Why Severe COVID-19 Patients Are at Greater Risk of Developing Depression: A Molecular Perspective

Abstract

The prevailing evidence suggests that patients with severe COVID-19 seem to have an overreaction of the immune system demonstrating exacerbated levels of inflammation caused by a “cytokine storm.” At this early stage, the mechanisms underpinning COVID-19 are still subject to intense scrutiny and the long-term mental health consequences as a result of the disease are unknown. Here we discuss the hypothesis that patients who survive severe COVID-19 and who experience significant activation of the immune system, are at greater risk of developing depression. We posit that a phenomenon known as cytokine storm dramatically activates the enzyme indoleamine 2,3-dioxygenase (IDO-1), resulting in the increase in kynurenine metabolites. Kynurenine is metabolized by IDO-1 in the brain, producing chemokines, in which a prolonged exposure may result long-term brain impairment. In this article, we also propose the possibility that a SARS-CoV-2 neuroinvasion increases the local levels of angiotensin II by angiotensin-converting enzyme 2 down-regulation. Thereby, angiotensin II could increase kynurenine metabolites producing pro-oxidative and pro-inflammatory effects, resulting in impairment of cognitive function, enhanced oxidative stress and decreased brain-derived neurotrophic factor. It is our premise that patients who experience such a cytokine storm may be at increased risk of long-term mental illness, such as depression.

Keywords

cytokine storm severe COVID-19 long-term mental illness brain impairment depression

Introduction

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to a family of coronaviruses that have high pathogenicity and are associated with a range of respiratory outcomes (Wang and others 2020). Coronaviruses are enveloped RNA viruses that infect and cause disease in a range of animals and humans (Weiss and Leibowitz 2011). The human coronavirus (HCoV) represents a major group of coronaviruses including severe acute respiratory coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) (Wang and others 2020). Genetic analysis has revealed that the novel SARS-CoV-2 is phylogenetically related with SARS-CoV and MERS-CoV sharing 79.6% sequence identity and the same cell receptor angiotensin-converting enzyme 2 (ACE2) with SARS-CoV (Zhou and others 2020).

Previous studies have reported the association of SARS-CoV with respiratory symptoms; however, converging evidence suggests that this virus is not confined to the lungs but rather can affect multiple organs and cells including immune cells, the spleen, lymph nodes, trachea, bronchi, distal renal tubules, intestine, and neurons (Gu and others 2005). More specifically, an immunohistochemistry analysis revealed that SARS-CoV is able to infect the central nervous system (CNS) and has been implicated in some brain immunopathologies (Xu and others 2005). These findings were confirmed by Arbour and colleagues, who reported the presence of the coronavirus in human brain autopsies of patients with multiple sclerosis (Arbour and others 2000). As most HCoVs share a similar viral structure and infection pathways reported for other CoVs (e.g., SARS-CoV), perhaps this previous finding may also be applicable for SARS-CoV-2 (Yuan and others 2017). Although, respiratory system involvement is most commonly observed in patients confirmed with COVID-19, several neurological manifestations have been reported, which raises the notion of the potential for neurotropism of SARS-CoV-2 (Conde Cardona and others 2020).

Most patients with COVID-19 have a good prognosis, but some individuals become critical unwell (Wang and others 2020). Critically ill patients seem to experience a severe immune system response characterized by a cascade of significantly elevated levels of inflammation, which is sometimes referred to as a “cytokine storm” (Liu and others 2016). A recent case report that employed magnetic resonance imaging reported that COVID-19 resulted in acute necrotising encephalopathy (Poyiadji and others 2020). This observation has been related to intracranial cytokine storm syndrome despite there being no evidence of a direct viral invasion (Rossi 2008). There is now compelling evidence that suggests inflammatory states in the body and/or CNS together with psychological stressors may affect a variety of brain functions, including mood disorders (Miller and Raison 2016).

