**7. Psychoneuroimmunity of COVID-19**

One of the strong hypotheses on COVID19 and neuro-psychoimmunology is the strong interlink between changes in the cytokines and interleukins across the immune system [38]. Further studies have demonstrated the lack of naïve T cells, an increase in the senescent population of T lymphocytes, and shortening of telomeres in major depression [39]. A plausible approach to explore the association between the virus and the immune system function in major depression and other mood-related disorders is to check their immune response to the antigenic substance injected, such as endotoxin. The outbreak of a viral infection would be a great challenge, yet an opportunity to investigate the significance of an acute immune challenge on different domains of the psychopathology of mood disorders.

A study published in JAMA Neurology by Ling Mao et al. (2020) found that among 214 COVID-19 patients with a mean age of 52.7 [15.5] years, 126 patients had a non-severe infection, while 88 patients developed severe illness based on the respiratory infections [24]. Moreover, out of 214, 78 patients had neurological manifestations. Compared to non-severe infections, the severe ones were all from the elderly population and had underlying medical conditions, especially hypertension. COVID-19 patients with more severe infection had neurologic conditions such as acute cerebrovascular diseases, impaired consciousness, and musculoskeletal symptoms [24]. Furthermore, they observed that COVID-19 patients with severe infection had higher D-dimer levels compared to non-severe infection patients, suggesting the reason behind an increased risk for cardiovascular diseases [24]. Besides, patients with musculoskeletal symptoms were found to have elevated creatine kinase levels (400 U/L), and higher creatine kinase and lactate dehydrogenase levels than those without such symptoms [24]. Additionally, three patients had higher neutrophil counts, lower lymphocyte counts, higher C-reactive protein, and higher-D-dimer levels. The COVID-19 patients who already developed musculoskeletal symptoms also had multiorgan damage, including severe liver damage with increased lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels [24]. Hence, the infection-mediated immune response might have possibly caused abnormalities in the CNS. secondary to the upsurged interleukins. Patients with severe mental illness are bound to neglect the prevention of infection due to cognitive decline. The reduced physical activity due to the anxiety, fear of infection, and negative symptoms further leads to dysfunctional immunity [40]. However, patients free from COVID-19 infection are also psychologically impacted by the COVID-19 pandemic. Psychiatric morbidity is a paramount concern, as the virus may affect the CNS and provoke systemic inflammation [41]. A recent paper by Conti et al. (2020) reported that COVID-19 infection triggers the release of pro-inflammatory cytokines, including interleukin (I.L.)-1b and IL-6. SARS-COV2 is neurotropic and hence can invade nervous tissues and impede immune-functioning macrophages, microglia, or astrocytes in the CNS [42]. A neurotropic virus might activate microglial cells and induce a pro-inflammatory state [17]. The serum level of Interleukin-6, an essential member of the cytokine storm, is positively correlated with the severity of COVID-2019 symptoms [41]. Additionally, experiments have confirmed that primary glial cells cultured in vitro secrete a large number of inflammatory factors such as IL-6, IL-12, IL-15, and tumor necrosis factor-alpha (TNF-α) after being infected with CoV [32]. Furthermore, the hyperactivation of immune cells in the brain would eventually result in chronic inflammation and brain damage [28].

Bo Diao et al. reviewed the counts of total T cells, CD4+, CD8+ T-cell subsets, and serum cytokine concentrations retrospectively from 522 in-patients from two hospitals in Wuhan as well as 40 healthy controls [43]. Moreover, they further checked the expression of T-cell exhaustion markers programmed death-1 (PD-1), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) were measured by flow cytometry in the peripheral blood of 14 COVID-19 cases. Based on their investigation, the T-cell count was found to be significantly reduced in COVID-19 patients, and the surviving T-cells were

functionally exhausted [43]. Patients who were not at the ICU had a total T-cells, CD8+ T-cells, and CD4+ T-cells count lower than 800/μL, 300/μL, and 400/μL, respectively. This has mandated a continued aggressive intervention even in the immediate absence of more severe symptoms to prevent further deterioration in their condition [43]. There are also reports from the post-mortem pathology of COVID-19 patients who died in the U.S., showing the infiltration of CD-8+ T-cells within the alveoli [29].

Given the above, the cytokine storm created by an imbalance between CD-4+ and CD-8+ T-cells might be the plausible cause of acute respiratory distress syndrome in COVID-19 patients. Figure 2 depicts the viral and host factors that influence the pathogenesis of SARS-CoV-2. Physical and biopsychosocial and psychoneurooimmune effects impacted by the virus can be improved by a healthy lifestyle, exercise, a balanced diet, staying connected with family and loved ones using telecommunication or internet, and maintaining quality sleep. Hence, in a nutshell, it is highly imperative to build psychosocial resilience to enhance psychoneuroimmunity against the virus [40].

**Figure 2.** Putative mechanisms underlying neurobiological and psychological events of COVID-19 and their effect on mental health-related issues through psychoneuroimmunity. Virus–host interactions affect viral entry and replication—left panel: viral factor. SARS-CoV-2 is an enveloped positive single-stranded R.N.A. coronavirus. Two-thirds of viral R.N.A. is located in the first open reading frame that encodes 16 non-structure proteins. Host factors (right panel) can also influence susceptibility to infection and disease progression. COV2 enters the brain through olfaction, and since the virus is known to cross the blood–brain barrier, it can cause neurological symptoms like Guillain–Barré syndrome and mental health issues, including fear and anxiety for recovery. All these events are regulated by the cytokines and interleukins within the immune system.

So far, clinical observations have substantiated that patients with COVD-19 may portray a variety of neurological signs and symptoms. Milder symptoms include headache and nausea, while in more severe cases, fatal encephalitis may develop. Meanwhile, older patients and those with underlying conditions are at higher risk for developing neurological symptoms. Of note, anosmia and ageusia are now known to be common early symptoms which people need to be aware of. The long-term effects of COVID-19 are yet to be researched. Therefore, only more long-term research will answer whether these neurological deficits are reversible, recurring, or permanent.
