scholarly journals The IκB Kinases Restrict Human Cytomegalovirus Infection

2019 ◽  
Vol 93 (9) ◽  
Author(s):  
Christopher M. Goodwin ◽  
Joshua Munger
Keyword(s):  
Viral Replication ◽  
Viral Infection ◽  
Host Cell ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Innate Immune ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Iκb Kinase ◽  
Cell Spread

ABSTRACTHuman cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes disease in immunosuppressed populations. HCMV has a complex relationship with innate immune signaling pathways. Specifically, HCMV has been found to block some aspects of inflammatory signaling while benefiting from others. Through analysis of knockout cell lines targeting the NF-κB regulatory kinases IκB kinase α (IKKα) and IKKβ, we find that the IKKs are host restriction factors that contribute to cytokine-mediated resistance to viral infection, limit the initiation of HCMV infection, and attenuate viral cell-to-cell spread. The HCMV UL26 protein is a viral immune modulator important for HCMV infection that has been shown to inhibit host cell NF-κB signaling, yet it has remained unclear how UL26-mediated NF-κB modulation contributes to infection. Here, we find that UL26 modulation of NF-κB signaling is separable from its contribution to high-titer viral replication. However, we find that IKKβ is required for the induction of cytokine expression associated with ΔUL26 infection. Collectively, our data indicate that the IKKs restrict infection but HCMV targets their signaling to modulate the cellular inflammatory environment.IMPORTANCEInnate immune signaling is a critical defense against viral infection and represents a central host-virus interaction that frequently determines the outcomes of infections. NF-κB signaling is an essential component of innate immunity that is extensively modulated by HCMV, a significant cause of morbidity in neonates and immunosuppressed individuals. However, the roles that various facets of NF-κB signaling play during HCMV infection have remained elusive. We find that the two major regulatory kinases in this pathway, IKKα and IKKβ, limit the initiation of infection, viral replication, and cell-to-cell spread. In addition, our results indicate that these kinases contribute differently to the host cell response to infection in the absence of a virally encoded NF-κB inhibitor, UL26. Given the importance of NF-κB in viral infection, elucidating the contributions of various NF-κB constituents to infection is an essential first step toward the possibility of targeting this pathway therapeutically.

scholarly journals How to rewire the host cell: A home improvement guide for intracellular bacteria

2017 ◽  
Vol 216 (12) ◽  
pp. 3931-3948 ◽  
Author(s):  
Elias Cornejo ◽  
Philipp Schlaermann ◽  
Shaeri Mukherjee
Keyword(s):  
Host Cell ◽  
Signaling Pathways ◽  
Membrane Trafficking ◽  
Defense Mechanisms ◽  
Bacterial Pathogens ◽  
Innate Immune ◽  
Intracellular Bacteria ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
The Unfolded Protein Response

Intracellular bacterial pathogens have developed versatile strategies to generate niches inside the eukaryotic cells that allow them to survive and proliferate. Making a home inside the host offers many advantages; however, intracellular bacteria must also overcome many challenges, such as disarming innate immune signaling and accessing host nutrient supplies. Gaining entry into the cell and avoiding degradation is only the beginning of a successful intracellular lifestyle. To establish these replicative niches, intracellular pathogens secrete various virulence proteins, called effectors, to manipulate host cell signaling pathways and subvert host defense mechanisms. Many effectors mimic host enzymes, whereas others perform entirely novel enzymatic functions. A large volume of work has been done to understand how intracellular bacteria manipulate membrane trafficking pathways. In this review, we focus on how intracellular bacterial pathogens target innate immune signaling, the unfolded protein response, autophagy, and cellular metabolism and exploit these pathways to their advantage. We also discuss how bacterial pathogens can alter host gene expression by directly modifying histones or hijacking the ubiquitination machinery to take control of several host signaling pathways.

P2Y2 purinergic receptor is induced following human cytomegalovirus infection and its activity is required for efficient viral replication

2016 ◽  
Author(s):  
Saisai Chen ◽  
Thomas Shenk ◽  
Maciej T. Nogalski
Keyword(s):  
Viral Replication ◽  
Host Cell ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Receptor Expression ◽  
Receptor Activity ◽  
P2y2 Receptor ◽  
Infected Cells

