwann cells, and neurons (Sakharnova and Vedunova, 2012). BDNF binds to tyrosine kinase B (Trk B), initiating a signal cascade that leads to the activation of the mechanistic target of rapamycin (mTOR), which promotes survival, growth, and differentiation of neurons (Bar-Yosef et al., 2019). SARS-CoV-2 has been demonstrated to enhance mTOR complex 1 (mTORC1) activity (Bar-Yosef et al., 2019). Calmodulin is not only an essential regulator of cellular activity, including apoptosis, neurotransmitter release, etc. (Yu et al., 2002; Ando et al., 2013; Schweitzer et al., 2021). Solute carrier family six-member 20 (SLC6A20) plays a role in the regulation of glycine as well as N-methyl-D-aspartate (NMDA) signaling (Bae et al., 2021).

SARS-CoV-2, like many other viruses, is thought to induce senescence in host cells through the increased binding of Angiotensin II (ANGII) to the Angiotensin II Type 1 receptor. ANGII acts as a toxin with respect to the host’s cells’ mitochondria through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the creation of reactive oxygen species (ROS), H₂O_s (Chang et al., 2020). This increase leads to the formation of hydroxyl radicals that cause DNA damage and the activation of poly ADP-ribose polymerases (PARPs), which are DNA damage sensors and deplete stores of NAD+ and exacerbate both the dysfunction of mitochondria. The depletion of NAD+ also results in the reduced mitophagy the increased formation of ROS, which in turn activates ADAM17 and inhibits nitric oxide (NO) synthesis (Dikalov and Nazarewicz, 2013; Chang et al., 2020; Sfera et al., 2020). ADAM17 is also a metalloprotease that has been reported to prime the SARS-CoV-2 spike protein (Heurich et al., 2014).

Autophagy plays an essential role in the homeostatic balance between cell survival and cell death. Previous work has shown that coronaviruses MERS-CoV and SARS-CoV can prevent autophagosomes from binding to lysosomes (Randhawa et al., 2020). The SARS-CoV-2 infection has been shown to reduce zinc finger FYVE and coiled-coil domain-containing autophagy adaptor 1 (FYCO1) expression, which participates in autophagosome maturation through the Rab7 effector protein, a late endosomal GTPase (Cheng et al., 2007; Pankiv et al., 2010; Randhawa et al., 2020). FYCO1 is expressed in several different cell types within the cortex (Mestres et al., 2020). The cysteine proteases cathepsin B (CTSB) and cathepsin L (CTSL) have also been implicated, alongside TMPRSS2, in the activation of the S proteins of the SARS-CoV-1, SARS-Cov-2, and MERS-CoV coronaviruses. These proteases are found in endosomes/lysosomes and participate in autophagy and apoptosis (Pišlar et al., 2020). Cathepsins consists of serine, aspartic, and cysteine proteases and are ubiquitously expressed (Vidak et al., 2019). Although the cysteine cathepsins are primarily located within the lysosome, where the acidic environment maintains their stability, the excess secretion of cathepsins is associated with inflammatory responses and disease (Huang et al., 2006; Gomes et al., 2020; Pišlar et al., 2020). Previous research has demonstrated host cell entry of corona-pseudoviruses via CTSL dependent endocytosis, and cysteine protease inhibitors effectively blocked viral entry (Simmons et al., 2005, 2011; Zhou et al., 2011; Rabaan et al., 2017). Much like ACE2 and TMPRSS2, CTSB/L is enriched in the lungs (Darbani, 2020). However, the gene expression of the CTSB/L in the cortex and cerebellum was greater relative to the gene expression of ACE2 and TMPRSS2, which were nearly undetectable in the same tissue (Darbani, 2020).

Testosterone levels have emerged as a risk factor for severe SARS-CoV-2 infection, and sex hormone signaling genes have been identified in previous investigations as potential targets in the treatment of SARS-CoV-2. Androgen receptors (ARs) are expressed through the CNS; however, the cortical expression of the AR is higher relative to other structures (Schumacher et al., 2021). The receptor influences the expression of ACE2 and TMPRSS2. Previous investigations of the effects of anti-androgenic drugs on the expression of genes related to the pathogenesis of SARS found that AR is a transcriptional regulator of ACE2, Furin, and TMPRSS2 (Samuel et al., 2020; Wambier et al., 2020). The TMPRSS2 gene is a target of the androgen receptor, which enhances transcription of TMPRSS2 (Clinckemalie et al., 2013; Samuel et al., 2020). It is, therefore, worth noting that hyperandrogenism in women has been associated with a greater risk of severe complications related to COVID-19 infection (Moradi et al., 2020). Previous investigations have demonstrated that the estrogen receptor (ER) is expressed by all neural cells and plays a role in resistance to infection and influences cytokine and macrophage activity (Seli and Arici, 2002; Villa et al., 2016). Interventions targeting estrogen and estradiol have been proposed as potential treatments for SARS-CoV-2 (Hussman, 2020). Sex-binding globulin (SHBG) is produced and secreted by the liver, and it binds sex hormones such as testosterone, and estrogen, thus regulating their levels in the bloodstream (Colangelo et al., 2012). An observational study of COVID-19 patients found lower SHBG levels in patients who died.

