scholarly journals Promotion of Alpha/Beta Interferon Induction during In Vivo Viral Infection through Alpha/Beta Interferon Receptor/STAT1 System-Dependent and -Independent Pathways

2002 ◽  
Vol 76 (9) ◽  
pp. 4520-4525 ◽  
Author(s):  
Lene Malmgaard ◽  
Thais P. Salazar-Mather ◽  
Casey A. Lewis ◽  
Christine A. Biron
Keyword(s):  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Beta Interferon ◽  
Interferon Induction ◽  
Elevated Expression ◽  
Alpha Beta ◽  
Β Receptor ◽  
Viral Components ◽  
Lcmv Infection

ABSTRACT Viruses and viral components can be potent inducers of alpha/beta interferons (IFN-α/β). In culture, IFN-α/β prime for their own expression, in response to viruses, through interferon regulatory factor 7 (IRF-7) induction. The studies presented here evaluated the requirements for functional IFN receptors and the IFN signaling molecule STAT1 in IFN-α/β induction during infections of mice with lymphocytic choriomeningitis virus (LCMV). At 24 h after infection, levels of induced IFN-α/β in serum were reduced 90 to 95% in IFN-α/β receptor-deficient (IFN-α/βR−/−) and STAT1−/− mice compared to those in wild-type mice. However, at 48 h, these mice showed elevated expression in the serum whereas IFN-α/β levels were still reduced >75% in IFN-α/βγR−/− mice even though the viral burden was heavy. Levels of IFN-β, IFN-α4, and non-IFN-α4 subtype mRNA expression correlated with IFN-α/β bioactivity, and all IFN-α/β subtypes were coincidentally detectable. IRF-7 mRNA was induced under conditions of IFN-α/β production, including late production in IFN-α/βR−/− mice. These data demonstrate that the presence of the virus alone is not sufficient to induce IFN-α/β during LCMV infection in vivo. Instead, autocrine amplification through the IFN-α/βR is necessary for optimal induction. In the absence of a functional IFN-α/βR, however, alternative mechanisms, independent of STAT1 but requiring a functional IFN-γR, take over.

scholarly journals Coordinated Regulation and Widespread Cellular Expression of Interferon-Stimulated Genes (ISG) ISG-49, ISG-54, and ISG-56 in the Central Nervous System after Infection with Distinct Viruses

2006 ◽  
Vol 81 (2) ◽  
pp. 860-871 ◽  
Author(s):  
Christie Wacher ◽  
Marcus Müller ◽  
Markus J. Hofer ◽  
Daniel R. Getts ◽  
Regina Zabaras ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Dominant Role ◽  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Cellular Expression ◽  
The Central Nervous System ◽  
The Brain ◽  
Lcmv Infection

ABSTRACT The interferon (IFN)-stimulated genes (ISGs) ISG-49, ISG-54, and ISG-56 are highly responsive to viral infection, yet the regulation and function of these genes in vivo are unknown. We examined the simultaneous regulation of these ISGs in the brains of mice during infection with either lymphocytic choriomeningitis virus (LCMV) or West Nile virus (WNV). Expression of the ISG-49 and ISG-56 genes increased significantly during LCMV infection, being widespread and localized predominantly to common as well as distinct neuronal populations. Expression of the ISG-54 gene also increased but to lower levels and with a more restricted distribution. Although expression of the ISG-49, ISG-54, and ISG-56 genes was increased in the brains of LCMV-infected STAT1 and STAT2 knockout (KO) mice, this was blunted, delayed, and restricted to the choroid plexus, meninges, and endothelium. ISG-56 protein was regulated in parallel with the corresponding RNA transcript in the brain during LCMV infection in wild-type and STAT KO mice. Similar changes in ISG-49, ISG-54, and ISG-56 RNA levels and ISG-56 protein levels were observed in the brains of wild-type mice following infection with WNV. Thus, the ISG-49, ISG-54, and ISG-56 genes are coordinately upregulated in the brain during LCMV and WNV infection; this upregulation, in the case of LCMV, was totally (neurons) or partially (non-neurons) dependent on the IFN-signaling molecules STAT1 and STAT2. These findings suggest a dominant role for the ISG-49, ISG-54, and ISG-56 genes in the host response to different viruses in the central nervous system, where, particularly in neurons, these genes may have nonredundant functions.

scholarly journals Characteristics of alpha/beta interferon induction after infection of murine fibroblasts with wild-type and mutant alphaviruses

