scholarly journals The brain parenchyma has a type I interferon response that can limit virus spread

2016 ◽  
Vol 114 (1) ◽  
pp. E95-E104 ◽  
Author(s):  
Eugene Drokhlyansky ◽  
Didem Göz Aytürk ◽  
Timothy K. Soh ◽  
Ryan Chrenek ◽  
Elaine O’Loughlin ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Type I Interferon ◽  
Brain Parenchyma ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Virus Spread ◽  
Viral Spread ◽  
The Brain

The brain has a tightly regulated environment that protects neurons and limits inflammation, designated “immune privilege.” However, there is not an absolute lack of an immune response. We tested the ability of the brain to initiate an innate immune response to a virus, which was directly injected into the brain parenchyma, and to determine whether this response could limit viral spread. We injected vesicular stomatitis virus (VSV), a transsynaptic tracer, or naturally occurring VSV-derived defective interfering particles (DIPs), into the caudate–putamen (CP) and scored for an innate immune response and inhibition of virus spread. We found that the brain parenchyma has a functional type I interferon (IFN) response that can limit VSV spread at both the inoculation site and among synaptically connected neurons. Furthermore, we characterized the response of microglia to VSV infection and found that infected microglia produced type I IFN and uninfected microglia induced an innate immune response following virus injection.

RNA sensors as a mechanism of innate immune evasion among SARS-CoV2, HIV and Nipah viruses

2021 ◽  
Vol 22 ◽  
Author(s):  
Dalia Cicily Kattiparambil Dixon ◽  
Chameli Ratan ◽  
Bhagyalakshmi Nair ◽  
Sabitha Mangalath ◽  
Rachy Abraham ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Vaccine Development ◽  
Innate Immune ◽  
Interferon Response ◽  
Host Immune System ◽  
Type I ◽  
Adaptive Responses ◽  
Rna Sensors

: Innate immunity is the first line of defence elicited by the host immune system to fight against invading pathogens such as viruses and bacteria. From this elementary immune response, the more complex antigen-specific adaptive responses are recruited to provide a long-lasting memory against the pathogens. Innate immunity gets activated when the host cell utilizes a diverse set of receptors known as pattern recognition receptors (PRR) to recognize the viruses that have penetrated the host and respond with cellular processes like complement system, phagocytosis, cytokine release and inflammation and destruction of NK cells. Viral RNA or DNA or viral intermediate products are recognized by receptors like toll-like receptors(TLRs), nucleotide oligomerization domain(NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) thereby, inducing type I interferon response (IFN) and other proinflammatory cytokines in infected cells or other immune cells. But certain viruses can evade the host innate immune response to replicate efficiently, triggering the spread of the viral infection. The present review describes the similarity in the mechanism chosen by viruses from different families -HIV, SARS-CoV2 and Nipah viruses to evade the innate immune response and how efficiently they establish the infection in the host. The review also addresses the stages of developments of various vaccines against these viral diseases and the challenges encountered by the researchers during vaccine development.

scholarly journals Cryptosporidium parvumInfection Rapidly Induces a Protective Innate Immune Response Involving Type I Interferon

2009 ◽  
Vol 200 (10) ◽  
pp. 1548-1555 ◽  
Author(s):  
Farah M. Barakat ◽  
Vincent McDonald ◽  
Graham R. Foster ◽  
Michael G. Tovey ◽  
Daniel S. Korbel
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I

scholarly journals Human Cytomegalovirus Immediate Early 86-kDa Protein Blocks Transcription and Induces Degradation of the Immature Interleukin-1β Protein during Virion-Mediated Activation of the AIM2 Inflammasome

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sara Botto ◽  
Jinu Abraham ◽  
Nobuyo Mizuno ◽  
Kara Pryke ◽  
Bryan Gall ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Innate Immune ◽  
Host Cells ◽  
Interleukin 1Β ◽  
Immediate Early ◽  
Interferon Response ◽  
Type I