SARS-CoV-2 entry protein, ACE2, exert neuroinhibitory influence within brain regions such as the middle temporal gyrus and posterior cingulate cortex (Chen et al., 2020). Angiotensin (Ang) 1–7, a product of ACE2, decreases the synthesis and reuptake of noradrenaline and increases its uptake (Gironacci et al., 2014). ACE-2 and Mas protein regulate brain function and release neurotrophic factors, like BDNF (Steenblock et al., 2020). This factor has several critical roles, including the formation, development, and inhibition of degeneration of the neurons. It also plays a role in stabilizing mood and in cognitive function. Decreases in ACE-2 activity or expression have been known to disturb normal neurologic functions. This inhibition of ACE2 and subsequent decrease in BDNF leads to neurodegeneration and may cause mental disorders such as anxiety, depression, and cognitive impairment (Steenblock et al., 2020). It is important to note that the AR regulates the expression of ACE2 and TMPRSS2. Both AR and TMPRSS2 are implicated in prostate cancer, and some data suggests that there may be an association between prostate cancer and depression and anxiety (Newby et al., 2015; Rice et al., 2018; Wang et al., 2020).

Other host proteins such as neuropilin and DPP4 also relate to depressive symptoms. The expression of neuropilin in olfactory epithelia seems to be related to major mental disorders such as MDD. In one investigation, the authors found a significantly higher expression of NRP1 in post-mortem samples from the PFC of patients diagnosed with MDD when compared to controls (p < 0.001) (Goswami et al., 2013). Similarly, the expression of neuropeptide Y (NPY), a ligand for the DPP4 receptor, has been proposed as a biomarker for diagnosing PTSD, depression, and other neuropsychiatric illnesses (Canneva et al., 2015; Schmeltzer et al., 2016; Gołyszny and Obuchowicz, 2019). NPY has anxiolytic effects, and in an investigation, NPY immunoreactivity was significantly decreased in the cerebral spinal fluid (CSF) of unmedicated patients with persistent unipolar depression (Heilig et al., 2004). There is currently a clinical trial underway to investigate the value of Vildagliptin, an anti-diabetic drug, as adjunctive therapy to the SSRI, Escitalopram, and PDE3 inhibitor, Cilostazol, for the treatment of MDD (Clinical Trial ID: NCT04410341). It is also worth noting that cathepsins play a role in processing proneuropeptides like neuropeptide Y and have been found to be moderately associated with higher cognitive function following exercise training (Funkelstein et al., 2008, 2012; Moon et al., 2016).

Neuroinflammatory and immune responses are known to contribute to the development of mental disorders. One investigation of postmortem tissue taken from the dorsolateral prefrontal cortex (DLPFC) found increased mRNA expression of TLR3 and TLR4 and the increased presence of pro-inflammatory factors in the brains of depressed non-suicidal, and suicidal subjects (Pandey et al., 2014). Increased expression of TLR3 also results in reduced expression of disrupted in schizophrenia 1 (DISC1), which leads to aberrant neuronal morphology (Chen et al., 2017). In fact, previous research has shown that treatment with endotoxin to stimulate inflammatory cytokines or even treatment with inflammatory kinases themselves can lead to symptoms of depression in people who were previously undiagnosed (Bonaccorso et al., 2002; Anttila et al., 2018). Another investigation of the unfolded protein response in rats found increased expression of TLRs 2, 4, 7, and 9 as well as inflammatory cytokines within the hippocampus (Timberlake et al., 2019). In patients with hepatitis C, interferon-alpha (IFN-α) treatment can lead to clinical symptoms of depression, which can be alleviated by antidepressant therapy. This finding suggests that depression is caused by inflammation, and typical presentations of depression may have some similar underlying mechanisms.

