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.

Clinical characterization of dysautonomia in long COVID-19 patients

“…Recent but few experimental studies have shown the possible interest of HRV as physiological measurement parameter for COVID-19 patients 23,24 . However, this non-invasive approach to evaluate the activity of the ANS remains too little understood and requires further investigations.…”

Virus-Induced Maternal Immune Activation as an Environmental Factor in the Etiology of Autism and Schizophrenia

“…Exposure to infections during pregnancy is quite common; almost 50% of pregnant women get respiratory tract infections while close to 20% getting urinary tract infections; nonetheless this high prevalence of maternal infection results in neurodevelopmental abnormalities in only a small portion of the exposed offspring ( Milada et al, 2017 ; Weber-Stadlbauer, 2017 ; Brown and Meyer, 2018 ). This dichotomy might hold the key to certain protective that make certain pregnancies less susceptible to others, and mechanistically evidence has suggested impairment of cholinergic anti-inflammatory pathways in some pregnant mothers to be linked to a heightened inflammatory response ( Reyes-Lagos et al, 2021 ).…”

“…Based on its clinical manifestation and past “similar” infections, theories have been proposed that suggest potential effects on the offspring ( Granja et al, 2021 ). Following infection with SARS-CoV-2, there is an uncontrolled release of inflammatory cytokines and chemokines that have been involved in brain development [e.g., interleukins (IL-1β,−2,−4,−6,−8,−10), tumor necrosis factor alpha, interferons (IFN-α, IFN-γ)] ( Reyes-Lagos et al, 2021 ). Amid the exacerbated long-term inflammatory effects observed in COVID-19 patients and the lessons learned from of viral-mediated MIA effects on the progeny’s brain, it is crucial to consider the neurological consequences of maternal SARS-CoV-2 infection on the offspring.…”

“…Case studies have associated viral infection from varicella, cytomegalovirus, mumps and herpes simplex virus with increased likelihood of autism ( Patterson, 2011 ; Estes and McAllister, 2015 ). Understanding of the effects of virus-mediated MIA have also led researchers to consider the potential effects of maternal SARS-CoV-2 infection on fetal development ( Reyes-Lagos et al, 2021 ).…”

Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

“…Furthermore, although gestational timing has been shown to have differential effects in adolescent and adult offspring (11,22), it is unclear how it affects neurodevelopment in its early phase. A better understanding of the neurodevelopmental sequelae of MIA-exposure on very early brain development is of importance in the context of the current COVID-19 pandemic, as mothers who contracted the virus during pregnancy were more likely to have obstetric complications leading to poor fetal health outcomes such as low birth weight, intrauterine growth restriction, and preterm birth (23,24).…”