ABSTRACTSecretion of interleukin-1β (IL-1β) represents a fundamental innate immune response to microbial infection that, at the molecular level, occurs following activation of proteolytic caspases that cleave the immature protein into a secretable form. Human cytomegalovirus (HCMV) is the archetypal betaherpesvirus that is invariably capable of lifelong infection through the activity of numerous virally encoded immune evasion phenotypes. Innate immune pathways responsive to cytoplasmic double-stranded DNA (dsDNA) are known to be activated in response to contact between HCMV and host cells. Here, we used clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9 (Cas9) genome editing to demonstrate that the dsDNA receptorabsentinmelanoma 2 (AIM2) is required for secretion of IL-1β following HCMV infection. Furthermore, dsDNA-responsive innate signaling induced by HCMV infection that leads to activation of the type I interferon response is also shown, unexpectedly, to play a contributory role in IL-1β secretion. Importantly, we also show that rendering virus particles inactive by UV exposure leads to substantially increased IL-1β processing and secretion and that live HCMV can inhibit this, suggesting the virus encodes factors that confer an inhibitory effect on this response. Further examination revealed that ectopic expression of the immediate early (IE) 86-kDa protein (IE86) is actually associated with a block in transcription of the pro-IL-1β gene and, independently, diminishment of the immature protein. Overall, these results reveal two new and distinct phenotypes conferred by the HCMV IE86 protein, as well as an unusual circumstance in which a single herpesviral protein exhibits inhibitory effects on multiple molecular processes within the same innate immune response.IMPORTANCEPersistent infection with HCMV is associated with the operation of diverse evasion phenotypes directed at antiviral immunity. Obstruction of intrinsic and innate immune responses is typically conferred by viral proteins either associated with the viral particle or expressed immediately after entry. In line with this, numerous phenotypes are attributed to the HCMV IE86 protein that involve interference with innate immune processes via transcriptional and protein-directed mechanisms. We describe novel IE86-mediated phenotypes aimed at virus-induced secretion of IL-1β. Intriguingly, while many viruses target the function of the molecular scaffold required for IL-1β maturation to prevent this response, we find that HCMV and IE86 target the IL-1β protein specifically. Moreover, we show that IE86 impairs both the synthesis of the IL-1β transcript and the stability of the immature protein. This indicates an unusual phenomenon in which a single viral protein exhibits two molecularly separate evasion phenotypes directed at a single innate cytokine.

scholarly journals A type I interferon response defines a conserved microglial state required for effective phagocytosis

2021 ◽  
Author(s):  
Leah C Dorman ◽  
Phi T Nguyen ◽  
Caroline C Escoubas ◽  
Ilia D Vainchtein ◽  
Yinghong Xiao ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Meta Analysis ◽  
Transcriptional Profiling ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Whole Cells ◽  
Microglial Phagocytosis ◽  
The Brain

Microglia, the innate immune cells of the brain, are exquisitely sensitive to dynamic changes in the brain environment. We used single cell RNA sequencing to define glial responses in the early postnatal somatosensory cortex after partial whisker lesion, revealing transcriptomic shifts in both astrocytes and microglia during the resulting topographic remapping. The most distinct change was the emergence of a type I interferon (IFN-I) responsive microglia population that was rare in the resting cortex but expanded 20-fold after whisker deprivation. The top gene candidate in this cluster, Ifitm3, marked a conserved but transient subset of microglia that were in the process of phagocytosing whole cells. IFITM3 protein identified this subset in vivo, where it was enriched in early microglial phagosomes. Loss of canonical IFN-I signaling in Ifnar1-/- animals resulted in abnormal 'bubble' microglia with deficient phagolysosomal processing. In a meta-analysis of transcriptomes, we identified the IFN-I signature in microglia across a range of pathologies. We identified phagocytic IFITM3+ microglia in two murine disease models: SARS-CoV-2 infection and Alzheimer's Disease. These data reveal the potential of transcriptional profiling after defined perturbation to elicit transient microglial states, and identify a novel role for IFN-I signaling in regulating microglial phagocytosis.

scholarly journals Japanese Encephalitis Virus NS5 Inhibits Type I Interferon (IFN) Production by Blocking the Nuclear Translocation of IFN Regulatory Factor 3 and NF-κB

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Jing Ye ◽  
Zheng Chen ◽  
Yunchuan Li ◽  
Zikai Zhao ◽  
Wen He ◽  
...  
Keyword(s):  
Immune Response ◽  
Japanese Encephalitis Virus ◽  
Innate Immune Response ◽  
Nuclear Translocation ◽  
Type I Interferon ◽  
Transport Proteins ◽  
Innate Immune ◽  
Type I ◽  
Regulatory Factor ◽  
Host Innate Immune Response

