Faculty Opinions recommendation of Host-specific response to HCV infection in the chimeric SCID-beige/Alb-uPA mouse model: role of the innate antiviral immune response.

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), is a reversible molecular process to remove Ub or Ub chains from the target proteins. Deubiquitination is an integral strategy within the UPS in regulating survival and proliferation of the infecting virus and the virus-invaded cells. Many viruses in the infected cells are reported to encode viral DUB, and these vial DUBs actively disrupt cellular Ub-dependent processes to suppress host antiviral immune response, enhancing virus replication and thus proliferation. This review surveys the types of DUBs encoded by different viruses and their molecular processes for how the infecting viruses take advantage of the DUB system to evade the host immune response and expedite their replication.

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Dual Role of Toll-Like Receptor 7 in the Pathogenesis of Rabies Virus in a Mouse Model

Journal of Virology ◽

10.1128/jvi.00111-20 ◽

2020 ◽

Vol 94 (9) ◽

Author(s):

Zhaochen Luo ◽

Lei Lv ◽

Yingying Li ◽

Baokun Sui ◽

Qiong Wu ◽

...

Keyword(s):

Immune Response ◽

Mouse Model ◽

Immune Responses ◽

Rabies Virus ◽

Mouse Brain ◽

Early Stage ◽

Toll Like Receptor ◽

Innate Recognition ◽

Recognition Receptor

ABSTRACT Rabies, caused by rabies virus (RABV), is a fatal encephalitis in humans and other mammals, which continues to present a public health threat in most parts of the world. Our previous study demonstrated that Toll-like receptor 7 (TLR7) is essential in the induction of anti-RABV antibodies via the facilitation of germinal center formation. In the present study, we investigated the role of TLR7 in the pathogenicity of RABV in a mouse model. Using isolated plasmacytoid dendritic cells (pDCs), we demonstrated that TLR7 is an innate recognition receptor for RABV. When RABV invaded from the periphery, TLR7 detected viral single-stranded RNA and triggered immune responses that limited the virus’s entry into the central nervous system (CNS). When RABV had invaded the CNS, its detection by TLR7 led to the production of cytokines and chemokines and an increase the permeability of the blood-brain barrier. Consequently, peripheral immune cells, including pDCs, macrophages, neutrophils, and B cells infiltrated the CNS. While this immune response, triggered by TLR7, helped to clear viruses, it also increased neuroinflammation and caused immunopathology in the mouse brain. Our results demonstrate that TLR7 is an innate recognition receptor for RABV, which restricts RABV invasion into the CNS in the early stage of viral infection but also contributes to immunopathology by inducing neuroinflammation. IMPORTANCE Developing targeted treatment for RABV requires understanding the innate immune response to the virus because early virus clearance is essential for preventing the fatality when the infection has progressed to the CNS. Previous studies have revealed that TLR7 is involved in the immune response to RABV. Here, we establish that TLR7 recognizes RABV and facilitates the production of some interferon-stimulated genes. We also demonstrated that when RABV invades into the CNS, TLR7 enhances the production of inflammatory cytokines which contribute to immunopathology in the mouse brain. Taken together, our findings suggest that treatments for RABV must consider the balance between the beneficial and harmful effects of TLR7-triggered immune responses.

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Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease

Glia ◽

10.1002/glia.22935 ◽

2015 ◽

Vol 64 (3) ◽

pp. 386-395 ◽

Cited By ~ 26

Author(s):

Heather L. Martin ◽

Matteo Santoro ◽

Sarah Mustafa ◽

Gernot Riedel ◽

John V. Forrester ◽

...

Keyword(s):

Parkinson’S Disease ◽

Immune Response ◽

Parkinson's Disease ◽

Mouse Model ◽

Adaptive Immune Response ◽

Disease Pathogenesis ◽

Adaptive Immune

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Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle?

Virology Research and Treatment ◽

10.4137/vrt.s11046 ◽

2013 ◽

Vol 4 ◽

pp. VRT.S11046 ◽

Cited By ~ 1

Author(s):

Mohit Sehgal ◽

Zafar K. Khan ◽

Andrew H. Talal ◽

Pooja Jain

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Immunological Synapse ◽

Hcv Infection ◽

Dc Functions ◽

Antiviral Immune Response ◽

Persistent Infections ◽

Viral Therapy ◽

Host Genetic ◽

Hiv 1

Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them. Modulation of the immunological synapse between DC and T-cell, as well as dysregulation of the crosstalk between DCs and natural killer (NK) cells, are emerging as two crucial mechanisms. This review focuses on understanding the interaction of HIV-1 and HCV with DCs not only to understand the immunopathogenesis of chronic HIV-1 and HCV infection, but also to explore the possibilities of DC-based immunotherapeutic approaches against them. Host genetic makeup is known to play major roles in infection outcome and rate of disease progression, as well as response to anti-viral therapy in both HIV-1 and HCV-infected individuals. Therefore, we highlight the genetic variations that can potentially affect DC functions, especially in the setting of chronic viral infection. Altogether, we address if DCs’ potential as critical effectors of antiviral immune response could indeed be utilized to combat chronic infection with HIV-1 and HCV.

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Antiviral and Immunoregulatory Effects of Indoleamine-2,3-Dioxygenase in Hepatitis C Virus Infection

Journal of Innate Immunity ◽

10.1159/000375161 ◽

2015 ◽

Vol 7 (5) ◽

pp. 530-544 ◽

Cited By ~ 21

Author(s):

Quentin Lepiller ◽

Eric Soulier ◽

Qisheng Li ◽

Mélanie Lambotin ◽

Jochen Barths ◽

...

