scholarly journals Tsc2Haploinsufficiency Has Limited Effects on Fetal Brain Cytokine Levels during Gestational Immune Activation

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Dan Ehninger
Keyword(s):  
Immune Activation ◽  
Viral Infections ◽  
Genetic Disorder ◽  
Fetal Brain ◽  
Mtor Signaling ◽  
Interactive Effects ◽  
Poly I:C ◽  
Cellular Processes ◽  
Syndromic Autism ◽  
Cytokine Levels

Dysregulated TSC/mTOR signaling may play a pathogenetic role in forms of syndromic autism, such as autism associated with tuberous sclerosis, a genetic disorder caused by heterozygousTSC1orTSC2mutations. Environmental risk factors, such as gestational viral infections, may, in some cases, also contribute to the pathogenesis of autism and related neuropsychiatric disorders. We have recently found that a heterozygousTsc2mutation and the poly I:C model of maternal immune activation (MIA) interactively perturb fetal development and adult social behavior in mice, suggesting that these factors converge on shared pathways. TSC/mTOR signaling plays an important role in the modulation of immune responses, raising the possibility that the damage caused by MIA was greater inTsc2+/−than in wildtype fetuses because of an exacerbated immune response in the mutants. Here, cytokine antibody arrays were employed to measure relative cytokine abundances in the fetal brain and the placenta during MIA. Cytokines were induced by gestational poly I:C but there was no obvious modulatory effect ofTsc2haploinsufficiency. The data indicate that cytokine exposure during MIA is comparable inTsc2haploinsufficient and wildtype control fetuses, suggesting that downstream molecular and cellular processes may account for the interactive effects ofTsc2haploinsufficiency and MIA.

scholarly journals Mycobacterium tuberculosis-Induced Maternal Immune Activation Promotes Autism-Like Phenotype in Infected Mice Offspring

2021 ◽  
Vol 18 (9) ◽  
pp. 4513
Author(s):  
Wadzanai Manjeese ◽  
Nontobeko E. Mvubu ◽  
Adrie J. C. Steyn ◽  
Thabisile Mpofana
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Activation ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Necrosis Factor Alpha ◽  
Altered Expression ◽  
Maternal Immune Activation ◽  
Persistent Inflammation ◽  
Cytokine Levels ◽  
Fetal Brain Development

The maternal system’s exposure to pathogens during pregnancy influences fetal brain development causing a persistent inflammation characterized by elevated pro-inflammatory cytokine levels in offspring. Mycobacterium tuberculosis (Mtb) is a global pathogen that causes tuberculosis, a pandemic responsible for health and economic burdens. Although it is known that maternal infections increase the risk of autism spectrum disorder (ASD), it is not known whether Mtb infection is sufficient to induce ASD associated behaviors, immune dysregulation and altered expression of synaptic regulatory genes. The current study infected pregnant Balb/c mice with Mtb H37Rv and valproic acid (VPA) individually and in combination. Plasma cytokine profiles were measured in offspring using the Bio-plex Th17 pro mouse cytokine panel. Mtb infection increased plasma interleukin (IL)-6 and IL-17A, while tumor necrosis factor alpha (TNF-α), interferon (IFN)-γ and IL-1β were reduced when compared with saline. Mtb-induced maternal immune activation (MIA) offspring displayed increased grooming behavior. The study also revealed dysregulation in gene expression of synaptic molecules in the cerebellum. MIA rescued the VPA-induced effects on self-grooming and social interaction behaviors. Our finding therefore highlights a potential role of Mtb as a MIA agent that can potentially contribute to ASD.

scholarly journals The poly(I:C)-induced maternal immune activation model; a systematic review and meta-analysis of cytokine levels in the offspring

