Long-term effects of SARS-CoV-2 infection on human brain and memory

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have caused several waves of outbreaks. From the ancestral strain to Omicron variant, SARS-CoV-2 has evolved with the high transmissibility and increased immune escape against vaccines. Because of the multiple basic amino acids in the S1-S2 junction of spike protein, the widespread distribution of angiotensin-converting enzyme 2 (ACE2) receptor in human body and the high transmissibility, SARS-CoV-2 can infect multiple organs and has led to over 0.7 billion infectious cases. Studies showed that SARS-CoV-2 infection can cause more than 10% patients with the Long-COVID syndrome, including pathological changes in brains. This review mainly provides the molecular foundations for understanding the mechanism of SARS-CoV-2 invading human brain and the molecular basis of SARS-CoV-2 infection interfering with human brain and memory, which are associated with the immune dysfunction, syncytia-induced cell death, the persistence of SARS-CoV-2 infection, microclots and biopsychosocial aspects. We also discuss the strategies for reducing the Long-COVID syndrome. Further studies and analysis of shared researches will allow for further clarity regarding the long-term health consequences.

Fig. 1. The schematic map of SARS-CoV-2 infecting human brain and affecting human memory.

SARS-CoV-2 could directly infect the nasal cavity, lungs and eyes. High viral titers could be detected in the nasal cavity and lungs, which are likely to cause the direct viral invasion to brains through olfactory sensory neurons and the blood–brain barrier. The efficient viral replication in multiple organs can cause the exposure of these organs to high titers of SARS-CoV-2 and stimulate host immune responses and neuroinflammation to induce neurological symptoms. Persistent viral replication and syncytia formation can stimulate the production of cytokines and autoantibodies to affect the brain and memory with the long-term dysfunction. The eye infection with low viral replication is a potential route to affect the brain and memory. Color lines indicate the corresponding routes. Solid lines indicate the direct effects and dot lines indicate the routes of the potential effects.

Fig. 2. The model of SARS-CoV-2 infection causing syncytia and cell death.

Cells infected with SARS-CoV-2 could express spike protein on the cell surface, which can interact with ACE2 on the surface of infected or non-infected cells and then trigger the cell-cell fusion to form syncytia. The syncytia could induce apoptosis and cause inflammatory damages in different organs.