SARS-CoV-2 Entry and ACE2 Mechanism

The coronavirus contains at least four main structural proteins, including (1) envelop (E), (2) membrane (M), (3) nucleocapsid (N), and (4) transmembrane spike (S) (Tortorici and Veesler 2019). The S glycoprotein is a 1273 amino acid–long protein with a molecular weight of approximately 150 kDa. This transmembrane protein is located at the viral surface where it forms protruding homotrimers known as “corona” that promotes host attachment (Li 2016). The SARS-CoV-2 has a length of 29.9 kb, is approximately 65 to 125 nm in diameter and contain single strands of RNA. The virus invades the human respiratory epithelial cells mediated by the efficient binding of the S viral glycoprotein to the host ACE2 receptor (Hoffmann and others 2020). After fusion of SARS-CoV-2 and ACE2, the type II transmembrane serine protease (TMPRSS2) that is present on the surface of the host cell is activated, leading to activation of the receptor-attached S proteins (Hoffmann and others 2020). Both ACE2 and TMPRSS2 are required for the entry of the SARS-CoV-2 into the cell (Hoffmann and others 2020). SARS-CoV-2 infection leads to down-regulation of the ACE2 receptors and this might be an aggravating factor for patients with medical conditions (Verdecchia and others 2020).

The presence of the ACE2 is not limited to the respiratory system, it is also expressed in various tissues, including mouth, tongue, kidneys, heart, endothelium, intestine, and brain (Gu and others 2005). ACE2 is a crucial regulatory enzyme of the renin-angiotensin system (RAS) (Clarke and Turner 2012). It is composed of 805 amino acids and uses a single extracellular catalytic domain to remove one amino acid from the octapeptide angiotensin II (Ang II) to convert into Ang-(1-7) (Clarke and Turner 2012). This mechanism is fundamental to maintain lower blood pressure through vasodilatation. The dysregulated brain RAS has been implicated in neurodegeneration due to neuroinflammation, oxidative stress, and other pathophysiological changes (Labandeira-Garcia and others 2017). Feng and coworkers reported that the overexpression of ACE2 in the brain constituted a protective role in several cardiovascular complications, possibly mediated by sympathetic nerve activity (Feng and others 2012). Recently, Hussain and colleagues reported that genetic variations of human ACE2 are associated with lower binding to the viral S protein. Thus it might be suggested that patients who present these variations in ACE2 have a potential resistance against SARS-CoV-2 infection (Hussain and others 2020).

SARS-CoV2 and Pattern Recognition Receptors

Once SARS-CoV2 infects the host cell an immune response is triggered, recruiting the frontline innate immune system cells via antigen presenting cells (APC), for exampple, macrophage and lymphocyte cells (Astuti and Ysrafil 2020). After infection, SARS-CoV-2 releases its genomic RNA material into the cellular cytosol; subsequently, the viral RNA is detected by pattern recognition receptors (PRRs) (Astuti and Ysrafil 2020). These receptors are able to recognize highly conserved molecular structures known as pathogen-associated molecular patterns (PAMPS) derived from nucleic acids (e.g., RNA), fungi, and bacteria (Suresh and Mosser 2013). PRRs are involved not only in the detection of invading microorganism products, but they are also able to identify “danger signals” from the host, known as damage-associated molecular patterns (DAMPs) (Suresh and Mosser 2013). DAMPs are endogenous molecular products of tissue damage or dying cells released from the extracellular or intracellular space, such as high-mobility group box 1 (HMGB1), histones and heat-shock proteins (HSPs) (Roh and Sohn 2018).

To date several types of PRRs has been identified, including melanoma-differentiation-associated gene 5 (MDA-5) and retinoic acid–inducible gene I (RIG-1)-like helicases (RLHs), that have similar functions, nucleotide-biding oligomerization domain (NOD)-like receptors (NLRs), and Toll-like receptors (TLRs) (Suresh and Mosser 2013). TLR are a family of receptors composed by 10 members (TLR-1 to TLR-10) in humans, which are located on the cell surface or in the intracellular compartments (Suresh and Mosser 2013). Coronaviruses are potentially recognised by Toll-like receptor 7, a viral receptor, which is activated in endosomes. In addition RIG-1 or MDA-5 both are cytosolic receptors that detect double-stranded RNA (dsRNA), which are products of viral infection (Lim and others 2016). After this recognition, a signalling cascade is triggered culminating in the oligomerisation of these receptors and the activation of transcription factors such as, the interferon regulator factors (IRFs) and nuclear factor kappa B (NF-κB) (Hur 2019). The activation of IRF and NF-κB result in the production of an antiviral defence mediated by transcriptional stimulation of type I and III interferons (IFN-I and IFN-III) and the expression of inflammatory cytokines, for controlling viral replication (Lim and others 2016). Coronaviruses, such as SARS-CoV have developed a sophisticated invasion mechanism to prevent the early induction of IFNs (Zust and others 2011). The virus encodes an enzyme that adds a 2′-O-methyl group to viral RNA preventing its recognition, thus resulting in the inability of the immune system to control the viral replication, leading to cell damage and in some cases an inflammatory cytokine storm (Zust and others 2011).