Virology ◽  
2009 ◽  
Vol 395 (1) ◽  
pp. 121-132 ◽  
Author(s):  
Crystal W. Burke ◽  
Christina L. Gardner ◽  
Joshua J. Steffan ◽  
Kate D. Ryman ◽  
William B. Klimstra
Keyword(s):  
Wild Type ◽  
Beta Interferon ◽  
Interferon Induction ◽  
Murine Fibroblasts ◽  
Alpha Beta

scholarly journals Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11

Blood ◽  
2013 ◽  
Vol 121 (4) ◽  
pp. 595-603 ◽  
Author(s):  
Fernando E. Sepulveda ◽  
Franck Debeurme ◽  
Gaël Ménasché ◽  
Mathieu Kurowska ◽  
Marjorie Côte ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Late Onset ◽  
Lymphocytic Choriomeningitis ◽  
Immune Disorder ◽  
Genetic Abnormalities ◽  
Life Threatening ◽  
Syntaxin 11 ◽  
Lcmv Infection ◽  
Cytotoxic Effector

Abstract Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11–deficient (Stx11−/−) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11−/− murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal–truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11–deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication.

scholarly journals Interleukin-6 Deficiency Increases Inflammatory Bone Destruction

2001 ◽  
Vol 69 (2) ◽  
pp. 744-750 ◽  
Author(s):  
Khaled Balto ◽  
Hajime Sasaki ◽  
Philip Stashenko
Keyword(s):  
Bone Resorption ◽  
Interleukin 1 ◽  
Bone Destruction ◽  
Fusobacterium Nucleatum ◽  
Wild Type ◽  
Periapical Lesions ◽  
Elevated Expression ◽  
Pulp Exposure ◽  
Anti Inflammatory

ABSTRACT Periapical bone destruction occurs as a consequence of pulpal infection. In previous studies, we showed that interleukin-1 (IL-1) is the primary stimulator of bone destruction in this model. IL-6 is a pleiotropic cytokine that is induced in these infections and has both pro- and anti-inflammatory activities. In the present study, we determined the role of IL-6 in regulating IL-1 expression and bone resorption. The first molars of IL-6 knockouts (IL-6−/−) and wild-type mice were subjected to surgical pulp exposure and infection with a mixture of four common pulpal pathogens, includingPrevotella intermedia, Fusobacterium nucleatum,Peptostreptococcus micros, and Streptococcus intermedius. Mice were killed after 21 days, and bone destruction and cytokine expression were determined. Surprisingly, bone destruction was significantly increased in IL-6−/− mice versus that in wild-type mice (by 30%; P < 0.001). In a second experiment, the effects of chronic (IL-6−/−) IL-6 deficiency and short-term IL-6 deficiency induced by in vivo antibody neutralization were determined. Both IL-6−/− (30%;P < 0.001) and anti-IL-6 antibody-treated mice (40%;P < 0.05) exhibited increased periapical bone resorption, compared to wild-type controls. The increased bone resorption in IL-6-deficient animals correlated with increases in osteoclast numbers, as well as with elevated expression of bone-resorptive cytokines IL-1α and IL-1β, in periapical lesions and with decreased expression of the anti-inflammatory cytokine IL-10. These data demonstrate that endogenous IL-6 expression has significant anti-inflammatory effects in modulating infection-stimulated bone destruction in vivo.

scholarly journals Targeted Disruption of Ras-Grf2 Shows Its Dispensability for Mouse Growth and Development

2002 ◽  
Vol 22 (8) ◽  
pp. 2498-2504 ◽  
Author(s):  
Alberto Fernández-Medarde ◽  
Luis M. Esteban ◽  
Alejandro Núñez ◽  
Ángel Porteros ◽  
Lino Tessarollo ◽  
...  
Keyword(s):  
Memory Loss ◽  
Long Term Memory ◽  
Null Mutant ◽  
Nucleotide Exchange ◽  
Wild Type ◽  
Mouse Development ◽  
Elevated Expression ◽  
Null Mutant Mice ◽  
Histopathological Studies

