Cytokine-Mediated Tissue Injury in Non-human Primate Models of Viral Infections

AbstractMonoclonal antibodies (mAbs) and remdesivir, a small-molecule antiviral, are promising monotherapies for many viruses, including members of the genera Marburgvirus and Ebolavirus (family Filoviridae), and more recently, SARS-CoV-2. One of the major challenges of acute viral infections is the treatment of advanced disease. Thus, extending the window of therapeutic intervention is critical. Here, we explore the benefit of combination therapy with a mAb and remdesivir in a non-human primate model of Marburg virus (MARV) disease. While rhesus monkeys are protected against lethal infection when treatment with either a human mAb (MR186-YTE; 100%), or remdesivir (80%), is initiated 5 days post-inoculation (dpi) with MARV, no animals survive when either treatment is initiated alone beginning 6 dpi. However, by combining MR186-YTE with remdesivir beginning 6 dpi, significant protection (80%) is achieved, thereby extending the therapeutic window. These results suggest value in exploring combination therapy in patients presenting with advanced filovirus disease.

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The activation of bystander CD8+ T cells and their roles in viral infection

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0316-1 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Tae-Shin Kim ◽

Eui-Cheol Shin

Keyword(s):

T Cells ◽

Viral Infections ◽

Hepatitis A Virus ◽

Tissue Injury ◽

Strong Association ◽

Killer Cell ◽

Type I Interferons ◽

Type I ◽

Dependent Manner ◽

Bystander Activation

AbstractDuring viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as “bystander activation.” Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.

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Animal models for viral diseases: Non-human primate and humanized mouse models for viral infections

Current Opinion in Virology ◽

10.1016/j.coviro.2017.09.001 ◽

2017 ◽

Vol 25 ◽

pp. v-vii

Author(s):

James P Di Santo ◽

Cristian Apetrei

Keyword(s):

Animal Models ◽

Mouse Models ◽

Viral Infections ◽

Viral Diseases ◽

Humanized Mouse ◽

Humanized Mouse Models ◽

Human Primate

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Congenital Cytomegalovirus Infection: A Cause of Renal Dysplasia?

Pediatric and Developmental Pathology ◽

10.2350/06-06-0099.1 ◽

2007 ◽

Vol 10 (4) ◽

pp. 300-304 ◽

Cited By ~ 5

Author(s):

Maren Chan ◽

Jonathan L. Hecht ◽

Theonia Boyd ◽

Seymour Rosen

Keyword(s):

Viral Infections ◽

Tissue Injury ◽

Clinical Manifestations ◽

Renal Dysplasia ◽

Cmv Infection ◽

Congenital Cytomegalovirus Infection ◽

Congenital Cytomegalovirus ◽

Wide Range ◽

The Central Nervous System ◽

Multicystic Dysplasia

Cytomegalovirus (CMV) infection is one of the most frequently encountered viral infections of the fetus and induces a wide range of histologic and clinical manifestations. Congenital abnormalities are typically restricted to the central nervous system despite evidence of CMV inclusions occurring in most epithelial cells. Although tissue injury and even glomerulonephritis have been observed in congenital CMV infections, renal multicystic dysplasia has not been reported. Herein, we describe a case of unilateral renal dysplasia in a 19-week fetus with concurrent CMV infection. We believe the present case to be the first description of a virus apparently inducing renal multicystic dysplasia.

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Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure

Cell Death and Disease ◽

10.1038/s41419-019-2115-y ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 1

Author(s):

Miriam Bittel ◽

Andreas E. Kremer ◽

Michael Stürzl ◽

Stefan Wirtz ◽

Iris Stolzer ◽

...

Keyword(s):

Cell Death ◽

Viral Infections ◽

Tissue Injury ◽

Multiple Organ ◽

Severe Liver ◽

Transgenic Expression ◽

Effector Caspase ◽

The Impact

AbstractDuring viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi’s sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.