Expression of inflammatory markers, such as chemokine CXCR6, by meningeal γδ T cells, has been shown to influence anxiety in mice (Alves de Lima et al., 2020). Mice deficient in CXCR6 have been demonstrated to have fewer γδ T cells than controls. The γδ T cells, in turn, release IL-17, a gene implicated in autism spectrum disorder (ASD) and SCZ (Debnath and Berk, 2017; Alves de Lima et al., 2020). γδ T cell-deficient mice demonstrated reduced anxiety behavior in the open field test. The authors showed that these cells could control anxiety behavior through IL-17 signaling (Alves de Lima et al., 2020).

Sex hormones and neuroimmune responses play converging roles in the etiology of mental disorders (Kokkosis and Tsirka, 2020). Lower testosterone is a predictor of depression symptoms in men, while higher levers of free testosterone in serum have been linked to manic episodes in men (Ozcan and Banoglu, 2003; Sankar and Hampson, 2012). Anti-androgenic therapies have been considered as a potential treatment for vulnerable populations (Bravaccini et al., 2021). A greater risk of depressive symptoms was positively associated with SHBG in a study of depressive disorders in post-menopausal women. SHBG was positively and statistically associated with depression risk (p = 0.003) in all women (Colangelo et al., 2012). In a study of schizophrenic male patients and a group of undiagnosed adults, the authors found that both treated and untreated patients had lower serum levels of SHBG (33.3 and 26.6 nmol/L) than undiagnosed controls (48.4 nmol/L, p < 0.05) (Costa et al., 2006).

Several infections, such as cytomegalovirus, herpes simplex virus, and parasitic infection by T. gondii, have been noted for interacting with the HLA system and for their association with affective disorders like BPD and SCZ (Parks et al., 2018). SCZ has been linked to several polymorphisms in the major histocompatibility complex (MHC) or the HLA system through several GWAS (Parks et al., 2018). HLA genes are expressed in astrocytes and microglia within the brain, although primarily in microglia (Tian et al., 2012). Previous investigations have identified HLA-B*4601, HLA-B*0703, HLA-B*4601, HLA-C*0801, and HLA-DRB1*1202 as alleles associated with severe illness following SARS-CoV-2 infection (Lin et al., 2003; Ng et al., 2004; Morsy and Morsy, 2021). The HLA-DRB*0301 and HLA-Cw*1502 alleles were associated with a reduced frequency of severe infection. These clusters, namely HLA-B, HLA-DRB1, HLA-C, HLA-DRA, HLA-DQA, HLA-DQB, HLA-DPB, have been associated with mental health disorders, i.e., SCZ, BPD, and PTSD (Carter, 2009). A gene-wide association study of 13,4982 cases and 663 controls found significant associations between the Notch 4 intronic variant rs3131296 and HLA alleles: HLA-DRB1*0301 and HLA-B*0801 (R² = 0.86 and 0.81, respectively) (Stefansson et al., 2009). In a separate investigation of molecular pathways underlying SCZ and BPD, the authors found that patients demonstrate more variation in the HLA-C and HLA-DRA genes than would be expected by chance (Marco et al., 2015). It is also worth noting that PTSD has also been found to be associated with HLA alleles (HLA-B*5801, HLA-C*0701, HLA-DQA1*0101, HLA-DQB1*0501, and HLA-DPB1*1701) in a case-control study of 403 diagnosed patients with 369 individuals who had been exposed to trauma (Katrinli et al., 2019).

Differential levels of cytokines and cytokine receptors have been found between the first episode, acute relapse of psychosis, and post-treatment patients diagnosed with SCZ (Capuzzi et al., 2017). A previous meta-analysis of first-episode psychosis, acute relapse, and post-treatment SCZ patients compared effect sizes of blood levels of inflammatory markers (cytokines, cytokine receptors, and antagonists) (Miller et al., 2011). Significant differences between the effect sizes of several inflammatory markers were found between post-treatment patients diagnosed with SCZ and first-episode psychosis and acutely relapsed patients (Miller et al., 2011). These cytokines and receptors include including IL-6, IL-12, TNF-α, IL-1β, IL-8, transforming growth factor-β (TGF-β), IL-1RA, IFN-γ, sIL-2R, and IL-10 (Miller et al., 2011). It is worth noting that levels of IL-6 and TNF-α were significantly correlated with survival in SARS-CoV-2 in a previous investigation (Del Valle et al., 2020). Increased levels of circulating IL-1β, IL-12, IL-6, CXCL10, CCL2 have been reported in severe cases of SARS-CoV-2 infection (Coperchini et al., 2020). TGF-beta plays a role in regulating immune response and plays a role in the development of mental disorders like SCZ and symptoms such as psychosis (Sanjabi et al., 2017; Roomruangwong et al., 2020). Increased expression of chemokines such as CCR1 has been shown in postmortem brain tissue in patients diagnosed with SCZ compared to patients diagnosed with BPD (de Baumont et al., 2015).

