Study On The Mechanism Of Anti-SARS-CoV-2 Antibody Induced Psychosis-like Phenotype In Mice

Background:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is widespread among the world,which can cause not only respiratory symptoms but also neurological symptoms,including but not limited to headache,dizziness,Loss of taste and smell,muscle pain,disturbance of meaning,etc.Clinical studies have found that most of the antibodies produced by COVID-19 patients are non-neutralizing antibodies,and anti-SARS-CoV-2 antibodies can be detected in the brains of COVID-19 patients with central nervous system(CNS)diseases.The relationship between non-neutralizing antibodies and neurological symptoms in COVID-19 patients is unclear.Objectives:This study intends to conduct research on the non-neutralizing antibody anti-S1-111 IgG in the nervous system complications of COVID-19 patients,and explore:1)whether the S1-111(S protein fragment)could trigger corresponding antibody and exist stably;2)In animals model,whether the anti-S1-111 IgG can increase the release of inflammatory factors and activate glial cells;3)whether this process will affect the gene expression in the brain of the animal model;4)whether anti-S1-111 IgG can alter the behavioral phenotypes of mice.Methods:1)Selection of S protein epitopes:Based on the serum data of COVID-19 patients/convalescent,we selected the epitopes(S1-111)corresponding to non-neutralizing antibodies with high antibody titers and high response frequency in serum for research;2)Establishment of animals Model:S1-111 polypeptide was introduced to immunize ApoE-/-mice(model mice with open blood-brain barrier)to produce anti-S1-111 IgG in their circulatory system;3)Model detection:detect whether the anti-S1-111 IgG can affect the mouse CNS through behavioral tests,neuropathological evaluation,qPCR and ranscriptome sequencing.Results:1)The peptide fragment S1-111 can induce a certain level of anti-S1-111 antibody in the serum and brain homogenate of ApoE-/-mice;2)Anti-S1-111 IgG leads to the up-regulation of brain inflammation in ApoE-/-mice,the up-regulation of synaptic plasticity-related genes,and the increase of number and activation of microglia and astrocytes;3)Anti-S1-111 IgG caused sensorimotor gating defects,olfactory system disturbance and anxiety-like behavior in ApoE-/-mice.Conclusion:Non-neutralizing anti-S1-111 IgG can change the gene expression in the cerebral cortex and hippocampus of ApoE-/-mice after infiltrating the brain,cause the proliferation and activation of glial cells,and finally lead to the change of synaptic plasticity and psychopathic behavior in mice.