ABSTRACT The type I interferon (IFN) response is part of the first-line defense against viral infection. To initiate replication, viruses have developed powerful evasion strategies to counteract host IFN responses. In the present study, we found that the Japanese encephalitis virus (JEV) NS5 protein could inhibit double-stranded RNA (dsRNA)-induced IFN-β expression in a dose-dependent manner. Our data further demonstrated that JEV NS5 suppressed the activation of the IFN transcriptional factors IFN regulatory factor 3 (IRF3) and NF-κB. However, there was no defect in the phosphorylation of IRF3 and degradation of IκB, an upstream inhibitor of NF-κB, upon NS5 expression, indicating a direct inhibition of the nuclear localization of IRF3 and NF-κB by NS5. Mechanistically, NS5 was shown to interact with the nuclear transport proteins KPNA2, KPNA3, and KPNA4, which competitively blocked the interaction of KPNA3 and KPNA4 with their cargo molecules, IRF3 and p65, a subunit of NF-κB, and thus inhibited the nuclear translocation of IRF3 and NF-κB. Furthermore, overexpression of KPNA3 and KPNA4 restored the activity of IRF3 and NF-κB and increased the production of IFN-β in NS5-expressing or JEV-infected cells. Additionally, an upregulated replication level of JEV was shown upon KPNA3 or KPNA4 overexpression. These results suggest that JEV NS5 inhibits the induction of type I IFN by targeting KPNA3 and KPNA4. IMPORTANCE JEV is the major cause of viral encephalitis in South and Southeast Asia, with high mortality. However, the molecular mechanisms contributing to the severe pathogenesis are poorly understood. The ability of JEV to counteract the host innate immune response is potentially one of the mechanisms responsible for JEV virulence. Here we demonstrate the ability of JEV NS5 to interfere with the dsRNA-induced nuclear translocation of IRF3 and NF-κB by competitively inhibiting the interaction of IRF3 and NF-κB with nuclear transport proteins. Via this mechanism, JEV NS5 suppresses the induction of type I IFN and the antiviral response in host cells. These findings reveal a novel strategy for JEV to escape the host innate immune response and provide new insights into the pathogenesis of JEV.

scholarly journals Recognition of HIV-1 capsid licenses innate immune response to viral infection

2022 ◽  
Author(s):  
sunnie M yoh ◽  
Joao Mamede ◽  
Derrick Lau ◽  
Narae Ahn ◽  
Maria T Sanchez ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Immune Surveillance ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Dna Viruses ◽  
Rna Genome ◽  
Hiv 1

Cyclic GMP-AMP synthase (cGAS) is a primary sensor of aberrant DNA that governs an innate immune signaling cascade, leading to the induction of the type-I interferon response. We have previously identified polyglutamine binding protein 1, PQBP1, as an adaptor molecule required for cGAS-mediated innate immune response of lentiviruses, including the human immunodeficiency virus 1 (HIV-1), but dispensable for the recognition of DNA viruses. HIV-1-encoded DNA is synthesized as a single copy from its RNA genome, and is subsequently integrated into the host chromatin. HIV-1 then produces progeny through amplification and packaging of its RNA genome, thus, in contrast to DNA viruses, HIV-1 DNA is both transient and of low abundance. However, the molecular basis for the detection and verification of this low abundance HIV-1 DNA pathogen-associated molecular pattern (PAMP) is not understood. Here, we elucidate a two-factor authentication strategy that is employed by the innate immune surveillance machinery to selectively respond to the low concentration of PAMP, while discerning these species from extranuclear DNA molecules. We find that, upon HIV-1 infection, PQBP1 decorates intact viral capsid, which serves as a primary verification step for the viral nucleic acid cargo. As the reverse transcription and capsid disassembly initiate, cGAS protein is then recruited to the capsid in a PQBP1-dependent manner, enabling cGAS molecules to be co-positioned at the site of PAMP generation. Thus, these data indicate that PQBP1 recognition of the HIV-1 capsid sanctions a robust cGAS-dependent response to a limited abundance and short-lived DNA PAMP. Critically, this illuminates a molecular strategy wherein the modular recruitment of co-factors to germline encoded pattern recognition receptors (PRRs) serves to enhance repertoire of pathogens that can be sensed by the innate immune surveillance machinery.