Metalloproteases ADAM10/17 have been implicated in neurodegenerative disorders. They play a role in the proteolysis of the amyloid precursor protein (APP) and several other proteins (Vincent and Govitrapong, 2011; Qian et al., 2016). Similarly, another protein affected by SARS-CoV-2 infection, FYCO1, has been linked to neurodegenerative disorders, neuropsychiatric disorders, and senescence in age-accelerated mice (Cheng et al., 2007; Saridaki et al., 2018). However, ADAM10/17 have also been linked to SCZ, depression, BPD, and conduct disorder, a condition that has been found to be comorbid with mood disorders (Jian et al., 2011; Marballi et al., 2012; Qian et al., 2016; Hoseth et al., 2017; Yuan et al., 2017; Pantazopoulos et al., 2020). A family-based association study found 20 variants associated significantly associated with conduct disorder; among these single nucleotide polymorphisms (SNPs), rs383902 was located within ADAM10 (p = 0.00036) (Jian et al., 2011). In one investigation of postmortem brain tissue from BA9, using ANCOVA analysis, investigators found a significant difference in ADAM17 expression between the control and bipolar groups and levels observed in the schizophrenic group (p < 0.007). The authors also found a significant negative correlation between levels of neuregulin-1 (NRG-1) and ADAM17 in Broca’s area 9 samples taken from the post-mortem tissues of patients diagnosed with SCZ (Marballi et al., 2012). Similarly, Hoseth et al. (2017) found greater mRNA expression of ADAM17 in the plasma of SCZ patients vs. that seen in controls (Hoseth et al., 2017). ADAM10/17 influences glutamatergic signaling, which is also impacted by the SLC6A20 transporter protein. In a GWAS of NMDA receptors and the detection of their coagonists in cerebrospinal fluid, the authors found that a missense variant in SLC6S20 as associated with increased L-proline levels in CSF, thus demonstrating that SLC6A20 plays a role in the trafficking of proline to the CSF (Luykx et al., 2015). Hyperprolinemia has been previously reported in conjunction with SCZ and schizoaffective disorder (Jacquet et al., 2005; Clelland et al., 2011).

Neurotransmission may also be related to the expression of SARS-CoV-2 entry protease FURIN. FURIN was found among several genes linked to comorbidity SCZ and cardiometabolic illness, which gives insight into the etiology of these conditions (Liu et al., 2020). Several studies underscore the importance of furin in the CNS, as it has been linked to Alzheimer’s disease (AD) and SCZ (Scamuffa et al., 2006; Schrode et al., 2019; Yang et al., 2020). In a GWAS of 49 ancestry matched non-overlapping case-controls and 1,235 parent affected offspring trios, the authors found 108 loci that were significantly associated with SCZ (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Of those, Fromer et al. (2016) found nineteen of the SCZ risk loci were enriched for eQTLs. However, only eight involved a single gene; among them was the gene encoding furin protease. The authors found that furin expression was downregulated by the risk variant rs4702 (GG to AA allelic conversion), a 3′ UTR variant, which was both the most significant SNP detected by GWAS and eQTL analyses (Fromer et al., 2016). The rs4702 SNP results in the alteration in the binding site for miR-338-3p. miR-338-3p is an mRNA that is expressed predominantly in mature neurons within the dentate gyrus (Howe et al., 2017). The authors noted that cells in which miR-338-3p was effectively knocked down showed aberrations in the number of primary dendrites as well as the angles of their extension from the soma (Howe et al., 2017). Interestingly enough, the rs4702 variant, which is associated with SCZ, may be protective against SARS-CoV-2 infection, as cells expressing rs4702 had reduced levels of vRNA relative to cells expressing the normative allele (AA) (Dobrindt et al., 2021). In a separate investigation, the rs4702 specific reduction in the expression of FURIN and BDNF was “mediated” by miR-338-3p (Hou et al., 2018). BDNF is a member of the BDNF-mTORC1, which helps to regulate synaptic plasticity, glutamatergic signaling, monoaminergic signaling, and autophagy. The SARS-CoV-2 infection has been demonstrated to increase the activity of mTORC in Vero kidney epithelial cells 24 h post-infection (Mullen et al., 2021). A common SNP of BDNF, rs62265, is a missense mutation that has been associated with anxiety, major depression, suicide, and neurodegenerative disease, as has dysregulation of mTOR signaling (Dincheva et al., 2016; Youssef et al., 2018; Bar-Yosef et al., 2019). Additionally, decreased BDNF expression has also been associated with SCZ (Suchanek-Raif et al., 2020). Epigenetic regulation of BDNF has also been demonstrated to play a role in mental illness, as methylation of genes associated with SCZ, like BDNF, has been linked to psychosis (Gavin et al., 2010).

