Investigação de alterações na expressão de genes inflamatórios e retrovírus endógenos na placenta de gestantes com SARS-CoV-2: comparação com a expressão sanguínea em pacientes portadores de Esquizofrenia

Abstract

Schizophrenia is a mental disorder with a neurodevelopmental nature. The high heritability of schizophrenia indicates an important role of genetic variations in its etiology. Several placenta-specific genes have been associated with genomic risk for the long-term development of schizophrenia. Maternal immune activation by viral infections can trigger a hyperinflammatory state in the placenta and impair fetal development. SARS-CoV-2, the causative agent of COVID-19, can induce the release of pro-inflammatory cytokines into the maternal circulation and triggering the reactivation of human endogenous retroviruses (HERVs). These changes, when affecting the maternal-fetal interface, may alter the expression of risk genes associated with schizophrenia development. In this study, we investigated the expression of inflammatory genes and endogenous retroviruses in the placenta of pregnant women infected with SARS-CoV-2 and compared this expression to that observed in individuals with schizophrenia. For this purpose, pregnant women in the third trimester were recruited from the emergency unit of the Assis Chateaubriand Maternity School Hospital, and individuals diagnosed with schizophrenia were recruited from the Professor José Pinto Mental Health Hospital (HSM). The pregnant women were divided into two groups: COVID-19 negative (n=9) and COVID-19 positive (n=9). Blood samples were collected from the pregnant women to measure cytokine and chemokine levels. After delivery, placentas were collected and dissected into maternal (MF) and fetal (FF) sides. Gene expression of GPER1, RelA, HERV-W1, and HERV-W-env was analyzed in both placental compartments. The patients recruited from HSM were divided into two groups: control (n=9) and schizophrenia (n=12). Blood samples were collected to evaluate inflammatory mediators (IL-6, IL-1β, IL-4, and IFN-γ), and the expression of the same genes was quantified in the buffy coat. The results showed upregulation of inflammatory mediators in maternal blood. Gene expression analysis revealed that SARS-CoV-2 infection increased the expression of GPER1, HERV-W1, HERV-W-env, and RelA in the maternal side of the placenta compared to the uninfected group. Notably, HERV-W-env expression in the MF showed a negative correlation with GPER1 expression and a positive correlation with neonatal weight. HERV-W-env expression in the FF correlated negatively with neonatal length. No correlations were found between gene expression in the MF and the same genes in the FF. In individuals with schizophrenia, there was an increase in IL-6 and IL-1β levels. These individuals also showed lower GPER1 mRNA levels and higher expression of HERV-W1, HERV-W-env, and RelA compared to controls. GPER1 expression in the schizophrenia group was positively correlated with age, and IL-1β levels were positively correlated with age of onset. Lastly, HERV-W1 expression in the schizophrenia group was positively correlated with HERV-W-env expression in the MF of COVID-19 placentas. HERV-W-env expression in schizophrenia was also positively correlated with HERV-W1 mRNA levels in the FF of COVID-19 placentas. No correlations were found between gene expression and cytokine levels in the blood of individuals with schizophrenia. In conclusion, the convergence of our findings suggests that placental alterations during critical periods of fetal development may represent an underlying mechanism in the programming of neuropsychiatric vulnerabilities. Our data not only identify potential risk genes but also highlight the placenta as a key organ for understanding the interface between gestational infections and neurodevelopmental disorders, opening new perspectives for preventive and early intervention strategies in schizophrenia.