Editorial: The Pathogenesis of Long-Term Neuropsychiatric COVID-19 and the Role of Microglia, Mitochondria, and Persistent Neuroinflammation: A Hypothesis

Background

Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a pandemic disease for more than a year. Worldwide, medical practitioners have become acutely aware of the clinical presentation of long-term comorbidities following recovery from COVID-19. Long-term COVID-19, or ‘long COVID,’ can include compromise to integrative neurological functions that regulate key cognitive and affective processes in the CNS, resulting in neuropsychiatric disease [1]. Based on recent empirical data, SARS-CoV-2 infection may functionally divert the bioenergetics capacity of infected cells to support viral replication [1–3]. It is possible that mitochondrial targeting by the virus may be the substrate for the emergence of cognitive impairment or ‘brain fog’ [3].

Constitutively high levels of mitochondrial oxygen consumption, oxidative phosphorylation, and ATP production are required for normal neuronal function within the CNS. Recent research has shown that operational hijacking of mitochondria by intracellular SARS-CoV-2 RNA and protein components also occurs during infection with the Ebola, Zika, and influenza A viruses [4]. Viral targeting of mitochondria may be an evolutionarily conserved adaptive process for viruses and bacteria as mitochondria are organelles with a prokaryotic origin [5,6]. Therefore, this short review aims to discuss the hypothesis that the pathogenesis of long-term neuropsychiatric COVID-19 involves microglia, mitochondria, and persistent neuroinflammation.

A Hypothesis for the Pathogenesis of Long-term Neuropsychiatric COVID-19

Viral targeting of neural tissues is a complex process, and SARS-CoV-2 may also initiate dysautonomia and alter temperature, blood pressure, cardiac function and rhythm, and gastrointestinal motility [7]. The effects of SARS-CoV-2 infection may manifest as altered stress responses. In 2020, Goldstein proposed that chronic activation of the extended autonomic system (EAS), which includes the neuroendocrine and neuroimmune systems, is associated with an increased risk of developing ‘long COVID’ [8]. Long-term, viral-induced disease pathogenesis is associated with conditions that include myalgic encephalomyelitis, chronic fatigue syndrome, and postural orthostatic tachycardia syndrome (POTS) [3,9–11]. Acute cognitive impairment, similar to ‘brain fog,’ may also occur in Lyme disease and infection with influenza, West Nile virus, and Ebola virus [10,12–16]. These findings raise the possibility that the neuropsychiatric sequelae of some infectious diseases may have similar pathogenesis. Accordingly, a chronic state of pro-inflammation within CNS structures may be perpetuated by chronic activation of populations of circulating T and B lymphocytes by cross-reacting viral epitopes ultimately targeting brain microglia. We therefore propose that integrative studies employing bioinformatics analyses to identify small peptides with homologous amino acid sequences across classes of human pathogenic viruses linked to state of the art flow cytometry analyses of activated T and B lymphocytes will provide validating data sets in support of these contentions. However, it is still unclear whether the infectious organism persists in the affected tissues or whether the infection alters the tissue to evade the immune response. A reasonable assumption is that the persistent long-term pathological consequences of SARS-CoV-2 infection involving the CNS arise from an immune response resulting in neuroinflammation with dysfunction of mitochondria and microglia (Figure 1) [17–19].

In 2020, Boziki et al. reviewed the immunopathology of COVID-19 infection of the CNS [20]. SARS-CoV-2 infection exacerbates demyelinating CNS disorders, including multiple sclerosis [20]. Possibly, that this long-term effect of SARS-CoV-2 has gone unrecognized [20]. It is also possible that cognitive dysfunction may be a common but unrecognized long-term effect of several viral infections [2,13,19]. Given the common presenting clinical features of some viral infections, we hypothesize that dysfunctional chronic inflammatory conditions may result in long-term comorbid neuropsychiatric syndromes and other syndromes (Figure 2).

Recent reports by medical journalists indicate that the second dose of the vaccine to SARS-CoV-2 may reduce the incidence ‘long COVID’ syndromes, including ‘brain fog’ [21]. This association has not been formally investigated, possibly because SARS-CoV-2 vaccine programs have only recently been developed and delivered. Hopefully, continuing studies on the long-term sequelae of COVID-19 may increase our understanding of viral pathogenesis and neuropsychiatric disease.

Conclusions

In this editorial, we have presented the hypothesis that neuropsychiatric disorders such as brain fog and chronic fatigue syndrome may support that viral and bacterial infections have damaging effects on normal immune processes that persist due to our persisting lack of understanding of the pathogenesis of long-term neuroinflammation. Therefore, because ‘long COVID’ is now recognized to affect up to one-third of people following SARS-CoV-2 infection, increased studies and resources should be directed to understanding the pathogenesis of these new post-viral syndromes, including long-term neuropsychiatric COVID-19. Further research on microglia, mitochondria, and neuroinflammation may answer the questions raised by the hypothesis discussed in this editorial.