Increased levels of GSK-3β in blood, serum, and CSF have been associated with SCZ (Mohammadi et al., 2018). The GSK-3β inhibitor lithium, which is utilized as a treatment for psychiatric disorders such as SCZ and BPD, has been shown to inhibit infection by several viruses, including coronaviruses (Murru et al., 2020). One investigation examined gene expression in 12 BPD patients and ten controls following two laser microdissections of the olfactory epithelia: one pretreatment with lithium in the second after 6 weeks of daily lithium treatment. The BPD patients demonstrated greater levels of GSK-3β than controls (Narayan et al., 2014). Lithium has been shown to inhibit GSK-3β, and similar to those studies the authors found that GSK-3β was reduced in the second microdissection samples taken from BPD patients following 6 weeks of daily lithium treatment (Harrison et al., 2007; Narayan et al., 2014; Zhao et al., 2017).

Genes responsible for chromatin remodeling are implicated in SCZ as well. The SWI/SNF complex protein ARID1A is typically associated with craniofacial abnormalities. However, mutations in the ARID1B gene have been associated with intellectual disability, ASD, and SCZ as well (Son and Crabtree, 2014; Pagliaroli and Trizzino, 2021). SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, family a, member 2 gene (SMARCA2), encoding the SWI/SNF subunit, Brahma (BRM), has been associated with self-reported MDD and SCZ (Amare et al., 2020; Wu et al., 2020a). In an investigation of bivariate analyses of genome-wide association study results relating to depression combined with MDD, BPD, and SCZ, the authors found that the SMARCA2 gene and the SWI/SNF gene set were enriched. This indicated the role of epigenetic mechanisms in the etiology of complex mental health disorders (Amare et al., 2020). In a separate investigation, drugs capable of inducing psychosis were found to reduce BRM expression, while anti-psychotics led to increased expression of BRM (Koga et al., 2009).

Further demonstrating the importance of chromatin remodeling proteins in the etiology underlying SCZ is the HMGB1 protein. An investigation of gene expression in post-mortem tissue from 212 patients with SCZ and 214 undiagnosed controls found 87 genes demonstrated expression variability, including HMGB1 (Huang et al., 2020). In a separate study, serum levels of HMGB1 were significantly higher in bipolar patients than in undiagnosed controls. The authors found that serum levels of HMGB1 were significantly higher in the bipolar patients compared to the controls137. A systematic review of the literature also found increased levels of HMGB1 in conjunction with several studies of mouse models of depression (Zhang et al., 2019). One drug, minocycline, was found to reduce depressive-like symptoms in a mouse model of depression. This reduction was associated with a significant decrease in the translocation of HGMB1 from neurons and microglia (Wang et al., 2020).

Sex hormones have also been shown to play a role in the risk of developing SCZ (Kokkosis and Tsirka, 2020). Women with polycystic ovarian syndrome (PCOS) have also been demonstrated to be at greater risk of developing psychiatric disorders such as bipolar disorder and SCZ (Owens et al., 2019). An investigation of androgen receptor expression among individuals diagnosed with SCZ, BPD, and undiagnosed controls (n = 35, 31, and 34, respectively) found increased expression of AR among individuals diagnosed with bipolar disorder relative to individuals diagnosed with SCZ and control volunteers. No significant differences were observed in 5α-reductase between the experimental groups. However, a small but significant correlation was found between bipolar disorder and 5α-reductase expression (r = 0.422, p < 0.01) (Owens et al., 2019). Hormones have been demonstrated to affect neuropeptides involved in stress and anxiety, like oxytocin and corticotropin-releasing hormone (CRH) (Wang and Wang, 2021). Previous research has linked decreased oxytocin and oxytocin receptor levels to first-episode SCZ and bipolar II disorder (Liu et al., 2019b; Wei et al., 2020). The therapeutic use of OXT has been proposed as a treatment to protect against cardiovascular damage caused by SARS-CoV-2 infection (Wang and Wang, 2021).