The Role of Cytokines in Depression

Cytokines are signal molecules that instruct the homeostasis and function of immune cells. In the brain, normal levels of cytokines are required to maintain physiological conditions, which in turn promote normal learning, memory and cognition (Himmerich and others 2019). Any disturbance in the regulatory mechanisms that underpin the homeostasis of cytokines, such as might occur as a result of an infection or triggered by physical or emotional stressors can result in neuroinflammation and consequently neurodegeneration (Himmerich and others 2019). The activation of cytokines through these potential stressors can have an intense effect on the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal (HPA) axis (Bellavance and Rivest 2014). HPA axis activation provokes the release of glucocorticoids (GCs) which in turn trigger negative feedback onto immune cells to inhibit the further synthesis and release of cytokines. This process protects the host from detrimental consequences due to overreaction of the immune response (Silverman and others 2005). However, an exposure to a chronic or severe stressor can cause prolonged activation of the HPA axis and exacerbate cortisol release, causing an impairment in the function of GC receptors. This reduces the immune system’s capacity to respond to cortisol and control inflammation, sustaining high levels of pro-inflammatory cytokines (Nandam and others 2019). Several studies have reported that individuals with depression exhibit greater plasma concentrations of pro-inflammatory cytokines and cortisol. However, the association between cortisol and depression in humans is complex and appears to rely on both the severity and stage of illness (Stetler and Miller 2011).

Cytokines also play a critical role in physiological process and some studies have reported that administration of pro-inflammatory cytokines induce a behavioral pattern referred to as a sickness behaviour, including sleep disturbance, tiredness, and loss of appetite (Andreasson and others 2007). Interestingly, these sickness behaviours are similar to the symptoms of major depression. Cytokines are postulated to regulate orexigenic mechanisms of appetite such as food intake; therefore, these molecules may assume a regulatory role, such as impairing appetite as observed in some patients with depression (Andreasson and others 2007). Moreover, an inhibitor of the tumor necrosis factor α (TNF-α) cytokine has shown to improve mood symptoms and appetite in an anorexic patient, after 5 months of treatment (Barber and others 2003). Cytokines are considerate sleep-regulatory substances (SRSs), particularly TNF-α and interleukin-1β (IL-1β) induce the up- and down-regulation of many substances thought to be stimuli for the sleep-wake cycle. For instance, both these SRSs induce activation of the NF-κB, a key transcriptional control pathway in the inflammatory signaling cascade, which in turn up-regulates both IL-1β and TNF-α triggering a positive feedback, inhibiting sleep (Krueger and others 2001). Sleep disturbance is one of the primary symptoms of major depression and, although the interaction between inflammation, sleep, and depression are well documented, the precise mechanisms that connect them remain unclear.

Cytokines have also been reported to influence the response to antidepressant treatment. This has been shown through the significant percentage of patients with treatment-resistant depression (TRD) who present with increased inflammatory markers, such as TNF-α (Eller and others 2008). However, not only are TRD patients more likely to present high levels of inflammation, it seems that increased levels of inflammatory markers before treatment may also predict a lower response to treatment (Eller and others 2008). There are several pathways by which cytokines may influence the mechanisms of action of antidepressant medication, including (1) neurotransmitter metabolism (e.g., cytokines can block the reuptake pumps for serotonin, norepinephrine, and dopamine), (2) impact on neurogenesis (e.g., cytokines can reduce the proliferation of new neurons), and (3) impact on the neurocircuitry of mood and anxiety (e.g., cytokines may interact with the dorsal ACC [dACC] and subgenual ACC [sACC], both associated with treatment resistance) (Raison and others 2013).

