Connecting dots of long COVID-19 pathogenesis: a vagus nerve- hypothalamic-pituitary- adrenal-mitochondrial axis dysfunction

Abstract

The pathogenesis of long COVID (LC) still presents many areas of uncertainty. This leads to difficulties in finding an effective specific therapy. We hypothesize that the key to LC pathogenesis lies in the presence of chronic functional damage to the main anti-inflammatory mechanisms of our body: the three reflexes mediated by the vagus nerve, the hypothalamic-pituitary-adrenal (HPA) hormonal axis, and the mitochondrial redox status. We will illustrate that this neuro-endocrine-metabolic axis is closely interconnected and how the SARS-CoV-2 can damage it at all stages through direct, immune-inflammatory, epigenetic damage mechanisms, as well as through the reactivation of neurotropic viruses. According to our theory, the direct mitochondrial damage carried out by the virus, which replicates within these organelles, and the cellular oxidative imbalance, cannot be countered in patients who develop LC. This is because their anti-inflammatory mechanisms are inconsistent due to reduced vagal tone and direct damage to the endocrine glands of the HPA axis. We will illustrate how acetylcholine (ACh) and cortisol, with its cytoplasmatic and cellular receptors respectively, are fundamental players in the LC process. Both Ach and cortisol play multifaceted and synergistic roles in reducing inflammation. They achieve this by modulating the activity of innate and cell-mediated immunity, attenuating endothelial and platelet activation, and modulating mitochondrial function, which is crucial for cellular energy production and anti-inflammatory mechanisms. In our opinion, it is essential to study the sensitivity of the glucocorticoids receptor in people who develop LC and whether SARS-CoV-2 can cause long-term epigenetic variations in its expression and function.

Keywords: adrenergic anti-inflammatory reflex; cholinergic anti-inflammatory reflex; cortisol; glucocorticoids receptor; hypothalamic-pituitary-adrenal axis reflex; long COVID; mitochondrial dysfunction; vagus nerve dysfunction.

Figure 1

Anti-inflammatory pathways of the VN disrupted by SARS-CoV-2. 1) The HPA axis reflex (black) depicts the suppression of the hypothalamic-pituitary-adrenal axis reflex, leading to a reduction in cortisol production by SARS-CoV-2. This reduction in cortisol impairs the regulation of both innate and adaptive immune responses. Nerve fibers from the NTS stimulate the release of CRH by neurons in the PVH, a hypothalamic nucleus within the central autonomic network. The CAN, comprised of the thalamus, amygdala, hypothalamus, and brainstem nuclei, integrates emotional, sensory, and cognitive stimuli to produce autonomic and endocrine responses. 2) The cholinergic anti-inflammatory reflex (green) illustrates the VN projection to the gastrointestinal tract. This reflex is initiated by afferent fibers from the NTS, which relay peripheral visceral sensory information to the DMNV. ACh, released from DMNV efferent fibers, finally inhibits cytokine release from intestinal macrophages, thereby mitigating local inflammation. Moreover ACh suppress platelets activation. 3) The vago-sympathetic pathway (orange) is activated by vagal efferent stimuli originating from the NTS. This pathway regulates sympathetic outflow, thought the CAN. It targets preganglionic sympathetic neurons in the IML of the spinal cord and chromaffin cells. This complex network modulates peripheral blood tone, vasoconstriction, and immune responses. Enterochromaffin cells are involved in the gut metabolism of 5-HT. α7-nAChR, αlpha7-nicotinicACh-Receptor; ACh, acetylcholine; ACTH, adrenocorticotropic hormone; CAN, central autonomic network; DMNV, dorsal motor nucleus of vagus nerve; EPI, epinephrine; HPA, hypothalamic–pituitary–adrenal; IML, intermediolateral nucleus; NE, norepinephrine; NTS, nucleus tractus solitarius; PVH, parvo-cellular nucleus; VN, vagus nerve; 5-HT, serotonin.