scholarly journals Toll-like receptor 7 suppresses virus replication in neurons but does not affect viral pathogenesis in a mouse model of Langat virus infection

2013 ◽  
Vol 94 (2) ◽  
pp. 336-347 ◽  
Author(s):  
David G. Baker ◽  
Tyson A. Woods ◽  
Niranjan B. Butchi ◽  
Timothy M. Morgan ◽  
R. Travis Taylor ◽  
...  
Keyword(s):  
Virus Infection ◽  
Virus Replication ◽  
Type I ◽  
Toll Like Receptor ◽  
Virus Infections ◽  
Ssrna Virus ◽  
Langat Virus ◽  
The Central Nervous System ◽  
Interferon Responses ◽  
Deficient Mice

Toll-like receptor 7 (TLR7) recognizes guanidine-rich viral ssRNA and is an important mediator of peripheral immune responses to several ssRNA viruses. However, the role that TLR7 plays in regulating the innate immune response to ssRNA virus infections in specific organs such as the central nervous system (CNS) is not as clear. This study examined the influence of TLR7 on the neurovirulence of Langat virus (LGTV), a ssRNA tick-borne flavivirus. TLR7 deficiency did not substantially alter the onset or incidence of LGTV-induced clinical disease; however, it did significantly affect virus levels in the CNS with a log10 increase in virus titres in brain tissue from TLR7-deficient mice. This difference in virus load was also observed following intracranial inoculation, indicating a direct effect of TLR7 deficiency on regulating virus replication in the brain. LGTV-induced type I interferon responses in the CNS were not dependent on TLR7, being higher in TLR7-deficient mice compared with wild-type controls. In contrast, induction of pro-inflammatory cytokines including tumour necrosis factor, CCL3, CCL4 and CXCL13 were dependent on TLR7. Thus, although TLR7 is not essential in controlling LGTV pathogenesis, it is important in controlling virus infection in neurons in the CNS, possibly by regulating neuroinflammatory responses.

scholarly journals Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections

2021 ◽  
Vol 12 ◽  
Author(s):  
Nadine Szumilas ◽  
Odilia B. J. Corneth ◽  
Christian H. K. Lehmann ◽  
Heike Schmitt ◽  
Svenia Cunz ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Inflammatory Responses ◽  
Type I Interferon ◽  
Acute Infection ◽  
Murine Cytomegalovirus ◽  
Type I ◽  
Virus Infections ◽  
Mcmv Infection ◽  
Interferon Responses ◽  
Deficient Mice

Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.

scholarly journals Whole-brain fluorescence-MRI coregistration for precise anatomical mapping of virus infection

2021 ◽  
Author(s):  
Nunya Chotiwan ◽  
Stefanie M.A. Willekens ◽  
Erin Schexnaydre ◽  
Max Hahn ◽  
Federico Morini ◽  
...  
Keyword(s):  
Virus Infection ◽  
Type I Interferon ◽  
Ex Vivo ◽  
Interferon Response ◽  
Type I ◽  
Virus Infections ◽  
Whole Brain ◽  
Neurotropic Virus ◽  
Langat Virus ◽  
The Brain

Neurotropic virus infections cause tremendous disease burden. Methods visualizing infection in the whole brain remain unavailable which greatly impedes understanding of viral neurotropism and pathogenesis. We devised an approach to visualize the distribution of neurotropic virus infection in whole mouse brain ex vivo. Optical projection tomography (OPT) signal was coregistered with a unique magnetic resonance imaging (MRI) brain template, enabling precise anatomical mapping of viral distribution, and the effect of type I interferon on distribution of infection was analyzed. Guided by OPT-MR, we show that Langat virus specifically targets sensory brain systems and the lack of type I interferon response results in an anatomical shift in infection patterns in the brain. We confirm this regional tropism, observed with whole brain OPT-MRI, by confocal and electron microscopy to provide unprecedented insight into viral neurotropism. This approach can be applied to any fluorescently labeled target in the brain.

scholarly journals Novel Mode of ISG15-Mediated Protection against Influenza A Virus and Sendai Virus in Mice

2014 ◽  
Vol 89 (1) ◽  
pp. 337-349 ◽  
Author(s):  
David J. Morales ◽  
Kristen Monte ◽  
Lulu Sun ◽  
Jessica J. Struckhoff ◽  
Eugene Agapov ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Type I ◽  
Induced Genes

ABSTRACTISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15−/−mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replicationin vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15−/−mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugation-dependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15in vivo.IMPORTANCEIt has previously been demonstrated that ISG15−/−mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protectionin vivo. In these studies we have found that while ISG15−/−mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15in vivo.

