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LETTER TO THE EDITOR
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 58-60

Inflammatory cytokines induced by severe acute respiratory syndrome coronavirus 2 infection during pregnancy may alter fetal brain development predisposing the offspring to neurodevelopmental disorders


Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy

Date of Submission05-Nov-2020
Date of Acceptance08-Dec-2020
Date of Web Publication20-May-2021

Correspondence Address:
Dr. Chidiebere Emmanuel Okechukwu
Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_45_20

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How to cite this article:
Okechukwu CE. Inflammatory cytokines induced by severe acute respiratory syndrome coronavirus 2 infection during pregnancy may alter fetal brain development predisposing the offspring to neurodevelopmental disorders. Niger J Exp Clin Biosci 2021;9:58-60

How to cite this URL:
Okechukwu CE. Inflammatory cytokines induced by severe acute respiratory syndrome coronavirus 2 infection during pregnancy may alter fetal brain development predisposing the offspring to neurodevelopmental disorders. Niger J Exp Clin Biosci [serial online] 2021 [cited 2021 Oct 24];9:58-60. Available from: https://www.njecbonline.org/text.asp?2021/9/1/58/316532



Dear Editor,

Abnormal expression of interferon-gamma (IFN-γ), IFN-β, tumor necrosis factor-alpha, interleukin 6 (IL)-6, IL-17, and IL-1β disrupts fetal brain development; moreover, IL-6 and IL-17 induce aberrant brain development and behavior in animal models of maternal immune activation (MIA) [Figure 1].[1] Overactive IFN signaling is a possible cause of aberrant brain development during fetal development because of maternal infections.[1] Mental illnesses such as schizophrenia have been associated with maternal viral respiratory infection in early pregnancy because the upregulation of pro-inflammatory cytokines plays a crucial role in the alteration of fetal brain development [Figure 2].[2] The stimulation of maternal immune system by an infection during pregnancy induces the release of inflammatory cytokines, but the mechanisms in which the cytokines infiltrate fetal circulation and alter fetal brain development remain uncertain.[3] Upregulation of inflammatory cytokine activities in pregnant women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), may increase the risk for neurodevelopmental disorders in the newborn.[4] COVID-19 infection during early pregnancy is projected by the United States of America Centers for Disease Control to alter fetal development, likewise other respiratory coronaviruses via the adverse effects of maternal inflammatory response on the fetus and placenta.[5] Respiratory viral infections during pregnancy increase the risk of attention deficit disorder, autism spectrum disorder, and schizophrenia in neonates; furthermore, higher maternal C-reactive protein, which is an acute-phase protein that rises following IL-6 secretion by macrophages and T-cells, at the beginning of the second trimester, is associated with increased risk of schizophrenia in the offspring.[6] Variations in hormonal levels and immune function caused by pregnancy may increase pregnant women's vulnerability to infections; however, pregnant women have high mortality rates and complications associated with viral infections compared to the overall population.[7] Viruses can enter the decidua and placenta by ascending from the lower reproductive tract or via hematogenous transmission; viral tropism for the decidua and placenta is then reliant on viral entry receptor expression in these tissues as well as on the maternal immune response to the virus.[8] IFN-γ overexpression during fetal development can interrupt developmental pathways and differentiation in neurons, mouse models show a direct role for IFN-γ in modifying brain development, and genetic overexpression of IFN-γ in astrocytes leads to unusual cerebellar development and ataxia in mice.[9] Moreover, animal models indicate that a systemic maternal immune response is enough to induce neural tube defects, but the exact mechanisms and the contributions of cytokines, oxidative damage, and nutrient imbalances in abnormal fetal neurodevelopment are still uncertain.[10] MIA during pregnancy is associated with an increased risk of psychiatric diseases, including schizophrenia and autism spectrum disorder.[11]
Figure 1: (a) Exposure of embryos to IFN-γ in culture is lethal, and it increased IFN-γ at the time of implantation. Mouse models implicate that IFN-γ response after malaria and toxoplasma infection mediates some of the placental defects and that IFN-γ overexpression leads to abnormal brain development in mouse models. (b) Type I IFNs (including IFNα and IFNβ) contributes to aberrant placental development after ZIK virus infection, as described in mouse models. (c) Exposure of embryos to TNF-α can induce an inhibition in development. TNF-α is a mediator of fetal demise in mouse models of immune stimulation (CpG, LPS, and Poly(I:C). TNF-α injection in mice can cause neural tube defects. Intraamniotic infusion of TNF-α is sufficient to induce preterm birth in non-human primate models. (d) IL-6 induces aberration in brain development and behavior in mouse models of maternal immune activation. (e) IL17 induces abnormal brain development and behavior in mouse models of maternal immune activation. (f) IL-1 may induce preterm birth, as amniotic IL-1β administration is sufficient to induce preterm labor in non-human primates. Mouse models reveal that IL-1 may mediate defects associated with peripartum intrauterine inflammation including abnormal lung development associated with bronchopulmonary dysplasia and brain injury

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Figure 2: Role of prenatal viral infection in the developmental programming of schizophrenia[2]

