A Novel Mechanism Underlying the Innate Immune Response Induction upon Viral-Dependent Replication of Host Cell mRNA: A Mistake of +sRNA Viruses' Replicases

As with most viruses, mammalian reovirus can be recognized and attacked by the host-cell interferon response network. Similarly, many viruses have developed resistance mechanisms to counteract the host-cell response at different points of this response. Reflecting the complexity of the interferon signaling pathways as well as the resulting antiviral response, viruses can—and often have—evolved many determinants to interfere with this innate immune response and allow viral replication. In the last few years, it has been evidenced that mammalian reovirus encodes many different determinants that are involved in regulating the induction of the interferon response or in interfering with the action of interferon-stimulated gene products. In this brief review, we present our current understanding of the different reovirus proteins known to be involved, introduce their postulated modes of action, and raise current questions that may lead to further investigations.

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Role of metapneumoviral glycoproteins in the evasion of the host cell innate immune response

Infection Genetics and Evolution ◽

10.1016/j.meegid.2021.105096 ◽

2021 ◽

pp. 105096

Author(s):

Vira Bitko ◽

Sailen Barik

Keyword(s):

Immune Response ◽

Host Cell ◽

Innate Immune Response ◽

Innate Immune

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Vpu-Deficient HIV Strains Stimulate Innate Immune Signaling Responses in Target Cells

Journal of Virology ◽

10.1128/jvi.00424-12 ◽

2012 ◽

Vol 86 (16) ◽

pp. 8499-8506 ◽

Cited By ~ 20

Author(s):

Brian P. Doehle ◽

Kristina Chang ◽

Lamar Fleming ◽

John McNevin ◽

Florian Hladik ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Host Cell ◽

Innate Immune Response ◽

Innate Immune ◽

Target Cells ◽

Major Public Health Problem ◽

Type I ◽

Innate Defense ◽

Hiv 1

Acute virus infection induces a cell-intrinsic innate immune response comprising our first line of immunity to limit virus replication and spread, but viruses have developed strategies to overcome these defenses. HIV-1 is a major public health problem; however, the virus-host interactions that regulate innate immune defenses against HIV-1 are not fully defined. We have recently identified the viral protein Vpu to be a key determinant responsible for HIV-1 targeting and degradation of interferon regulatory factor 3 (IRF3), a central transcription factor driving host cell innate immunity. IRF3 plays a major role in pathogen recognition receptor (PRR) signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Here we interrogate the cellular responses to target cell infection with Vpu-deficient HIV-1 strains. Remarkably, in the absence of Vpu, HIV-1 triggers a potent intracellular innate immune response that suppresses infection. Thus, HIV-1 can be recognized by PRRs within the host cell to trigger an innate immune response, and this response is unmasked only in the absence of Vpu. Vpu modulation of IRF3 therefore prevents virus induction of specific innate defense programs that could otherwise limit infection. These observations show that HIV-1 can indeed be recognized as a pathogen in infected cells and provide a novel and effective platform for defining the native innate immune programs of target cells of HIV-1 infection.

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Whole-Genome Expression Profiling Reveals That Inhibition of Host Innate Immune Response Pathways by Ebola Virus Can Be Reversed by a Single Amino Acid Change in the VP35 Protein

Journal of Virology ◽

10.1128/jvi.00215-08 ◽

2008 ◽

Vol 82 (11) ◽

pp. 5348-5358 ◽

Cited By ~ 76

Author(s):

Amy L. Hartman ◽

Ling Ling ◽

Stuart T. Nichol ◽

Martin L. Hibberd

Keyword(s):

Immune Response ◽

Amino Acid ◽

Host Cell ◽

Innate Immune Response ◽

Ebola Virus ◽

Innate Immune ◽

Single Amino Acid ◽

Cell Responses ◽

Single Amino Acid Change ◽

Whole Genome Expression

ABSTRACT Ebola hemorrhagic fever is a rapidly progressing acute febrile illness characterized by high virus replication, severe immunosuppression, and case fatalities of ca. 80%. Inhibition of phosphorylation of interferon regulatory factor 3 (IRF-3) by the Ebola VP35 protein may block the host innate immune response and play an important role in the severity of disease. We used two precisely defined reverse genetics-generated Ebola viruses to investigate global host cell responses resulting from the inhibition of IRF-3 phosphorylation. The two viruses encoded either wild-type (WT) VP35 protein (recEbo-VP35/WT) or VP35 with an arginine (R)-to-alanine (A) amino acid substitution at position 312 (recEbo-VP35/R312A) within a previously defined IRF-3 inhibitory domain. When sucrose-gradient purified virus was used for infection, host cell whole-genome expression profiling revealed striking differences in human liver cell responses to these viruses differing by a single amino acid. The inhibition of host innate immune responses by WT Ebola virus was so potent that little difference in interferon and antiviral gene expression could be discerned between cells infected with purified WT, inactivated virus, or mock-infected cells. However, infection with recEbo-VP35/R312A virus resulted in a strong innate immune response including increased expression of MDA-5, RIG-I, RANTES, MCP-1, ISG-15, ISG-54, ISG-56, ISG-60, STAT1, IRF-9, OAS, and Mx1. The clear gene expression differences were obscured if unpurified virus stocks were used to initiate infection, presumably due to soluble factors present in virus-infected cell supernatant preparations. Ebola virus VP35 protein clearly plays a pivotal role in the potent inhibition of the host innate immune responses, and the present study indicates that VP35 has a wider effect on host cell responses than previously shown. The ability to eliminate this inhibitory effect with a single amino acid change in VP35 demonstrates the critical role this protein must play in the severe aspects this highly fatal disease.