2021 ◽  
Vol 11 ◽  
pp. 100192
Author(s):  
Bart C. Hameete ◽  
José M.S. Fernández-Calleja ◽  
Martje W.G.D.M. de Groot ◽  
Titia Rixt Oppewal ◽  
Machteld M. Tiemessen ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Activation ◽  
Meta Analysis ◽  
Poly I:C ◽  
Activation Model ◽  
Maternal Immune Activation ◽  
Cytokine Levels

scholarly journals Maternal immune activation induces sustained changes in fetal microglia motility

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kana Ozaki ◽  
Daisuke Kato ◽  
Ako Ikegami ◽  
Akari Hashimoto ◽  
Shouta Sugio ◽  
...  
Keyword(s):  
Immune Activation ◽  
Immune Status ◽  
Developmental Stages ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Behavioral Deficits ◽  
Maternal Immune Activation ◽  
Cytokine Levels ◽  
Spectrum Disorders ◽  
Increased Susceptibility

AbstractMaternal infection or inflammation causes abnormalities in brain development associated with subsequent cognitive impairment and in an increased susceptibility to schizophrenia and autism spectrum disorders. Maternal immune activation (MIA) and increases in serum cytokine levels mediates this association via effects on the fetal brain, and microglia can respond to maternal immune status, but consensus on how microglia may respond is lacking and no-one has yet examined if microglial process motility is impaired. In this study we investigated how MIA induced at two different gestational ages affected microglial properties at different developmental stages. Immune activation in mid-pregnancy increased IL-6 expression in embryonic microglia, but failed to cause any marked changes in morphology either at E18 or postnatally. In contrast MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits. Our research has identified an important microglial property that is altered by MIA and which may contribute to the underlying pathophysiological mechanisms linking maternal immune status to subsequent risks for cognitive disease.

scholarly journals Lessons From Zika and Other Virus Induced Skull Deformity

FACE ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. 44-50
Author(s):  
Mohamad Masoumy ◽  
Emily P. Masoumy ◽  
Babak Baban ◽  
Jack C. Yu
Keyword(s):  
Brain Development ◽  
Immune Activation ◽  
Viral Infections ◽  
Fetal Brain ◽  
Growth Dynamics ◽  
Cell Loss ◽  
Maternal Immune Activation ◽  
Skull Deformity ◽  
Critical Phases ◽  
The Impact

Objective: Viral infections during pregnancy can cause disturbance in normal craniofacial morphogenesis. While some pathogens such as cytomegalovirus and herpes simplex are familiar to us, others remain obscure. This review examines the arbovirus-induced cranial deformities and combines biomechanics with growth dynamics to gain a deeper appreciation of this complex morphogenetic process. Materials and Methods: Using Wolfram Alpha, we analyzed the impact of cell population changes. The growth dynamics of the brain, and thus the size of the calvarium, followed 2 potential logistic curves: compensated and uncompensated. To understand the potential mechanism of cell loss, we performed literature review on maternal immune activation and viral tropism for neurons and glial cells. Results: With arboviral infections such as Zika, uncompensated loss of cells during the critical phases of fetal brain development reduces the intracranial mass and therefore decreases the tensile stress across the cranial sutures. The deflationary effect produces microcephaly by subduction and reduced osteogenesis seen clinically in these infants. Conclusion: Many viral infections cause intense maternal immune activation, some have neurotropism and can result in cell loss within the developing cranium. Unable to overcome this loss, the cranium assumes a new, abnormal shape and volume. Secondary calvarial deformities is due to, and should not cause, changes in brain development.

scholarly journals The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

2021 ◽  
Vol 11 (3) ◽  
pp. 344
Author(s):  
Kinga Gzielo ◽  
Agnieszka Potasiewicz ◽  
Ewa Litwa ◽  
Diana Piotrowska ◽  
Piotr Popik ◽  
...  
Keyword(s):  
Immune Activation ◽  
Social Play ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Male Rats ◽  
Poly I:C ◽  
Maternal Immune Activation ◽  
Increased Risk ◽  
Adolescent Rats ◽  
The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

scholarly journals Potent Inhibition of Hendra Virus Infection via RNA Interference and Poly I:C Immune Activation

