Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress

AbstractViral infection during pregnancy is often associated with neuropsychiatric conditions. In mice, exposure of pregnant dams to the viral mimetic poly(I:C), serves as a model that simulates such pathology in the offspring, through a process known as Maternal Immune Activation (MIA). To investigate the mechanism of such effect, we hypothesized that maternal upregulation of Type-I interferon (IFN-I), as part of the dam’s antiviral response, might contribute to the damage imposed on the offspring. Using mRNA sequencing and flow cytometry analyses we found that poly(I:C) treatment during pregnancy caused reduced expression of genes related to proliferation and cell cycle in the offspring’s microglia relative to controls. This was found to be associated with an IFN-I signature in the embryonic yolk sac, the origin of microglia in development. Neutralizing IFN-I signaling in dams attenuated the effect of MIA on the newborn’s microglia, while systemic maternal administration of IFNβ was sufficient to mimic the effect of poly(I:C), and led to increased vulnerability of offspring’s microglia to subsequent stress. Furthermore, maternal elevation of IFNβ resulted in behavioral manifestations reminiscent of neuropsychiatric disorders. In addition, by adopting a “two-hit” experimental paradigm, we show a higher sensitivity of the offspring to postnatal stress subsequent to the maternal IFNβ elevation, demonstrated by behavioral irregularities. Our results suggest that maternal upregulation of IFN-I, in response to MIA, interferes with the offspring’s programmed microglial developmental cascade, increases their susceptibility to postnatal stress, and leads to behavioral abnormalities.

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Protective immunity against rock bream iridovirus (RBIV) infection and TLR3-mediated type I interferon signaling pathway in rock bream ( Oplegnathus fasciatus ) following poly (I:C) administration

Fish & Shellfish Immunology ◽

10.1016/j.fsi.2017.06.026 ◽

2017 ◽

Vol 67 ◽

pp. 293-301 ◽

Cited By ~ 8

Author(s):

Myung-Hwa Jung ◽

Sung-Ju Jung

Keyword(s):

Signaling Pathway ◽

Protective Immunity ◽

Type I Interferon ◽

Poly I:C ◽

Type I ◽

Interferon Signaling ◽

Oplegnathus Fasciatus ◽

Rock Bream

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Faculty Opinions recommendation of Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1165559.628567 ◽

2009 ◽

Author(s):

E Charles Snow

Keyword(s):

Dendritic Cells ◽

Lymph Node ◽

Type I Interferon ◽

Type I ◽

Interferon Signaling ◽

T Follicular Helper Cells ◽

Helper Cells ◽

Follicular Helper

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Faculty Opinions recommendation of Blockade of chronic type I interferon signaling to control persistent LCMV infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717999659.793474946 ◽

2013 ◽

Author(s):

Giorgio Trinchieri

Keyword(s):

Type I Interferon ◽

Type I ◽

Interferon Signaling ◽

Chronic Type ◽

Lcmv Infection

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Faculty Opinions recommendation of Persistent LCMV infection is controlled by blockade of type I interferon signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717999658.793476087 ◽

2013 ◽

Author(s):

Alan Landay

Keyword(s):

Type I Interferon ◽

Type I ◽

Interferon Signaling ◽

Lcmv Infection

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Faculty Opinions recommendation of USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718217888.793499915 ◽

2014 ◽

Author(s):

Ganes Sen ◽

Saurabh Chattopadhyay

Keyword(s):

Type I Interferon ◽

Type I ◽

Interferon Signaling

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Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression

Journal of Virology ◽

10.1128/jvi.01099-18 ◽

2018 ◽

Vol 92 (23) ◽

Cited By ~ 1

Author(s):

Keigo Kawashima ◽

Masanori Isogawa ◽

Susumu Hamada-Tsutsumi ◽

Ian Baudi ◽

Satoru Saito ◽

...

