Immunometabolism perturbations in post-COVID-19 condition: interleukin-6 and monoamine oxidase interactions drive neuropsychiatric syndromes

Neuropsychiatric disorders including depression or anxiety are common in persons with post-COVID-19 condition (PCC). In a clinical cohort, interleukin (IL)-1beta, −2, −6, −8, −10, and TNF-alpha were significantly elevated in serum from PCC compared to control subjects while serum IL-6 levels were selectively increased among PCC subjects with depression. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of primary human neural cells showed viral replication in astrocytes, although IL-6 was released by abortively-infected microglia. In C57BL6/J mice intranasally infected with mouse-adapted SARS-CoV-2, viral RNA was detected in the lungs and multiple brain regions, which persisted in 33 % of infected animals up to 21 days post-infection (dpi), associated with increased brainstem IL-6 expression. As catecholamines are implicated in mood and anxiety, we analyzed monoamine oxidase (MAO) expression, revealing elevated transcript and protein levels for both MAO isoforms in infected human and mouse brain tissues, particularly in glial cells, which was correlated with increased MAO enzymatic activity. Neurobehavioral assessments showed depressive behaviors until 7dpi, transitioning to anxiety behaviors by 21dpi among virus-infected mice, which was attenuated by MAO inhibition. These findings highlight the immunometabolic mechanisms, involving cytokine-enzyme interactions that contribute to PCC-associated neuropsychiatric syndromes while also identifying potential diagnostic and therapeutic options.