ABSTRACT The mammalian Grf1 and Grf2 proteins are Ras guanine nucleotide exchange factors (GEFs) sharing a high degree of structural homology, as well as an elevated expression level in central nervous system tissues. Such similarities raise questions concerning the specificity and/or redundancy at the functional level between the two Grf proteins. grf1-null mutant mice have been recently described which showed phenotypic growth reduction and long-term memory loss. To gain insight into the in vivo function of Grf2, we disrupted its catalytic CDC25-H domain by means of gene targeting. Breeding among grf2 +/− animals gave rise to viable grf2 −/− adult animals with a normal Mendelian pattern, suggesting that Grf2 is not essential for embryonic and adult mouse development. In contrast to Grf1-null mice, analysis of grf2 −/− litters showed similar size and weight as their heterozygous or wild-type grf2 counterparts. Furthermore, adult grf2 −/− animals reached sexual maturity at the same age as their wild-type littermates and showed similar fertility levels. No specific pathology was observed in adult Grf2-null animals, and histopathological studies showed no observable differences between null mutant and wild-type Grf2 mice. These results indicate that grf2 is dispensable for mouse growth, development, and fertility. Furthermore, analysis of double grf1/grf2 null animals did not show any observable phenotypic difference with single grf1 −/− animals, further indicating a lack of functional overlapping between the two otherwise highly homologous Grf1 and Grf2 proteins.

scholarly journals Virus-induced Transient Bone Marrow Aplasia: Major Role of Interferon-α/β during Acute Infection with the Noncytopathic Lymphocytic Choriomeningitis Virus

1997 ◽  
Vol 185 (3) ◽  
pp. 517-530 ◽  
Author(s):  
Daniel Binder ◽  
Jörg Fehr ◽  
Hans Hengartner ◽  
Rolf M. Zinkernagel
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Acute Infection ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Mouse Strains ◽  
Interferon Α ◽  
Wild Type ◽  
Ifn Γ ◽  
Lcmv Infection

The hematologic consequences of infection with the noncytopathic lymphocytic choriomeningitis virus (LCMV) were studied in wild-type mice with inherent variations in their interferon (IFN)-α/β responder ability and in mutant mice lacking α/β (IFN-α/β R0/0) or γ IFN (IFN-γ R0/0) receptors. During the first week of infection, wild type mice demonstrated a transient pancytopenia. Within a given genetic background, the extent of the blood cell abnormalities did not correlate with the virulence of the LCMV isolate but variations were detected between different mouse strains; they were found to depend on their IFN-α/β responder phenotype. Whereas IFN-γ R0/0 mice were comparable to wild-type mice, IFN-α/β R0/0 mice exhibited unchanged peripheral blood values during acute LCMV infection. In parallel, the bone marrow (BM) cellularity, the pluripotential and committed progenitor compartments were up to 30-fold reduced in wild type and IFN-γ R0/0, but remained unchanged in IFN-α/β R0/0 mice. Viral titers in BM 3 d after LCMV infection were similar in these mice, but antigen localization was different. Viral antigen was predominantly confined to stromal BM in normal mice and IFN-γ R0/0 knockouts, whereas, in IFN-α/β R0/0 mice, LCMV was detected in &gt;90% of megakaryocytes and 10–15% of myeloid precursors, but not in erythroblasts. Although IFN-α/β efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-α/β R0/0 mice did not interfere with the number of circulating blood cells. Natural killer (NK) cell expansion and activity in the BM was comparable on day 3 after infection in mutant and control mice. Adaptive immune responses did not play a major role because comparable kinetics of LCMV-induced pancytopenia and transient depletion of the pluripotential and committed progenitor compartments were observed in CD80/0 and CD40/0 mice, in mice depleted of NK cells, in lpr mice, and in perforin-deficient (P0/0) mice lacking lytic NK cells. Thus, the reversible depression of hematopoiesis during early LCMV infection was not mediated by LCMV-WE–specific cytotoxic T lymphocyte, cytolysis, or secreted IFN-γ from virally induced NK cells but was a direct effect of IFN-α/β.

scholarly journals Characterization of the untranslated region of lymphocytic choriomeningitis virus S segment

2019 ◽  
Author(s):  
Satoshi Taniguchi ◽  
Tomoki Yoshikawa ◽  
Masayuki Shimojima ◽  
Shuetsu Fukushi ◽  
Takeshi Kurosu ◽  
...  
Keyword(s):  
Viral Genome ◽  
Lethal Dose ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Untranslated Regions ◽  
Genome Replication ◽  
Wild Type ◽  
Viral Genome Replication