Cytokines have been associated with suicidal behaviours. In particular, elevated levels of interleukin 6 (IL-6) and TNF-α have been reported in depressed individuals with a history of suicide behaviours compared with nonsuicidal depressed patients. This suggest that suicidal individuals may have a unique cytokine profile that distinguishes them from depressive individuals who do not exhibit suicidal behaviour (O’Donovan and others 2013). O’Donovan and colleagues reported that pronounced degree of suicidal ideation is associated with elevated inflammatory index in patients regardless of the depressive symptoms. Several mechanisms can promote suicidal behaviour by inflammatory cytokine, including alterations of the HPA-axis and dysregulation in monoamine metabolism (O’Donovan and others 2013).

SARS-CoV-2 and Cytokines Storm

Cytokine storm is an uncontrolled release of proinflammatory cytokines which are associated with a wide variety of infectious diseases (Tisoncik and others 2012). It is well documented that high levels of cytokines/chemokines correlate strongly with disease severity (Liu and others 2016).

Severe SARS-CoV-2 infection triggers an aggressive inflammatory response in susceptible individuals, and it relies not only on the viral infection but also on the host immune system response (Merad and Martin 2020). Potential mechanisms that could trigger cytokine storms include high rates of viral replication, which could result in increased host cell cytolysis, delayed induction of IFN-γ responses due to virus escape mechanisms, which perpetuates viral damage, thus leading to excessive accumulation of monocytes, macrophages, and neutrophils in the lungs (Merad and Martin 2020). The severe inflammation can spill cytokines/chemokines into the circulation promoting systemic cytokine storms, which are then responsible for multiorgan dysfunction (Tisoncik and others 2012).

A recent meta-analysis of delirium between intensive care patients of mixed conditions showed that beyond the acute effects of cytokine storm, persistent neurocognitive deficits were reported up to 18 months post-discharge, including mild cognitive impairment (Salluh and others 2015).

COVID-19: A Hypothesis for Depression

Major depressive disorder (MDD) is a multifactorial disorder that involves genetic changes, as well as psychological, immunological, and neuroendocrinological factors (Leonard 2010). Previous studies have showed how a subgroup of patients with MDD have exhibited features of an activated immune response. In particular, the increased levels of chemokines, adhesion molecules and acute phase proteins in the blood such as IL-1β, IL-6, and TNF-α (Eyre and others 2016).

These observations have also been reported in patients who present with increased levels of inflammation, resultant from a chronic medical illness, who interestingly go on to develop symptoms of depression at higher rates than the general population (Katon 2011). Comparisons can be drawn to severe cases of COVID-19 patients that required intensive care. These patients exhibit higher plasma concentrations of granulocyte colony stimulating factor, macrophage inflammatory protein 1α (MIP-1α), interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), and TNF-α as compared with cases that did not require intensive care (Huang and others 2020). This supports the hypothesis that a dysfunctional immune response, triggering a cytokine storm that results in widespread respiratory inflammation could be a mediating factor for disease severity. Another feature in severe COVID-19 disease is the global T-cell lymphopenia, characterized by an excessive initial activation and subsequent exhaustion of CD8+ T-cells (Zheng and others 2020). One explanation for this could be an activation of the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1) which exerts important immunosuppressive functions (Wu and others 2018). This enzyme expression can be induced in multiple organs, including brain, lungs, gut, kidneys, and dendritic cells. IDO-1 is activated by inflammatory cytokines such as TNF-α and IFN-γ responsive elements, including NF-κB. (Widner and others 2000; Wu and others 2018). This activation causes degradation (and subsequent depletion) of tryptophan and increases in metabolites of the kynurenine (KYN) pathway. The depletion of tryptophan and accumulation of its derived catabolites by IDO-1 leads to the suppression of T-cell proliferation and the induction of T, B, and natural killer cell apoptosis (Wu and others 2018).

