Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected hundreds of millions of individuals worldwide, disrupting public health and the economy. Post-COVID (or Long-COVID), the collection of symptoms and pathophysiologies that occur in patients after an initial COVID infection encompasses a vast assortment of systems including cardiac, digestive, vascular, and others. Of particular interest has been the impact on mental health and the nervous system. Besides the prevalent symptom of anosmia (loss of smell) during the initial infection, the list of neurological symptoms post-infection is quite extensive; see Table 1.

This has raised the question of COVID’s mechanism of action for neurological impact and damage to the nervous system. Typically, COVID has been shown to selectively bind to the ACE2 (angiotensin-converting enzyme 2) receptors, especially those in the upper bronchial and nasal epithelia, wherein it gains entry into the aforementioned and several other cell types which express ACE2; namely in the intestines, kidneys, testis, gallbladder, and heart. However, the expression of ACE2 is virtually non-existent in the neural and glial tissue of the human cortex; yet neurological symptoms persist. A recent study from Andrews, et al., (2022) suggests that cortical neurons can be victims of dysregulation and damage as a secondary effect due to the primary infection of astrocytes with SARS-CoV-2.

Table 1 Neurological/neuropsychiatric symptoms associated with long-COVID/post-infection

SARS-CoV-2 Proposed Neural Tropism via Astrocyte Infection

The paper from Andrews, et al., (2022) suggests that mechanism for viral tropism (the ability of a virus to productively infect a particular cell, tissue, or host species) is due to COVID’s affinity for the receptors CD147 and DPP4 which are highly expressed in activated astrocytes (astrocyte reaction to infections or other stressful pathophysiology) in the CNS. Astrocytes are very important for their role in regulating neurotransmitter concentration and reuptake as well as neural metabolism, inflammation, and their role in the blood-brain-barrier. Andrews et al. showed that CD147 is necessary and DPP4 is sufficient to mediate infection in cortical astrocyte by means of both blocking and over expressing these receptors (Figure 1). The outcome of the experiments showed that overexpression of CD147 or DPP4 resulted in a significant increase in infected cells (SARS-CoV-2 N+ and dsRNA+ cells). Further, the blocking of DPP4 with Vildagliptin resulted in a 35% reduction in the number of SARS-CoV-2 N+ cells with a 60% reduction in dsRNA+ cells. Utilizing a lentiviral construct to knockdown the expression of CD147 also yielded a significant decrease in infected cells. Finally, they propose that the infection of the astrocytes impacts neurons, and thus psychological and behavioral outputs (Olabarria and Goldman, 2017).

Figure 1 SARS-CoV-2 infects astrocytes via CD147  and DPP4

References

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