ABSTRACTLymphocytic choriomeningitis virus (LCMV) is a prototypic arenavirus. The viral genome consists of two RNA segments, L and S. The 5’- and 3’-termini of both L and S segments are highly conserved among arenaviruses. These regions consist of 19 complementary base pairs and are essential for viral genome replication and transcription. In addition to these 19 nucleotides in the 5’- and 3’-termini, there are untranslated regions (UTRs) composed of 58 and 41 nucleotide residues in the 5’ and 3’ UTRs, respectively, in the LCMV S segment. Their functional roles, however, have yet to be elucidated. In this study, a reverse genetics and a minigenome system for the LCMV strain WE were established and used to analyze the function of these regions. The results obtained from these analyses, plus RNA secondary structure prediction, revealed that not only these 19 nucleotides but also the 20th–40th and 20th–38th nucleotides located downstream of the 19 nucleotides in the 5’- and 3’-termini, respectively, are heavily involved in viral genome replication and transcription. Furthermore, the introduction of mutations in these regions depressed viral propagation in vitro and enhanced attenuation in vivo. Conversely, recombinant LCMVs (rLCMVs), which had various deletions in the other UTRs, propagated as well as wild-type LCMV in vitro but were attenuated in vivo. Most mice previously infected with rLCMVs with mutated UTRs, when further infected with a lethal dose of wild-type LCMV, survived. These results suggest that rLCMVs with mutated UTRs could be candidates for an LCMV vaccine.IMPORTANCEThe function of untranslated regions (UTRs) of the arenavirus genome has not well been studied except for the 19 nucleotides of the 5’- and 3’-termini. In this study the function of the UTRs of the LCMV S segment was analyzed. It was found that not only the 19 nucleotides of the 5’- and 3’-termini but also the 20th–40th and 20th–38th nucleotides located downstream of the 19 nucleotides in the 5’- and 3’-termini, respectively, were involved in viral genome replication and transcription. Furthermore, other UTRs in the S segment were involved in virulence in vivo. The introduction of mutations to these regions makes it possible to establish attenuated LCMV and potentially develop LCMV vaccine candidates.

scholarly journals Neuronal Ablation of Alpha/Beta Interferon (IFN-α/β) Signaling Exacerbates Central Nervous System Viral Dissemination and Impairs IFN-γ Responsiveness in Microglia/Macrophages

2020 ◽  
Vol 94 (20) ◽  
Author(s):  
Mihyun Hwang ◽  
Cornelia C. Bergmann
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Mrna Levels ◽  
Virus Spread ◽  
Beta Interferon ◽  
Ifn Γ ◽  
Alpha Beta ◽  
Β Receptor

ABSTRACT Alpha/beta interferon (IFN-α/β) signaling through the IFN-α/β receptor (IFNAR) is essential to limit virus dissemination throughout the central nervous system (CNS) following many neurotropic virus infections. However, the distinct expression patterns of factors associated with the IFN-α/β pathway in different CNS resident cell populations implicate complex cooperative pathways in IFN-α/β induction and responsiveness. Here we show that mice devoid of IFNAR1 signaling in calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) expressing neurons (CaMKIIcre:IFNARfl/fl mice) infected with a mildly pathogenic neurotropic coronavirus (mouse hepatitis virus A59 strain [MHV-A59]) developed severe encephalomyelitis with hind-limb paralysis and succumbed within 7 days. Increased virus spread in CaMKIIcre:IFNARfl/fl mice compared to IFNARfl/fl mice affected neurons not only in the forebrain but also in the mid-hind brain and spinal cords but excluded the cerebellum. Infection was also increased in glia. The lack of viral control in CaMKIIcre:IFNARfl/fl relative to control mice coincided with sustained Cxcl1 and Ccl2 mRNAs but a decrease in mRNA levels of IFNα/β pathway genes as well as Il6, Tnf, and Il1β between days 4 and 6 postinfection (p.i.). T cell accumulation and IFN-γ production, an essential component of virus control, were not altered. However, IFN-γ responsiveness was impaired in microglia/macrophages irrespective of similar pSTAT1 nuclear translocation as in infected controls. The results reveal how perturbation of IFN-α/β signaling in neurons can worsen disease course and disrupt complex interactions between the IFN-α/β and IFN-γ pathways in achieving optimal antiviral responses. IMPORTANCE IFN-α/β induction limits CNS viral spread by establishing an antiviral state, but also promotes blood brain barrier integrity, adaptive immunity, and activation of microglia/macrophages. However, the extent to which glial or neuronal signaling contributes to these diverse IFN-α/β functions is poorly understood. Using a neurotropic mouse hepatitis virus encephalomyelitis model, this study demonstrated an essential role of IFN-α/β receptor 1 (IFNAR1) specifically in neurons to control virus spread, regulate IFN-γ signaling, and prevent acute mortality. The results support the notion that effective neuronal IFNAR1 signaling compensates for their low basal expression of genes in the IFN-α/β pathway compared to glia. The data further highlight the importance of tightly regulated communication between the IFN-α/β and IFN-γ signaling pathways to optimize antiviral IFN-γ activity.