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Human metapneumovirus - what we know now

F1000Research ◽

10.12688/f1000research.12625.1 ◽

2018 ◽

Vol 7 ◽

pp. 135 ◽

Cited By ~ 20

Author(s):

Nazly Shafagati ◽

John Williams

Keyword(s):

Viral Infections ◽

Clinical Manifestations ◽

Adult Life ◽

Small Animal ◽

The Elderly ◽

Human Metapneumovirus ◽

Subtype C ◽

Polymerase Chain ◽

Human Primate ◽

Made In

Human metapneumovirus (HMPV) is a leading cause of acute respiratory infection, particularly in children, immunocompromised patients, and the elderly. HMPV, which is closely related to avian metapneumovirus subtype C, has circulated for at least 65 years, and nearly every child will be infected with HMPV by the age of 5. However, immunity is incomplete, and re-infections occur throughout adult life. Symptoms are similar to those of other respiratory viral infections, ranging from mild (cough, rhinorrhea, and fever) to more severe (bronchiolitis and pneumonia). The preferred method for diagnosis is reverse transcription-polymerase chain reaction as HMPV is difficult to culture. Although there have been many advances made in the past 16 years since its discovery, there are still no US Food and Drug Administration-approved antivirals or vaccines available to treat HMPV. Both small animal and non-human primate models have been established for the study of HMPV. This review will focus on the epidemiology, transmission, and clinical manifestations in humans as well as the animal models of HMPV pathogenesis and host immune response.

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Interleukin-22 (IL-22) Production by Pulmonary Natural Killer Cells and the Potential Role of IL-22 during Primary Influenza Virus Infection

Journal of Virology ◽

10.1128/jvi.00187-10 ◽

2010 ◽

Vol 84 (15) ◽

pp. 7750-7759 ◽

Cited By ~ 71

Author(s):

Hailong Guo ◽

David J. Topham

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Nk Cells ◽

Viral Infections ◽

Tissue Injury ◽

Influenza Virus Infection ◽

Interleukin 22 ◽

Virus Clearance ◽

Ifn Γ

ABSTRACT We set out to test the hypothesis that interleukin-22 (IL-22), a cytokine crucial for epithelial cell homeostasis and recovery from tissue injury, would be protective during influenza virus infection. Recent studies have identified phenotypically and functionally unique intestinal NK cells capable of producing the cytokine IL-22. Unlike gut NK cells that produce IL-22, the surface phenotypes of lung NK cells were similar to those of spleen NK cells and were characteristically mature. With mitogen stimulation, both single and double IL-22- and gamma interferon (IFN-γ)-producing lung NK cells were detected. However, only the IL-22+ IFN-γ− lung NK subset was observed after stimulation with IL-23. IL-23 receptor (IL-23R) blocking dramatically inhibited IL-22 production, but not IFN-γ production. Furthermore, we found that NK1.1+ or CD27− lung NK cells were the primary sources of IL-22. After influenza virus infection, lung NK cells were quickly activated to produce both IFN-γ and IL-22 and had increased cytotoxic potential. The level of IL-22 in the lung tissue declined shortly after infection, gradually returning to the baseline after virus clearance, although the IL-22 gene expression was maintained. Furthermore, depletion of NK cells with or without influenza virus infection reduced the protein level of IL-22 in the lung. Anti-IL-22 neutralization in vivo did not dramatically affect weight loss and survival after virus clearance. Unexpectedly, anti-IL-22-treated mice had reduced virus titers. Our data suggest that during primary respiratory viral infection, IL-22 seems to a play a marginal role for protection, indicating a differential requirement of this cytokine for bacterial and viral infections.

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Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22031301 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1301

Author(s):

Ioannis Kienes ◽

Tanja Weidl ◽

Nora Mirza ◽

Mathias Chamaillard ◽

Thomas A. Kufer

Keyword(s):

Viral Infections ◽

Type I Interferon ◽

Tissue Injury ◽

Interferon Response ◽

Type I ◽

Interferon Signaling ◽

Microbial Products ◽

Interferon Responses

Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.