Kynurenines are produced in several different tissues including cells of the immune system and brain, where IDO-1 catalyzes the conversion of tryptophan to KYN. The KYN are catabolised to either kynurenic acid (KYNA), to 3-hydroxykynurenine (3-HK), which in turn can result in neuronal apoptosis and quinolinic acid (QUINA), which is an N-methyl-d-aspartate receptor (NMDAR) agonist that is associated with excitotoxic neurodegeneration (Kindler and others 2019). The dysregulation in the KYN pathway has been suggested to cause depression. There have been several mechanisms suggested that underpin the emergence of depression and these include the activation of microglia, production of reactive oxygen species (ROS), nitric oxide (NO) as well as inflammation (Widner and others 2000). Recently, it has been reported that de novo depression patients have increased levels of plasma inflammatory mediators. More specific, TNF-α has been strongly associated with plasma KYN and KYN/tryptophan, which has in turn been associated with KYN metabolites (kynurenic acid and quinolinic acid) in the cerebrospinal fluid (CSF) (Haroon and others 2020). Moreover, it has been shown that patients with depression that also have high TNF-α-KYN/tryptophan levels exhibit greater depression severity (Haroon and others 2020). Raison and coworkers have reported that an increase in KYN metabolites in CSF and plasma is associated with the onset of depression and severity in patients receiving the inflammatory cytokine IFN-α (Raison and others 2010). While tryptophan depletion can occur independent of KYN metabolism by IDO-1 in patients with minimal inflammation (Hughes and others 2012), there is equal evidence to indicate that a subset of MDD patients with a high level of underlying inflammation are associated with a dysregulation in KYN metabolism that relates to depressive symptom (Mackay and others 2009).

The KYN biosynthesis has been postulated to be regulated in other viruses, including influenza virus infection (Gaelings and others 2017). However, different from the SARS-CoV-2 which binds ACE2 receptor, the viral attachment protein of influenzas, hemagglutinin, interacts to and uses sialic acid-containing molecules as receptors (Garcia-Sastre 2010; Hoffmann and others 2020). Thus, the activation of the KYN pathway in SARS-CoV-2 has marked differences compared to influenza following an infection. In this context, we hypothesise that severe COVID-19 patients who present with overexpression of pro-inflammatory cytokines (e.g., TNF-α), otherwise considered a key cytokine in cytokine storm related to escalation in severity (Liu and others 2016), could increase dramatically IDO-1 and KYN metabolites, producing chemokines, such as MIP-1α and MCP-1. The MIP-1α is a chemokine that peripherally recruits monocytes, T lymphocytes, and dendritic cells (Menten and others 2002). In the CNS, MIP-1α is induced by picolinic acid (PA), a metabolite of KYN pathway that regulates the inflammatory activation of microglia and promotes leukocyte attraction across the blood-brain barrier (BBB) (Bosco and others 2000). This chemokine has been implicated in modifications of neuronal transmission and alterations in cognitive function (Marciniak and others 2015). It has been reported that the serum levels of MIP-1α are proportional to the severity of depression in depressed patients with and without posttraumatic stress disorder (Oglodek 2018). Similarly, the chemokine MCP-1 has been shown to attract peripheral monocytes to the brain, more specifically in the cerebral cortex, hippocampus, and hypothalamus regions, which are all implicated in the pathophysiology of depression (Pae 2014). A recent meta-analysis reported that depressed patients have higher serum concentrations of the chemokine MCP-1 compared with control subjects (Eyre and others 2016). Furthermore, the MCP-1 gene is located on the chromosome 17q11.2-q12, which is adjacent to the encoding area of the well-known candidate gene for depression, serotonin transporter (5-HTTLPR) (Pae 2014). Supporting our hypothesis is the detection of high concentrations of these chemokines in the serum of COVID-19 patients who required intensive care. As such we postulate that prolonged inflammation as a consequence of COVID-19 could result in long-term brain changes that predispose patients to depression.

Coronaviruses have also been showed to have neuroinvase capacities through the migration from the respiratory tract to the CNS, where they can induce other pathologies (Desforges and others 2014). Several routes of CNS invasion can be used by viral pathogens, including the infection of the endothelium (hematogenous route) and the peripheral nerves or olfactory system (McGavern and Kang 2011). Previous studies reported that SARS-CoV is able to infect the CNS (Arbour and others 2000), and recently, SARS-CoV-2 genome was detected in the CSF of a COVID-19 patient (Zhou and others 2020). Although, SARS-CoV and SARS-CoV2 are phylogenetically related, the affinity of SARS-CoV-2 for ACE2 is 10- to 20-fold higher than SARS-CoV (Hoffmann and others 2020), and this may account for the more aggressive host immune response that has been observed. Zhou and colleagues reported that SARS-CoV-2 was detected in the CSF of a COVID-19 patient diagnosed with viral encephalitis suggesting direct virus damage to the brain (Zhou and others 2020). Likewise, it was reported that SARS-CoV-2 RNA was not detected in the nasopharyngeal swab of a patient with meningitis/encephalitis; however, the virus was detected in the CSF indicating its neuroinvasive potential. The brain magnetic resonance image of this particular patient showed hyperintense signal changes in the right mesial temporal lobe and hippocampus, suggesting the possibility of SARS-CoV-2 meningitis (Moriguchi and others 2020).