scholarly journals Toll-Like Receptor 3 Mediates Establishment of an Antiviral State against Hepatitis C Virus in Hepatoma Cells

2009 ◽  
Vol 83 (19) ◽  
pp. 9824-9834 ◽  
Author(s):  
Nan Wang ◽  
Yuqiong Liang ◽  
Santhana Devaraj ◽  
Jie Wang ◽  
Stanley M. Lemon ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis Virus ◽  
Hepatoma Cells ◽  
Human Hepatocytes ◽  
Hcv Infection ◽  
Type I Interferons ◽  
Type I ◽  
Toll Like Receptor ◽  
Virus Infections

ABSTRACT Toll-like receptor-3 (TLR3) senses double-stranded RNA, initiating signaling that activates NF-κB and interferon regulatory factor 3 (IRF-3), thereby inducing the synthesis of proinflammatory cytokines, type I interferons, and numerous interferon-stimulated genes (ISGs). This pathway has not been extensively investigated in human hepatocytes, and its role in sensing and protecting against hepatitis virus infections is uncertain. We show here that primary human hepatocytes express TLR3 and robustly upregulate ISGs upon poly(I·C) stimulation. We also show that TLR3 senses hepatitis C virus (HCV) infection when expressed in permissive hepatoma cells, acting independently of retinoic acid-inducible gene I and inducing IRF-3 activation and the synthesis of ISGs that restrict virus replication. In turn, HCV infection reduces the abundance of TRIF, an essential TLR3 adaptor, and impairs poly(I·C)-induced signaling. The induction and disruption of TLR3 signaling by HCV may be important factors in determining the outcome of infection and the ability of HCV to establish persistent infections.

scholarly journals Neuroinvasion of SARS-CoV-2 in human and mouse brain

2021 ◽  
Vol 218 (3) ◽  
Author(s):  
Eric Song ◽  
Ce Zhang ◽  
Benjamin Israelow ◽  
Alice Lu-Culligan ◽  
Alba Vieites Prado ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Immune Cell ◽  
Multiple Organ ◽  
Type I ◽  
Organ Systems ◽  
The Central Nervous System ◽  
Interferon Responses ◽  
The Brain ◽  
Immune Cell Infiltrates

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

scholarly journals Endogenous Retroviruses Provide Protection Against Vaginal HSV-2 Disease

2022 ◽  
Vol 12 ◽  
Author(s):  
Radeesha Jayewickreme ◽  
Tianyang Mao ◽  
William Philbrick ◽  
Yong Kong ◽  
Rebecca S. Treger ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Endogenous Retroviruses ◽  
Protective Mechanism ◽  
Type I ◽  
Toll Like Receptor ◽  
Matrix Organization ◽  
Simplex Virus ◽  
Deficient Mice ◽  
Eukaryotic Genomes

Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, but whether ERVs contribute to antiviral immunity is not well understood. Here, we used herpes simplex virus type 2 (HSV-2) infection as a model and found that Toll-like receptor 7 (Tlr7-/-) deficient mice that have high systemic levels of infectious ERVs are protected from intravaginal HSV-2 infection and disease, compared to wildtype C57BL/6 mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7-/- background (Emv2-/-Tlr7-/-) and found that Emv2-/-Tlr7-/- mice lose protection against HSV-2 infection. Intravaginal application of purified ERVs from Tlr7-/- mice prior to HSV-2 infection delays disease in both wildtype and highly susceptible interferon-alpha receptor-deficient (Ifnar1-/-) mice. However, intravaginal ERV treatment did not protect Emv2-/-Tlr7-/- mice from HSV-2 disease, suggesting that the protective mechanism mediated by exogenous ERV treatment may differ from that of constitutively and systemically expressed ERVs in Tlr7-/- mice. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7-/- mice, and instead found enrichment in genes associated with extracellular matrix organization. Together, our results revealed that constitutive and/or systemic expression of ERVs protect mice against vaginal HSV-2 infection and delay disease.

TLR 7/8 regulates Type I and Type III Interferon Signalling in RV1b induced Allergic Asthma

2020 ◽  
pp. 2001562
Author(s):  
Jasmin Krug ◽  
Alexander Kiefer ◽  
Julia Koelle ◽  
Tytti Vuorinen ◽  
Paraskevi Xepapadaki ◽  
...  
Keyword(s):  
Preschool Age ◽  
Lung Cells ◽  
Type I ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Type Iii ◽  
Β Receptor ◽  
Primary School Age ◽  
Interferon Responses ◽  
Type Iii Interferon