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Idiopathic chronic diarrhea in rhesus macaques is not associated with enteric viral infections

10.1101/2021.07.01.450785 ◽

2021 ◽

Author(s):

Eric Delwart ◽

Michael J Tisza ◽

Eda Altan ◽

Yanpeng Li ◽

Xutao Deng ◽

...

Keyword(s):

Rhesus Macaque ◽

Viral Infections ◽

Chronic Diarrhea ◽

Rhesus Macaques ◽

Viral Metagenomics ◽

Primate Research ◽

Healthy Controls ◽

Viral Loads ◽

Common Causes ◽

Human Primate

While recent changes in treatment have reduced the lethality of idiopathic chronic diarrhea (ICD), this condition remains one of the most common causes of rhesus macaque deaths in non-human primate research centers. We compared the eukaryotic viromes in fecal swabs from 52 animals with ICD and 41 healthy animals. Viral metagenomics targeting virus-like particles was used to identify viruses shed by each animal. Five viruses belonging to the Picornaviridae, one to the Caliciviridae, one to the Parvoviridae, and one to the Adenoviridae families were identified. The fraction of reads matching each viral species was then used to estimate and compare viral loads in ICD cases versus healthy controls. None of the eukaryotic viruses detected in fecal swabs were strongly associated with ICD. Other potential causes of ICD are discussed.

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Increased Neutrophil-Subset Associated With Severity/Mortality In ARDS And COVID19-ARDS Expresses The Dual Endothelin-1/VEGFsignal-Peptide Receptor (DEspR): An Actionable Therapeutic Target

10.21203/rs.3.rs-846250/v1 ◽

2021 ◽

Author(s):

Victoria L. M. Herrera ◽

Allan J. Walkey ◽

Mai Q. Nguyen ◽

Christopher M. Gromisch ◽

Julie Z. Mosaddhegi ◽

...

Keyword(s):

Tissue Injury ◽

Ex Vivo ◽

Neutrophil Function ◽

Therapeutic Approaches ◽

Apoptosis Resistance ◽

Peptide Receptor ◽

Endothelin 1 ◽

Activated Neutrophils ◽

Secondary Tissue ◽

Human Primate

Abstract Neutrophil-mediated secondary tissue injury underlies acute respiratory distress syndrome (ARDS) and progression to multi-organ-failure (MOF) and death, processes linked to severe COVID19. This ‘innocent bystander’ tissue injury arises in dysregulated hyperinflammatory states from neutrophil functions and neutrophil extracellular traps (NETs) intended to kill pathogens, but injure cells instead, causing MOF. Insufficiency of prior therapeutic approaches suggest need to identify dysregulated neutrophil-subset(s) and induce subset-specific apoptosis critical for neutrophil function-shutdown and clearance. We hypothesized that neutrophils expressing the pro-survival dual endothelin-1/signal peptide receptor, DEspR, are apoptosis-resistant just like DEspR+ cancer cells, hence comprise a consequential pathogenic neutrophil-subset in ARDS and COVID19-ARDS. Here, we report correlation of circulating DEspR+CD11b+ activated neutrophils (DESpR+actNs) and NETosing-neutrophils with severity in ARDS and in COVID19-ARDS, increased DEspR+ neutrophils and monocytes in post-mortem ARDS-patient lung sections, and neutrophil DEspR/ET1 receptor/ligand autocrine loops in severe COVID19. Unlike DEspR[-] neutrophils, ARDS patient DEspR+actNs exhibit apoptosis-resistance, which decreased upon ex vivo treatment with humanized anti-DEspR-IgG4S228P antibody, hu6g8. Ex vivo live-cell imaging of non-human primate DEspR+actNs showed hu6g8 target-engagement, internalization, and induction of apoptosis. Altogether, data differentiate DEspR+actNs as a targetable neutrophil-subset associated with ARDS and COVID19-ARDS severity, and suggest DEspR-inhibition as a potential therapeutic paradigm. 1-sentence summary: Circulating DEspR+CD11b+ neutrophils and NETosing neutrophils are associated with severity and mortality in ARDS and COVID19-ARDS.

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