Keyword(s):

Immune Response ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Inhibitory Effect ◽

Hcv Infection ◽

Antiviral Immune Response ◽

Host Immune Responses ◽

Indoleamine 2,3 Dioxygenase ◽

Important Regulator ◽

Innate Defence

In patients with hepatitis C virus (HCV) infection, enhanced activity of indoleamine-2,3-dioxygenase 1 (IDO) has been reported. IDO - a tryptophan-catabolizing enzyme - has been considered as both an innate defence mechanism and an important regulator of the immune response. The molecular mechanism of IDO induction in HCV infection and its role in the antiviral immune response remain unknown. Using primary human hepatocytes, we show that HCV infection stimulates IDO expression. IDO gene induction was transient and coincided with the expression of types I and III interferons (IFNs) and IFN-stimulated genes in HCV-infected hepatocytes. Overexpression of hepatic IDO prior to HCV infection markedly impaired HCV replication in hepatocytes, suggesting that IDO limits the spread of HCV within the liver. siRNA-mediated IDO knock-down revealed that IDO functions as an IFN-mediated anti-HCV effector. Hepatic IDO was most potently induced by IFN-γ, and ongoing HCV replication could significantly upregulate IDO expression. IRF1 (IFN-regulatory factor 1) and STAT1 (signal transducer and activator of transcription 1) regulated hepatic IDO expression. Hepatic IDO expression also had a significant inhibitory effect on CD4+ T-cell proliferation. Our data suggest that hepatic IDO plays a dual role during HCV infection by slowing down viral replication and also regulating host immune responses.

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CD1d-dependent Activation of NKT Cells Aggravates Atherosclerosis

Journal of Experimental Medicine ◽

10.1084/jem.20030997 ◽

2004 ◽

Vol 199 (3) ◽

pp. 417-422 ◽

Cited By ~ 239

Author(s):

Emmanuel Tupin ◽

Antonino Nicoletti ◽

Rima Elhage ◽

Mats Rudling ◽

Hans-Gustaf Ljunggren ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Mouse Model ◽

Natural Killer ◽

Nkt Cells ◽

Lesion Size ◽

T And B Cells ◽

Lipid Antigens ◽

Adaptive And Innate Immunity

Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E–deficient (apoE−/−) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE−/− mice crossed with CD1d−/− (CD1d−/−apoE−/−) mice exhibited a 25% decrease in lesion size compared with apoE−/− mice. Administration of α-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE−/− mice, whereas it did not affect lesion size in apoE−/−CD1d−/− mice. Treatment was accompanied by an early burst of cytokines (IFNγ, MCP-1, TNFα, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNγ and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis.

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Mechanism of IL-10 Protective Effect in Development of Childhood B Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v128.22.4075.4075 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4075-4075

Author(s):

Briana Fitch ◽

Michelle L. Hermiston ◽

Joseph L. Wiemels ◽

Scott C. Kogan

Keyword(s):

Immune Response ◽

Acute Lymphoblastic Leukemia ◽

Mouse Model ◽

B Cell ◽

Knockout Mice ◽

Lymphoblastic Leukemia ◽

Host Immune System ◽

Increased Risk ◽

Cell Acute Lymphoblastic Leukemia

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. While significant progress has been made in the treatment of B-ALL, the factors that influence the development of B-ALL remain poorly understood. Epidemiological studies have established a role of early childhood infections in altering leukemia risk. The focus of these studies has been on documenting the number and timing of infectious exposures; however, the role of host immune response to infections in B-ALL development is largely unknown. Low birth levels of the immunomodulatory cytokine interleukin 10 (IL-10) are associated with a 25 fold increased risk of developing childhood B-ALL. Mechanistically, IL-10 plays a critical role in controlling the neonatal immune response to infections. Together, these findings suggest that IL-10, an important regulator of host immune responsiveness, protects against childhood B-ALL. To establish whether loss of IL-10 has an impact on leukemogenesis, we crossed Il10 knockout mice to the TEL-AML1 (ETVX6-RUNX1I) Ckdn2anull mouse model of childhood B-ALL. ETV6-RUNX1 t(12;21) is the most frequent chromosomal translocation in childhood B-ALLand one-fourth of these leukemias are observed in combination with loss of the Cdkn2a locus. The leukemia incidence in TEL-AML1 Ckdn2anull mice is 60%, therefore this is a robust and clinically relevant mouse model of childhood B-ALL. We used this model to assess the role of IL-10 in leukemogenesis by following Il10 knockout TEL-AML1 Ckdn2anull mice for the development of disease in comparison with control IL-10 expressing TEL-AML1 Ckdn2anull mice. We found that Il10 knockout accelerated leukemogenesis in the presence of TEL-AML1. The cancer free survival of the IL-10 expressing TEL-AML1 Ckdn2anull mice (n=74) was 227 days, whereas the survival of IL-10 knockout mice (n=40) was reduced to 180 days (p<0.0005). These data support a causal role of low levels of IL-10 in the development of B-ALL and raise the possibility of using an IL-10 receptor agonist for leukemia prevention in children with high risk of B-ALL. Thus, IL-10 loss is a defect in the host immune system that accelerates childhood B-ALL development, potentially through modifying immune responses to infections. Studies to understand the mechanism of how low IL-10 levels interact with infections to influence leukemogenesis are underway. Disclosures No relevant conflicts of interest to declare.

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