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-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.

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 Noncytopathic Clearance of Lymphocytic Choriomeningitis Virus from the Hepatocyte

1999 ◽  
Vol 189 (10) ◽  
pp. 1555-1564 ◽  
Author(s):  
Luca G. Guidotti ◽  
Persephone Borrow ◽  
Amy Brown ◽  
Heike McClary ◽  
Rick Koch ◽  
...  
Keyword(s):  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Tubular Epithelial Cells ◽  
Nonparenchymal Cells ◽  
Hbv Replication ◽  
B Virus ◽  
The Face ◽  
Lcmv Infection ◽  
Necrosis Factor

We have previously shown that interferon and tumor necrosis factor noncytopathically abolish hepatitis B virus (HBV) replication from the hepatocyte and kidney tubular epithelial cells in vivo. Here we show that a persistent lymphocytic choriomeningitis virus (LCMV) infection is cleared from the hepatocyte noncytopathically when the same cytokines are induced in the liver by antigen-nonspecific stimuli. These results indicate that, like HBV, LCMV is also susceptible to intracellular inactivation by cytokine-induced antiviral mechanisms that are operative in the hepatocyte. In contrast, LCMV is not cleared from intrahepatic nonparenchymal cells or splenocytes, indicating that, unlike the hepatocyte, these cells do not produce the factors required to inactivate LCMV. Antiviral mechanisms like these may have evolved to maintain the functional integrity of vital organs in the face of massive infection.

scholarly journals HLA-A2-Restricted Protection against Lethal Lymphocytic Choriomeningitis

2006 ◽  
Vol 81 (5) ◽  
pp. 2307-2317 ◽  
Author(s):  
Jason Botten ◽  
J. Lindsay Whitton ◽  
Polly Barrowman ◽  
John Sidney ◽  
Jason K. Whitmire ◽  
...  
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Lymphocytic Choriomeningitis ◽  
Target Cells ◽  
Primary Role ◽  
Protein Z ◽  
Glycoprotein Precursor ◽  
Antigen Presenting ◽  
Lcmv Infection

ABSTRACT The consequences of human lymphocytic choriomeningitis virus (LCMV) infection can be severe, including aseptic meningitis in immunocompetent individuals, hydrocephalus or chorioretinitis in fetal infection, or a highly lethal outcome in immunosuppressed individuals. In murine models of LCMV infection, CD8+ T cells play a primary role in providing protective immunity, and there is evidence that cellular immunity may also be important in related arenavirus infections in humans. For this reason, we sought to identify HLA-A2 supertype-restricted epitopes from the LCMV proteome and evaluate them as vaccine determinants in HLA transgenic mice. We identified four HLA-A*0201-restricted peptides—nucleoprotein NP69-77, glycoprotein precursor GPC10-18, GPC447-455, and zinc-binding protein Z49-58—that displayed high-affinity binding (≤275 nM) to HLA-A*0201, induced CD8+ T-cell responses of high functional avidity in HLA-A*0201 transgenic mice, and were naturally processed from native LCMV antigens in HLA-restricted human antigen presenting cells. One of the epitopes (GPC447-455), after peptide immunization of HLA-A*0201 mice, induced CD8+ T cells capable of killing peptide-pulsed HLA-A*0201-restricted target cells in vivo and protected mice against lethal intracranial challenge with LCMV.

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 In vivo expression of perforin by CD8+ lymphocytes during an acute viral infection.

1989 ◽  
Vol 169 (6) ◽  
pp. 2159-2171 ◽  
Author(s):  
L H Young ◽  
L S Klavinskis ◽  
M B Oldstone ◽  
J D Young
Keyword(s):  
Nk Cells ◽  
Lymphocytic Choriomeningitis ◽  
Acute Stage ◽  
Acute Viral Infection ◽  
First Time ◽  
Cryostat Sections ◽  
Lcmv Infection ◽  
Asialo Gm1