The neuroinvasive potential of SARS-CoV-2 could be an aggravating factor due to the binding to ACE2 which are expressed in neurons and glial cells, that may act as a target and be vulnerable to infection (Xia and Lazartigues 2008). Thus we posit that through neuroinvasion (migration or direct infection), ACE2 down-regulation by SARS-CoV-2 leads to an increase in Ang II levels which is released locally in the brain. Centrally, Ang II is mediated mainly by two receptors: AT1R and AT2R, that are dominant in astroglial cells (Jackson and others 2018). The interaction with AT1R promotes pro-oxidative and pro-inflammatory effects, activating microglial kinase pathway, inducing nitric oxide synthase (iNOS), cyclooxygenase-2, and also TNF-α (Jackson and others 2018). These mechanisms all contribute to neuroinflammation and evidence has shown a clear association between Ang II and depression (Vian and others 2017). Zakrocka and colleagues reported that Ang II receptor blockers (irbesartan, losartan, and telmisartan) are able to decrease KYNA (a metabolite of tryptophan produced by kynurenine aminotransferase II [KAT II]) production by direct inhibition of KAT II in rat brain cortex, improving cognition (Zakrocka and others 2017). KYNA has been further implicated in cognitive impairment (Chess and others 2007). Ang II receptor blockers have also been showed to prevent impairment in memory via up-regulation of BDNF, which plays a critical role in neuronal survival, growth, plasticity, and is essential for learning and memory (Wincewicz and others 2016). In the same way, Wang and coworkers have demonstrated that ACE2 knockout mice exhibit significant impairments of cognitive function, enhanced oxidative stress and decrease in BDNF in the hippocampus region, compared with WT mice (Wang and others 2016).

Both hypotheses suggested, either through the IDO-1 activation and subsequent increases in KYN or SARS-CoV-2 neuroinvasion, seem to converge on a common pathway that culminate in strong persistent inflammation and a decline in cognition function. All of these pathways raise the possibility of patients affected by severe COVID-19 with prolonged exposure to inflammation, may have long-term neurological sequels.

Previous data from SARS-CoV and MERS suggest the prevalence of depression, anxiety and posttraumatic stress disorder might be elevated. However, data from COVID-19 patients are preliminary (Rogers and others 2020). Moreover, most studies that have shown an association between SARS-COV-2 infection and psychiatric disorders such as psychosis and mania, have evaluated the short-term effects (Iqbal and others 2020). Hitherto, only a few articles have been published that have established an association between stable COVID-19 patients and psychological distress (Bo and others 2020). Zhang and colleagues reported an increased prevalence of depression (29.2%) in individual who experienced SARS-COV-2 infection (Zhang and others 2020). However, there are numerous ways by which mental health might be affected by this pandemic, including social support, length of isolation, and exposure to constant negative media reporting of the current pandemic. Here we discuss the hypothesis that patients who survive severe COVID-19 and who experience significant activation of the immune system are at greater risk of developing depression.

Summarizing our hypothesis, SARS-CoV-2 infection within the respiratory system can trigger a strong immune response and susceptible patients can develop severe COVID-19. The so-called “cytokine storm” can then dramatically activate the enzyme IDO-1, depleting tryptophan and leading to an excessive initial activation and subsequent exhaustion of CD8+ T cells. The high activity of this enzyme increases the levels of KYN, which is metabolised by IDO-1 in the brain producing ROS and inflammation, with which prolonged exposure may cause long-term brain damage. Moreover, the infection of the SARS-CoV-2 from the respiratory tract to the CNS or direct infection into the brain, increases the local levels of Ang II by ACE2 down-regulation. The interaction of Ang II with AT1 receptor increases KYN metabolites, producing pro-oxidative and pro-inflammatory effects, resulting in impairment of cognitive function, enhanced oxidative stress, and decreased levels of BDNF (Fig. 1). All these elements play a critical role in a highly orchestrated immune inflammatory response that ultimately could result in the development of depression.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ana P. Bouças

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