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

Type I Interferon ◽

T Cell Responses ◽

Antigen Expression ◽

Type I ◽

Interferon Signaling ◽

Cell Responses ◽

B Virus

ABSTRACT Robust virus-specific CD8+ T cell responses are required for the clearance of hepatitis B virus (HBV). However, the factors that determine the magnitude of HBV-specific CD8+ T cell responses are poorly understood. To examine the impact of genetic variations of HBV on HBV-specific CD8+ T cell responses, we introduced three HBV clones (Aa_IND [Aa], C_JPN22 [C22], and D_IND60 [D60]) that express various amounts of HBV antigens into the livers of C57BL/6 (B6) (H-2b) mice and B10.D2 (H-2d) mice. In B6 mice, clone C22 barely induced HBV-specific CD8+ T cell responses and persisted the longest, while clone D60 elicited strong HBV-specific CD8+ T cell responses and was rapidly cleared. These differences between HBV clones largely diminished in H-2d mice. Interestingly, the magnitude of HBV-specific CD8+ T cell responses in B6 mice was associated with the HB core antigen expression level during the early phase of HBV transduction. Surprisingly, robust HBV-specific CD8+ T cell responses to clone C22 were induced in interferon-α/β receptor-deficient (IFN-αβR–/–) (H-2b) mice. The induction of HBV-specific CD8+ T cell responses to C22 in IFN-αβR–/– mice reflects enhanced HBV antigen expression because the suppression of antigen expression by HBV-specific small interfering RNA (siRNA) attenuated HBV-specific T cell responses in IFN-αβR–/– mice and prolonged HBV expression. Collectively, these results suggest that HBV genetic variation and type I interferon signaling determine the magnitude of HBV-specific CD8+ T cell responses by regulating the initial antigen expression levels. IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8+ T cell responses are required for the clearance of HBV. However, the relative contributions of genetic variation and innate immune responses to the induction of HBV-specific CD8+ T cell responses are not fully understood. In this study, we discovered that different clearance rates between HBV clones after hydrodynamic transduction were associated with the magnitude of HBV-specific CD8+ T cell responses and initial HB core antigen expression. Surprisingly, type I interferon signaling negatively regulated HBV-specific CD8+ T cell responses by reducing early HBV antigen expression. These results show that the magnitude of the HBV-specific CD8+ T cell response is regulated primarily by the initial antigen expression level.

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Lung Epithelial Regulation of BCL2 Related Protein A1 (BCL2A1) by Coronaviruses (SARS-CoV) and Type I Interferon Signaling

10.1101/2021.07.21.453244 ◽

2021 ◽

Author(s):

Ramana Chilakamarti

Keyword(s):

Epithelial Cells ◽

Human Lung ◽

Type I Interferon ◽

Respiratory Viruses ◽

Lung Epithelial Cells ◽

Type I ◽

Related Protein ◽

Interferon Signaling ◽

Lung Epithelial ◽

Human Lung Epithelial Cells

Highly pathogenic respiratory viruses such as 1918 influenza (HIN1) and coronavirus (SARS-CoV-2) induce significant lung injury with diffuse alveolar damage, capillary leak, and extensive cell death resulting in acute respiratory distress syndrome (ARDS). Direct effects of the virus, as well as host immune response such as proinflammatory cytokine production, contribute to programmed cell death or apoptosis. Alveolar lung epithelial type II (AT2) cells play a major role in the clearance of respiratory viruses, secretion of surfactant proteins and antimicrobial substances into the bronchoalveolar fluid as well as repair of lung injury. Gene expression in AT2 cells is regulated in a tissue and cell-specific manner and in a temporal fashion. The availability of tissue and cell-specific RNA datasets in Human Protein Atlas led to the identification of localized expression patterns of BCL-2 family members such as BCL2 related protein A1 (BCL2A1) in AT2 cells and immune cells of the lung. BCL2A1 expression was regulated by multiple stimuli including Toll-like receptor (TLR) ligands, interferons (IFNs), inflammatory cytokines, and inhibited by the steroid dexamethasone. In this study, regulation of BCL2A1 gene expression in human lung epithelial cells by several respiratory viruses and type I interferon signaling was investigated. SARS-CoV-2 infection significantly induced BCL2A1 expression in human lung epithelial cells within 24 hours that required the expression of Angiotensin-converting enzyme 2 (ACE2). BCL2A1 mRNA induction by SARS-CoV-2 was correlated with the induced expression of IFN-β and IFN-regulated transcription factor mRNA. BCL2A1 was induced by IFN-β treatment or by infection with influenza virus lacking the non-structural protein1(NS1) in NHBE cells. Furthermore, bioinformatics revealed that a subset of BCL-2 family members involved in the control of apoptosis and transcription such as BCL2A1, BCL2L14, BCL3, and BCL6 were regulated in the lung epithelial cells by coronaviruses and in the lung tissue samples of COVID-19 patients. Transcriptomic data also suggested that these genes were differentially regulated by the steroid drug dexamethasone.

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