Psycho-Neuroendocrine-Immune Interactions in COVID-19: Potential Impacts on Mental Health

Abstract

Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The impacts of the disease may be beyond the respiratory system, also affecting mental health. Several factors may be involved in the association between COVID-19 and psychiatric outcomes, such as fear inherent in the pandemic, adverse effects of treatments, as well as financial stress, and social isolation. Herein we discuss the growing evidence suggesting that the relationship between SARS-CoV-2 and host may also trigger changes in brain and behavior. Based on the similarity of SARS-CoV-2 with other coronaviruses, it is conceivable that changes in endocrine and immune response in the periphery or in the central nervous system may be involved in the association between SARS-CoV-2 infection and impaired mental health. This is likely to be further enhanced, since millions of people worldwide are isolated in quarantine to minimize the transmission of SARS-CoV-2 and social isolation can also lead to neuroendocrine-immune changes. Accordingly, we highlight here the hypothesis that neuroendocrine-immune interactions may be involved in negative impacts of SARS-CoV-2 infection and social isolation on psychiatric issues.

Keywords: COVID-19; HPA axis; SARS-CoV-2; central nervous system; cytokine; mental health; pandemic; social isolation.

Figure 1

Hypothetical mechanisms by which SARS-CoV-2 may lead to changes in the activity of the hypothalamus-pituitary-adrenal (HPA). (A) During a viral infection (e.g., SARS-CoV-2), pro-inflammatory cytokines are released by immune cells present in the periphery (e.g., macrophages, T and NK cells) and/or in the brain (microglia). These cytokines can act at three levels of the HPA axis: increasing (i) the secretion of the corticotrophin-releasing hormone (CRH) in the hypothalamus, (ii) the secretion of adrenocorticotropic hormone (ACTH) in the pituitary, and (iii) release of glucocorticoids (e.g., cortisol) through the adrenal cortex. By any of these actions, the result is an increased release of glucocorticoids, which bind to their receptors present in immune cells, suppressing the synthesis and release of pro-inflammatory cytokines. Therefore, it is possible that increased pro-inflammatory cytokine levels in COVID-19 may lead to hyperactivity of the HPA axis. However, due to a dysfunction in the negative feedback between the HPA axis and the immune system, this neuroendocrine axis is not able to reduce the production of inflammatory mediators, a possible explanation for why SARS-CoV-2 infection leads to cytokine storm. (B) Hypothalamic ACE2 overexpression decreases the activity of the HPA axis in mice, reducing the CRH content in the hypothalamus and corticosterone plasma levels. Since SARS-CoV infection is able to reduce the expression of ACE2 in other tissues, one hypothesis (based on molecular similarities between SARS-CoV-2 and SARS-CoV) is that SARS-CoV- 2 can induce a decrease in hypothalamic ACE2 levels, thus contributing to HPA hyperactivity. (C) Although pro-inflammatory cytokines classically increase the activity of the HPA axis, some cytokines (e.g., TGF-β) can decrease the activity of this neuroendocrine axis under specific conditions that remain unclear. This is another mechanism by which the SARS-CoV-2 infection, inducing an exacerbated inflammatory response, may lead to changes in the HPA axis, in this case, hypoactivity. Continuous arrows: stimulation; dashed arrows: inhibition.

Figure 2

Possible neuroendocrine-immune interactions involved in impacts of SARS-CoV-2 infection and social isolation on mental health. Based on the similarity of SARS-CoV-2 and SARS-CoV, hematogenic or neuronal retrograde dissemination routes (via olfactory nerve) may be involved in the entry of the SARS-CoV-2 into the central nervous system (CNS). In the CNS (left) the virus can lead to increase in cytokines levels (e.g., IL-2, IL-6, TNF-α, IL-1β, INF-γ, and IL-10) due to its local or peripheral (right) actions. Increased cytokine levels are associated to neuronal death, synaptic plasticity impairments, dysfunction in the neurotransmitter metabolism and in the hypothalamic-pituitary-adrenocortical (HPA) axis. Likewise, social isolation can also lead to these neuroendocrine-immune disturbances, for instance: increase in cytokine levels, changes in neurotransmitter systems, HPA axis hyperactivity and disturbances in neuroplasticity-related signaling pathways. Through these common mechanisms, both SARS-CoV-2 infection and social isolation can lead to mental health impairments [e.g., impaired memory, depression, psychoses, anxiety and posttraumatic stress disorder symptoms (PTSD)]. IL, Interleukin; TNF-α, tumor necrosis factor alpha; INF-γ, interferon gamma.