A Translational Perspective of Maternal Immune Activation by SARS-CoV-2 on the Potential Prenatal Origin of Neurodevelopmental Disorders: The Role of the Cholinergic Anti-inflammatory Pathway

Abstract

The emergent Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) could produce a maternal immune activation (MIA) via the inflammatory response during gestation that may impair fetal neurodevelopment and lead to postnatal and adulthood mental illness and behavioral dysfunctions. However, so far, limited evidence exists regarding long-term physiological, immunological, and neurodevelopmental modifications produced by the SARS-CoV-2 in the human maternal-fetal binomial and, particularly, in the offspring. Relevant findings derived from epidemiological and preclinical models show that a MIA is indeed linked to an increased risk of neurodevelopmental disorders in the offspring. We hypothesize that a gestational infection triggered by SARS-CoV-2 increases the risks leading to neurodevelopmental disorders of the newborn, which can affect childhood and the long-term quality of life. In particular, disruption of either the maternal or the fetal cholinergic anti-inflammatory pathway (CAP) could cause or exacerbate the severity of COVID-19 in the maternal-fetal binomial. From a translational perspective, in this paper, we discuss the possible manifestation of a MIA by SARS-CoV-2 and the subsequent neurodevelopmental disorders considering the role of the fetal-maternal cytokine cross-talk and the CAP. Specifically, we highlight the urgent need of preclinical studies as well as multicenter and international databanks of maternal-fetal psychophysiological data obtained pre-, during, and post-infection by SARS-CoV-2 from pregnant women and their offspring.

Keywords: COVID-19; SARS-CoV-2; cholinergic anti-inflammatory pathway; heart rate variability; human development; maternal immune activation; neurodevelopmental disorders; quality of life.

Figure 1

A gestational infection triggered by SARS-CoV-2 may produce a maternal immune activation (MIA) and cytokine storm syndrome (CSS). The activation of the maternal and/or fetal cholinergic anti-inflammatory pathway (CAP) via the efferent vagus nerve and transplacental interactions could downregulate such CSS. The analysis of maternal and fetal heart rate variability (mHRV and fHRV) might be considered for assessing maternal and fetal CAP activation. Also, a gestational infection by SARS-CoV-2 may produce fetal neuroinflammation and microglial activation, increasing the risks of several neurodevelopmental disorders in the offspring and even an altered long-term cognitive function in adulthood: (1) neuronal migration; (2) axonal and dendritic growth; (3) programmed cell death; (4) synaptogenesis; (5) myelination; and (6) process modeling/synaptic refinement. ASD, autism spectrum disorder; SCZ, schizophrenia; AD, anxiety disorders; MD, mood disorders; ICD, impulse-control disorders.