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e64360 ◽  
Author(s):  
Jana L. McCaskill ◽  
Glenn A. Marsh ◽  
Paul Monaghan ◽  
Lin-Fa Wang ◽  
Timothy Doran ◽  
...  
Keyword(s):  
Rna Interference ◽  
Virus Infection ◽  
Immune Activation ◽  
Hendra Virus ◽  
Poly I:C ◽  
Potent Inhibition

Maternal Immune Activation in the Rat Alters Maternofetal Leucine Transport and Fetal Brain Growth

Placenta ◽  
2021 ◽  
Vol 112 ◽  
pp. e13
Author(s):  
Hager M. Kowash ◽  
Harry G. Potter ◽  
Nick Ashton ◽  
Reinmar Hager ◽  
Joanna C. Neill ◽  
...  
Keyword(s):  
Immune Activation ◽  
Fetal Brain ◽  
Brain Growth ◽  
Maternal Immune Activation ◽  
Leucine Transport

scholarly journals Clozapine Prevents Poly (I:C) Induced Inflammation by Modulating NLRP3 Pathway in Microglial Cells

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 577
Author(s):  
Vijayasree V. Giridharan ◽  
Giselli Scaini ◽  
Gabriela D. Colpo ◽  
Tejaswini Doifode ◽  
Omar F. Pinjari ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Nlrp3 Inflammasome ◽  
Antipsychotic Drugs ◽  
Poly I:C ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Primary Microglial Cell ◽  
Anti Inflammatory ◽  
The Brain ◽  
Nlrp3 Expression

Schizophrenia is a complex psychiatric disorder that exhibits an interconnection between the immune system and the brain. Experimental and clinical studies have suggested the presence of neuroinflammation in schizophrenia. In the present study, the effect of antipsychotic drugs, including clozapine, risperidone, and haloperidol (10, 20 and 20 μM, respectively), on the production of IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IL-18, INF-γ, and TNF-α was investigated in the unstimulated and polyriboinosinic-polyribocytidilic acid [poly (I:C)]-stimulated primary microglial cell cultures. In the unstimulated cultures, clozapine, risperidone, and haloperidol did not influence the cytokine levels. Nevertheless, in cell cultures under strong inflammatory activation by poly (I:C), clozapine reduced the levels of IL-1α, IL-1β, IL-2, and IL-17. Risperidone and haloperidol both reduced the levels of IL-1α, IL-1β, IL-2, and IL-17, and increased the levels of IL-6, IL-10, INF-γ, and TNF-α. Based on the results that were obtained with the antipsychotic drugs and observing that clozapine presented with a more significant anti-inflammatory effect, clozapine was selected for the subsequent experiments. We compared the profile of cytokine suppression obtained with the use of NLRP3 inflammasome inhibitor, CRID3 to that obtained with clozapine, to test our hypothesis that clozapine inhibits the NLRP3 inflammasome. Clozapine and CRID3 both reduced the IL-1α, IL-1β, IL-2, and IL-17 levels. Clozapine reduced the level of poly (I:C)-activated NLRP3 expression by 57%, which was higher than the reduction thay was seen with CRID3 treatment (45%). These results suggest that clozapine might exhibit anti-inflammatory effects by inhibiting NLRP3 inflammasome and this activity is not typical with the use of other antipsychotic drugs under the conditions of strong microglial activation.

scholarly journals Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

2019 ◽  
Author(s):  
Paulino Barragan-Iglesias ◽  
Úrzula Franco-Enzástiga ◽  
Vivekanand Jeevakumar ◽  
Andi Wangzhou ◽  
Vinicio Granados-Soto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Mrna Translation ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Drg Neurons ◽  
Pain Hypersensitivity ◽  
Type I Ifns ◽  
Pain Sensitization

ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

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