scholarly journals Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation

Blood ◽  
2020 ◽  
Vol 136 (19) ◽  
pp. 2162-2174 ◽  
Author(s):  
Paul Tsoukas ◽  
Emily Rapp ◽  
Lauren Van Der Kraak ◽  
Eric S. Weiss ◽  
Vinh Dang ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Inflammatory Responses ◽  
Interferon Γ ◽  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Interleukin 18 ◽  
Promising Therapeutic Target ◽  
Life Threatening ◽  
Cd8 Depletion ◽  
Lcmv Infection

Abstract Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes typically associated with underlying hematologic and rheumatic diseases, respectively. Familial HLH is associated with genetic cytotoxic impairment and thereby to excessive antigen presentation. Extreme elevation of serum interleukin-18 (IL-18) has been observed specifically in patients with MAS, making it a promising therapeutic target, but how IL-18 promotes hyperinflammation remains unknown. In an adjuvant-induced MAS model, excess IL-18 promoted immunopathology, whereas perforin deficiency had no effect. To determine the effects of excess IL-18 on virus-induced immunopathology, we infected Il18-transgenic (Il18tg) mice with lymphocytic choriomeningitis virus (LCMV; strain Armstrong). LCMV infection is self-limited in wild-type mice, but Prf1−/− mice develop prolonged viremia and fatal HLH. LCMV-infected Il18-transgenic (Il18tg) mice developed cachexia and hyperinflammation comparable to Prf1−/− mice, albeit with minimal mortality. Like Prf1−/− mice, immunopathology was largely rescued by CD8 depletion or interferon-γ (IFNg) blockade. Unlike Prf1−/− mice, they showed normal target cell killing and normal clearance of viral RNA and antigens. Rather than impairing cytotoxicity, excess IL-18 acted on T lymphocytes to amplify their inflammatory responses. Surprisingly, combined perforin deficiency and transgenic IL-18 production caused spontaneous hyperinflammation specifically characterized by CD8 T-cell expansion and improved by IFNg blockade. Even Il18tg;Prf1-haplosufficient mice demonstrated hyperinflammatory features. Thus, excess IL-18 promotes hyperinflammation via an autoinflammatory mechanism distinct from, and synergistic with, cytotoxic impairment. These data establish IL-18 as a potent, independent, and modifiable driver of life-threatening innate and adaptive hyperinflammation and support the rationale for an IL-18–driven subclass of hyperinflammation.

Sto1p, a fission yeast protein similar to tubulin folding cofactor E, plays an essential role in mitotic microtubule assembly

1999 ◽  
Vol 112 (12) ◽  
pp. 1979-1988 ◽  
Author(s):  
E.L. Grishchuk ◽  
J.R. McIntosh
Keyword(s):  
Fission Yeast ◽  
Microtubule Assembly ◽  
Wild Type ◽  
Beta Tubulin ◽  
Alpha Tubulin ◽  
Cold Sensitive ◽  
Alpha Beta ◽  
Sensitive Allele ◽  
Delta Cells

The proper functioning of microtubules depends crucially on the availability of polymerizable alpha/beta tubulin dimers. Their production occurs concomitant with the folding of the tubulin polypeptides and is accomplished in part by proteins known as Cofactors A through E. In the fission yeast, Schizosaccharomyces pombe, this tubulin folding pathway is essential. We have taken advantage of the excellent cytology available in S. pombe to examine the phenotypic consequences of a deletion of sto1(+), a gene that encodes a protein similar to Cofactor E, which is required for the folding of alpha-tubulin. The interphase microtubule cytoskeleton in sto1-delta cells is severely disrupted, and as cells enter mitosis their spindles fail to form. After a transient arrest with condensed chromosomes, the cells exit mitosis and resume DNA synthesis, whereupon they septate abnormally and die. Overexpression of Spo1p is toxic to cells carrying a cold-sensitive allele of the alpha- but not the beta-tubulin gene, consistent with the suggestion that this protein plays a role like that of Cofactor E. Unlike its presumptive partner Cofactor D (Alp1p), however, Sto1p does not localize to microtubules but is found throughout the cell. Overexpression of Sto1p has no toxic effects in wild-type cells, suggesting that it is unable to disrupt alpha/beta tubulin dimers in vivo.

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