scholarly journals RIOK3 Is an Adaptor Protein Required for IRF3-Mediated Antiviral Type I Interferon Production

2014 ◽  
Vol 88 (14) ◽  
pp. 7987-7997 ◽  
Author(s):  
Jun Feng ◽  
Paul D. De Jesus ◽  
Victoria Su ◽  
Stephanie Han ◽  
Danyang Gong ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Type I Interferon ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Responses ◽  
Interferon Pathway ◽  
Irf3 Activation

ABSTRACTDetection of cytosolic nucleic acids by pattern recognition receptors leads to the induction of type I interferons (IFNs) and elicits the innate immune response. We report here the identification of RIOK3 as a novel adaptor protein that is essential for the cytosolic nucleic acid-induced type I IFN production and for the antiviral response to gammaherpesvirus through two independent kinome-wide RNA interference screens. RIOK3 knockdown blocks both cytosolic double-stranded B-form DNA and double-stranded RNA-induced IRF3 activation and IFN-β production. In contrast, the overexpression of RIOK3 activates IRF3 and induces IFN-β. RIOK3 functions downstream of TBK1 and upstream of IRF3 activation. Furthermore, RIOK3 physically interacts with both IRF3 and TBK1 and is necessary for the interaction between TBK1 and IRF3. In addition, global transcriptome analysis shows that the expression of many gene involved antiviral responses is dependent on RIOK3. Thus, knockdown of RIOK3 inhibits cellular antiviral responses against both DNA and RNA viruses (herpesvirus and influenza A virus). Our data suggest that RIOK3 plays a critical role in the antiviral type I IFN pathway by bridging TBK1 and IRF3.IMPORTANCEThe innate immune response, such as the production of type I interferons, acts as the first line of defense, limiting infectious pathogens directly and shaping the adaptive immune response. In this study, we identified RIOK3 as a novel regulator of the antiviral type I interferon pathway. Specifically, we found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. The identification of a cellular kinase that plays a role the type I interferon pathway adds another level of complexity in the regulation of innate immunity and will have implications for developing novel strategies to combat viral infection.

scholarly journals Lipocalin 2 is a Choroid Plexus Acute-Phase Protein

2007 ◽  
Vol 28 (3) ◽  
pp. 450-455 ◽  
Author(s):  
Fernanda Marques ◽  
Ana-João Rodrigues ◽  
João C Sousa ◽  
Giovanni Coppola ◽  
Daniel H Geschwind ◽  
...  
Keyword(s):  
Immune Response ◽  
Choroid Plexus ◽  
Innate Immune Response ◽  
Acute Phase ◽  
Acute Phase Protein ◽  
Brain Parenchyma ◽  
Innate Immune ◽  
Lipocalin 2 ◽  
Phase Protein ◽  
The Brain

Lipocalin 2 (LCN2) is able to sequester iron-loaded bacterial siderophores and, therefore, is known to participate in the mammalian innate immune response. Of notice, LCN2 was shown to display bacteriostatic effects both in in vitro and in vivo. To reach the brain, bacteria must cross the blood—brain or the choroid plexus (CP)/cerebrospinal fluid (CSF) barriers. Additionally, as the CP is responsible for the production of most of the CSF, responses of the CP mediate signaling into the brain. We show here that in conditions of peripheral inflammation, LCN2 behaves as an acute phase protein in the CP. As early as 1 h after lipopolysaccharide peripheral administration, Lcn2 mRNA levels are upregulated, returning to basal levels after 72 h. Increased LCN2 protein is observed in choroidal epithelia and in endothelial cells of blood vessels in the brain parenchyma. Higher levels of LCN2 are also present in the CSF. These observations suggest that expression of LCN2 at the CP/CSF barrier might be bacteriostatic in the brain, avoiding bacteria dissemination within the CSF into the brain parenchyma. This study shows that the LCN2 is produced by the CP as a component of the innate immune response that protects the central nervous system from infection.

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