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The poly (I:C)-induced autism-like phenotype plays a role in particular defects in the dysgranular region of the somatosensory cortex and is facilitated by IL-17; IL-17 produced by maternal T-helper-17 (Th17) cells apparently penetrates the placenta to activate IL-17R in the fetal neurons, producing cortical and behavioral abnormalities.[12] Maternal gut microbiota, such as segmented filamentous bacteria, encourage the growth of Th17 cells and predispose the fetus to neurodevelopmental disorders following poly (I:C) challenge in mice.[12] Human subjects reveal an association between maternal IL-6 concentrations during pregnancy with offspring brain connectivity and executive memory at 2 years of age; this suggests that even a lesser inflammation during pregnancy could affect brain connectivity even without apparent disease; apart from the direct action of cytokines on fetal brain development, MIA can control fetal neurodevelopment by altering placental tryptophan metabolism and increased serotonin formation; therefore, in MIA, inflammatory mediators released by the mother may have either a direct or an indirect consequence on fetal brain development.[12] Prenatal inflammation is a risk factor for neurodevelopment disorders such as cerebral palsy and autism; inflammatory cytokines can distress the function of glia in the developing brain, causing the modifications of these cells; moreover, raised cytokines IL-6 and IL-1β in the amniotic fluid and placental inflammation are prognosticators of brain injury in premature infants; however, animal models have aided in identifying the connections, and some of the inflammatory pathways, leading to abnormal brain development, however, blocking of IL-1 signaling using an IL-1 receptor antagonist, eradicate perinatal brain injury and abnormal dendrite formation.[13],[14] IL-1 might promote an adaptive immune response; moreover, reduction of maternal CD8+ T-cells overturns the cortical density and behavioral defects associated with inflammation-induced preterm delivery; gamma delta T-cells (γδ T-cells) cells could play a role in neuron injury because depletion of γδ T-cells in mouse models was enough to decrease brain injury; hence, the brain is vulnerable to neurodevelopmental interruption by amplified expression of type I immune cytokines, including type I and type II IFNs, IL-17, and IL-1β.[14]

In conclusion, increase in the activities of inflammatory cytokines, most especially IL-6, IL-17, and IFN-γ, in pregnant women with SARS-CoV-2 infection may disrupt fetal brain development, hence increasing the risk of neurodevelopmental disorders in their offspring; therefore, there is need for close monitoring of pregnant women who tested positive for SARS-CoV-2, during this period of COVID-19 pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Yockey LJ, Iwasaki A. Interferons and proinflammatory cytokines in pregnancy and fetal development. Immunity 2018;49:397-412.  Back to cited text no. 1
    
2.
Okechukwu CE. Prenatal exposure and fetal programming of schizophrenia. Niger J Exp Clin Biosci 2019;7:41-9.  Back to cited text no. 2
  [Full text]  
3.
Zheng R, Qin X, Li Y, Yu X, Wang J, Tan M, et al. Imbalanced anti-H1N1 immunoglobulin subclasses and dysregulated cytokines in hospitalized pregnant women with 2009 H1N1 influenza and pneumonia in Shenyang, China. Hum Immunol 2012;73:906-11.  Back to cited text no. 3
    
4.
Martins-Filho PR, Tanajura DM, Santos HP Jr. Santos VS. COVID-19 during pregnancy: Potential risk for neurodevelopmental disorders in neonates? Eur J Obstet Gynecol Reprod Biol 2020;250:255-6.  Back to cited text no. 4
    
5.
Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19) and Pregnancy; 2020. Available from: https://www.cdc.gov/coronavirus/2019-ncov/specific-groups/pregnancy-faq.html. [Last accessed on 2021 Feb 06].  Back to cited text no. 5
    
6.
Freedman R, Hunter SK, Law AJ, D'Alessandro A, Noonan K, Wyrwa A, et al. Maternal choline and respiratory coronavirus effects on fetal brain development. J Psychiatr Res 2020;128:1-4.  Back to cited text no. 6
    
7.
Racicot K, Mor G. Risks associated with viral infections during pregnancy. J Clin Invest 2017;127:1591-9.  Back to cited text no. 7
    
8.
Silasi M, Cardenas I, Kwon JY, Racicot K, Aldo P, Mor G, et al. Viral infections during pregnancy. Am J Reprod Immunol 2015;73:199-213.  Back to cited text no. 8
    
9.
Wang J, Lin W, Popko B, Campbell IL. Inducible production of interferon-gamma in the developing brain causes cerebellar dysplasia with activation of the sonic hedgehog pathway. Mol Cell Neurosci 2004;27:489-96.  Back to cited text no. 9
    
10.
Shin Yim Y, Park A, Berrios J, Lafourcade M, Pascual LM, Soares N, et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 2017;549:482-7.  Back to cited text no. 10
    
11.
Brown AS, Meyer U. Maternal immune activation and neuropsychiatric illness: A Translational research perspective. Am J Psychiatry 2018;175:1073-83.  Back to cited text no. 11
    
12.
Shin Yim Y, Park A, Berrios J, Lafourcade M, Pascual LM, Soares N, et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 2017;549:482-7.  Back to cited text no. 12
    
13.
Leitner K, Al Shammary M, McLane M, Johnston MV, Elovitz MA, Burd I, et al. IL-1 receptor blockade prevents fetal cortical brain injury but not preterm birth in a mouse model of inflammation-induced preterm birth and perinatal brain injury. Am J Reprod Immunol 2014;71:418-26.  Back to cited text no. 13
    
14.
Albertsson AM, Zhang X, Vontell R, Bi D, Bronson RT, Supramaniam V, et al. γδ T cells contribute to injury in the developing brain. Am J Pathol 2018;188:757-67.  Back to cited text no. 14
    


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