CTL and NK cells cultured in vitro have been shown to contain a cytolytic pore-forming protein (PFP/perforin/cytolysin). To date, it has not been determined whether perforin is expressed by CTL that have been primed in vivo. Here, we have infected mice with two strains of lymphocytic choriomeningitis virus (LCMV), one of which mainly produces choriomeningitis and, the other, hepatitis. Brain and liver cryostat sections obtained from LCMV-infected mice were stained for various lymphocyte markers, including perforin. We were able to detect a large accumulation of perforin antigen in CD8+/Thy-1+/asialo GM1+/CD4- lymphocytes, which in fact represent the main infiltrating cell type found in brain and liver sections obtained during the late acute stage of LCMV infection. Perforin was also detected in a smaller population of CD8-/asialo GM1+/NK 1.1+/F480- cells, presumably corresponding to NK cells. Perforin-positive cells were found to have the morphology of blasts or large granular lymphocytes (LGL). These observations, together with in vitro studies performed in the past, indicate that perforin may be associated exclusively with LGL-like CTL blasts and NK cells. Our results demonstrate for the first time the presence of perforin in CTL that have been primed in vivo and suggest that perforin-positive CTL may be directly involved in producing the immunopathology associated with the LCMV infection.

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

2020 ◽  
Vol 20 ◽  
Author(s):  
Trinath Chowdhury ◽  
Gourisankar Roymahapatra ◽  
Santi M. Mandal
Keyword(s):  
Rna Polymerase ◽  
Viral Entry ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
Replication Complex ◽  
In Silico Study ◽  
Life Threatening ◽  
In Vivo Analysis ◽  
3Cl Protease

Background: COVID-19 is a life threatening novel corona viral infection to our civilization and spreading rapidly. Terrific efforts are generous by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/mol) revealed most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also perform the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast invitro to in-vivo analysis towards development of therapeutics against SARS-CoV-2.

scholarly journals Macrophage Activation Syndrome in Adults: A Retrospective Case Series

2021 ◽  
Vol 9 ◽  
pp. 232470962110264
Author(s):  
Taylor Warmoth ◽  
Malvika Ramesh ◽  
Kenneth Iwuji ◽  
John S. Pixley
Keyword(s):  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Pediatric Patients ◽  
Inflammatory Diseases ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Case Series ◽  
Adult Patients ◽  
Retrospective Case ◽  
Life Threatening ◽  
Activation Syndrome

Macrophage activation syndrome (MAS) is a form of hemophagocytic lymphohistocytosis that occurs in patients with a variety of inflammatory rheumatologic conditions. Traditionally, it is noted in pediatric patients with systemic juvenile idiopathic arthritis and systemic lupus erythematous. It is a rapidly progressive and life-threatening syndrome of excess immune activation with an estimated mortality rate of 40% in children. It has become clear recently that MAS occurs in adult patients with underlying rheumatic inflammatory diseases. In this article, we describe 6 adult patients with likely underlying MAS. This case series will outline factors related to diagnosis, pathophysiology, and review present therapeutic strategies.

scholarly journals Death of unknown cause? Post-mortem diagnosis of fulminant course of an EBV-associated secondary hemophagocytic lymphohistiocytosis

2021 ◽  
Author(s):  
Josia Fauser ◽  
Stefan Köck ◽  
Eberhard Gunsilius ◽  
Andreas Chott ◽  
Andreas Peer ◽  
...  
Keyword(s):  
Immune Response ◽  
Case Report ◽  
Macrophage Activation ◽  
Post Mortem ◽  
Life Threatening ◽  
Appropriate Therapy ◽  
Diagnostic Work ◽  
Work Up ◽  
Diagnostic Work Up ◽  
Secondary Hemophagocytic Lymphohistiocytosis

SummaryHLH is a life-threatening disease, which is characterized by a dysregulated immune response with uncontrolled T cell and macrophage activation. The often fulminant course of the disease needs a fast diagnostic work-up to initiate as soon as possible the appropriate therapy. We present herein the case of a 71-year-old patient with rapidly progressive hyperinflammatory syndrome, which post mortem resulted in the diagnosis of EBV-associated HLH. With this case report, we intend to highlight the relevance of the HScore in the diagnosis of HLH, to create a greater awareness for EBV as a trigger of HLH, and to demonstrate the importance of treating EBV-associated HLH as early as possible.

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