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Network-based identification and pharmacological targeting of host cell master regulators induced by SARS-CoV-2 infection

10.1101/2021.07.03.451001 ◽

2021 ◽

Author(s):

Pasquale Laise ◽

Megan L Stanifer ◽

Gideon Bosker ◽

Xiaoyun Sun ◽

Sergio Triana ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Viral Replication ◽

Cell Viability ◽

Host Cell ◽

Innate Immune Response ◽

Gene Expression Signature ◽

Innate Immune ◽

Master Regulators ◽

Precise Characterization

Precise characterization and targeting of host cell transcriptional machinery hijacked by SARS-CoV-2 remains challenging. To identify therapeutically targetable mechanisms that are critical for SARS-CoV-2 infection, here we elucidated the Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2. The analysis revealed coordinated inactivation of MR-proteins linked to regulatory programs potentiating efficiency of viral replication (detrimental host MR-signature) and activation of MR-proteins governing innate immune response programs (beneficial MR-signature). To identify MR-inverting compounds capable of rescuing activity of inactivated host MR-proteins, without adversely affecting the beneficial MR-signature, we developed the ViroTreat algorithm. Overall, >80% of drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 infection, without affecting cell viability. ViroTreat is fully generalizable and can be extended to identify drugs targeting the host cell-based MR signatures induced by virtually any pathogen.

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Interplay between Hepatitis E Virus and Host Cell Pattern Recognition Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms22179259 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9259

Author(s):

Pradip Devhare ◽

Mridula Madiyal ◽

Chiranjay Mukhopadhyay ◽

Shiran Shetty ◽

Shamee Shastry

Keyword(s):

Immune Response ◽

Pattern Recognition ◽

Host Cell ◽

Innate Immune Response ◽

Hepatitis E Virus ◽

Hepatitis E ◽

Pattern Recognition Receptors ◽

Innate Immune ◽

Renal Diseases ◽

Cell Pattern

Hepatitis E virus (HEV) usually causes self-limiting acute hepatitis, but the disease can become chronic in immunocompromised individuals. HEV infection in pregnant women is reported to cause up to 30% mortality, especially in the third trimester. Additionally, extrahepatic manifestations like neuronal and renal diseases and pancreatitis are also reported during the course of HEV infection. The mechanism of HEV pathogenesis remains poorly understood. Innate immunity is the first line of defense triggered within minutes to hours after the first pathogenic insult. Growing evidence based on reverse genetics systems, in vitro cell culture models, and representative studies in animal models including non-human primates, has implicated the role of the host’s innate immune response during HEV infection. HEV persists in presence of interferons (IFNs) plausibly by evading cellular antiviral defense. This review summarizes our current understanding of recognizing HEV-associated molecular patterns by host cell Pattern Recognition Receptors (PRRs) in eliciting innate immune response during HEV infection as well as mechanisms of virus-mediated immune evasion.

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Perspectives on the Pseudomonas aeruginosa Type III Secretion System Effector ExoU and Its Subversion of the Host Innate Immune Response to Infection

Toxins ◽

10.3390/toxins13120880 ◽

2021 ◽

Vol 13 (12) ◽

pp. 880

Author(s):

Kierra S. Hardy ◽

Maxx H. Tessmer ◽

Dara W. Frank ◽

Jonathon P. Audia

Keyword(s):

Immune Response ◽

Pseudomonas Aeruginosa ◽

Host Cell ◽

Innate Immune Response ◽

Type Iii Secretion ◽

Type Iii Secretion System ◽

Secretion System ◽

Innate Immune ◽

Type Iii ◽

T3ss Effector

Pseudomonas aeruginosa is an opportunistic, Gram-negative pathogen and an important cause of hospital acquired infections, especially in immunocompromised patients. Highly virulent P. aeruginosa strains use a type III secretion system (T3SS) to inject exoenzyme effectors directly into the cytoplasm of a target host cell. P. aeruginosa strains that express the T3SS effector, ExoU, associate with adverse outcomes in critically ill patients with pneumonia, owing to the ability of ExoU to rapidly damage host cell membranes and subvert the innate immune response to infection. Herein, we review the structure, function, regulation, and virulence characteristics of the T3SS effector ExoU, a highly cytotoxic phospholipase A2 enzyme.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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