QuestionInterferon responses have been reported to be defective in rhinovirus (RV) induced asthma. The heterodimeric receptor of type I Interferon (IFN) (IFN-α/-β) is composed by IFNαR-1 and IFNαR-2. Ligand binding to the IFN-α/-β receptor complex activates STAT1 and STAT2 intracellularly. Although type III Interferon (IFN-λ) binds to a different receptor containing IFNλRA and IL-10R2, its triggering leads to activation of the same downstream transcription factors. Here we analysed the effects of Rhinovirus to Interferon type I and III receptors and asked about possible Toll-like receptor 7/8 agonist R848 mediated IFNαR1 and IFNλRα regulation.MethodsWe measured IFN-α, -β, -λ and their receptor levels in PBMCs supernatants and cell pellets stimulated with RV1b and the Toll-like Receptor 7/8 (TLR7/8) agonist (R848), in two cohorts of children with and without asthma recruited at preschool age (PreDicta) and at primary school age (AGENDAS) as well as in cell supernatants from total lung cells isolated from mice.ResultsWe observed that R848 induced IFNλR mRNA expression in PBMCs of healthy and asthmatic children, but suppressed the IFNαR mRNA levels. In murine lung cells, RV1balone and together with R848 suppressed IFNαR protein in T cells compared to controls and in total lung IFNλR mRNA compared to RV1b infection alone.AnswerIn PBMCs from pre-school children, IFNαR mRNA was reduced and IFNλRα mRNA was induced upon treatment with TLR7/8 agonist thus suggesting new avenues for induction of anti-viral immune responses in pediatric asthma.

scholarly journals The Innate Immune Adaptor Molecule MyD88 Restricts West Nile Virus Replication and Spread in Neurons of the Central Nervous System

2010 ◽  
Vol 84 (23) ◽  
pp. 12125-12138 ◽  
Author(s):  
Kristy J. Szretter ◽  
Stephane Daffis ◽  
Jigisha Patel ◽  
Mehul S. Suthar ◽  
Robyn S. Klein ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
West Nile Virus ◽  
Virus Replication ◽  
Independent Effect ◽  
Type I ◽  
Rna Helicases ◽  
West Nile ◽  
The Central Nervous System ◽  
The Brain

ABSTRACT Type I interferons (IFN-α/β) control viral infection by triggering the expression of genes that restrict transcription, translation, replication, and assembly. Many viruses induce IFN responses after recognition by cytoplasmic or endosomal RNA sensors (RIG-I-like RNA helicases [RLR] and Toll-like receptors [TLR]), which signal through the cognate adaptor signaling molecules IPS-1, TRIF, and MyD88. Recent studies have demonstrated that IPS-1-dependent induction of IFN-α/β downstream of RLR recognition restricts West Nile virus (WNV) infection in many cell types, whereas TRIF-dependent TLR3 signaling limits WNV replication in neurons. Here, we examined the contribution of MyD88 signaling to the control of WNV by evaluating IFN induction and virus replication in genetically deficient cells and mice. MyD88 − / − mice showed increased lethality after WNV infection and elevated viral burden primarily in the brain, even though little effect on the systemic type I IFN response was observed. Intracranial inoculation studies corroborated these findings, as WNV spread more rapidly in the central nervous system of MyD88 − / − mice, and this phenotype preceded the recruitment of inflammatory leukocytes. In vitro, increased WNV replication was observed in MyD88 − / − macrophages and subsets of neurons but not in myeloid dendritic cells. MyD88 had an independent effect on recruitment of monocyte-derived macrophages and T cells into the brain that was associated with blunted induction of the chemokines that attract leukocytes. Our experiments suggest that MyD88 restricts WNV by inhibiting replication in subsets of cells and modulating expression of chemokines that regulate immune cell migration into the central nervous system.

Plasmacytoid dendritic cells and autoimmune inflammation

2014 ◽  
Vol 395 (3) ◽  
pp. 335-346 ◽  
Author(s):  
Georgina Galicia ◽  
Jennifer L. Gommerman
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Toll Like Receptor ◽  
Autoimmune Encephalomyelitis ◽  
Effector Cells ◽  
The Central Nervous System ◽  
Antigen Presenting ◽  
Experimental Autoimmune

Abstract Plasmacytoid dendritic cells (pDC) are a sub-population of dendritic cells (DC) that produce large amounts of type I interferon (IFN) in response to nucleic acids that bind and activate toll-like-receptor (TLR)9 and TLR7. Type I IFN can regulate the function of B, T, DC, and natural killer (NK) cells and can also alter the residence time of leukocytes within lymph nodes. Activated pDC can also function as antigen presenting cells (APC) and have the potential to prime and differentiate T cells into regulatory or inflammatory effector cells, depending on the context. In this review we discuss pDC ontogeny, function, trafficking, and activation. We will also examine how pDC can potentially be involved in regulating immune responses in the periphery as well as within the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE).

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