AbstractHuman cytomegalovirus (HCMV) manipulates many aspects of host cell biology to create an intracellular milieu optimally supportive of its replication and spread. The current study reveals a role for purinergic signaling in HCMV infection. The levels of several components of the purinergic signaling system, including the P2Y2 receptor, were altered in HCMV-infected fibroblasts. P2Y2 receptor RNA and protein are strongly induced following infection. Pharmacological inhibition of receptor activity or knockdown of receptor expression markedly reduced the production of infectious HCMV progeny. When P2Y2 activity was inhibited, the accumulation of most viral RNAs tested and viral DNA was reduced. In addition, the level of cytosolic calcium within infected cells was reduced when P2Y2 signaling was blocked. The HCMV-coded UL37x1 protein was previously shown to induce calcium flux from the smooth endoplasmic reticulum to the cytosol, and the present study demonstrates that P2Y2 function is required for this mobilization. We conclude that P2Y2 supports the production of HCMV progeny, possibly at multiple points within the viral replication cycle that interface with signaling pathways induced by the purinergic receptor.ImportanceHCMV infection is ubiquitous and can cause life-threatening disease in immunocompromised patients, debilitating birth defects in newborns, and has been increasingly associated with a wide range of chronic conditions. Such broad clinical implications result from the modulation of multiple host cell processes. This study documents that cellular purinergic signaling is usurped in HCMV-infected cells and that the function of this signaling axis is critical for efficient HCMV infection. Therefore, we speculate that blocking P2Y2 receptor activity has the potential to become an attractive novel treatment option for HCMV infection.

scholarly journals Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing

2021 ◽  
Author(s):  
Kiramage Chathuranga ◽  
Asela Weerawardhana ◽  
Niranjan Dodantenna ◽  
Jong-Soo Lee
Keyword(s):  
Viral Infection ◽  
Innate Immune ◽  
Host Immune System ◽  
Immune Signaling ◽  
Antiviral Responses ◽  
Current State ◽  
Innate Immune Signaling ◽  
Genes Encoding ◽  
Host Antiviral Response ◽  
Recognition Receptor

AbstractA harmonized balance between positive and negative regulation of pattern recognition receptor (PRR)-initiated immune responses is required to achieve the most favorable outcome for the host. This balance is crucial because it must not only ensure activation of the first line of defense against viral infection but also prevent inappropriate immune activation, which results in autoimmune diseases. Recent studies have shown how signal transduction pathways initiated by PRRs are positively and negatively regulated by diverse modulators to maintain host immune homeostasis. However, viruses have developed strategies to subvert the host antiviral response and establish infection. Viruses have evolved numerous genes encoding immunomodulatory proteins that antagonize the host immune system. This review focuses on the current state of knowledge regarding key host factors that regulate innate immune signaling molecules upon viral infection and discusses evidence showing how specific viral proteins counteract antiviral responses via immunomodulatory strategies.

scholarly journals IκB Kinase β Phosphorylates the K63 Deubiquitinase A20 To Cause Feedback Inhibition of the NF-κB Pathway

2007 ◽  
Vol 27 (21) ◽  
pp. 7451-7461 ◽  
Author(s):  
Jessica E. Hutti ◽  
Benjamin E. Turk ◽  
John M. Asara ◽  
Averil Ma ◽  
Lewis C. Cantley ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Feedback Inhibition ◽  
Innate Immune ◽  
Negative Regulator ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Iκb Kinase ◽  
Phosphorylation Event

ABSTRACT Misregulation of NF-κB signaling leads to infectious, inflammatory, or autoimmune disorders. IκB kinase β (IKKβ) is an essential activator of NF-κB and is known to phosphorylate the NF-κB inhibitor, IκBα, allowing it to undergo ubiquitin-mediated proteasomal degradation. However, beyond IκBα, few additional IKKβ substrates have been identified. Here we utilize a peptide library and bioinformatic approach to predict likely substrates of IKKβ. This approach predicted Ser381 of the K63 deubiquitinase A20 as a likely site of IKKβ phosphorylation. While A20 is a known negative regulator of innate immune signaling pathways, the mechanisms regulating the activity of A20 are poorly understood. We show that IKKβ phosphorylates A20 in vitro and in vivo at serine 381, and we further show that this phosphorylation event increases the ability of A20 to inhibit the NF-κB signaling pathway. Phosphorylation of A20 by IKKβ thus represents part of a novel feedback loop that regulates the duration of NF-κB signaling following activation of innate immune signaling pathways.

scholarly journals Comparative Analysis of African and Asian Lineage-Derived Zika Virus Strains Reveals Differences in Activation of and Sensitivity to Antiviral Innate Immunity

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Katharina Esser-Nobis ◽  
Lauren D. Aarreberg ◽  
Justin A. Roby ◽  
Marian R. Fairgrieve ◽  
Richard Green ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Viral Replication ◽  
Zika Virus ◽  
Innate Immune ◽  
High Rate ◽  
Immune Signaling ◽  
Brazilian Strain ◽  
Innate Immune Signaling ◽  
Asian Lineage ◽  
Virus Strains

ABSTRACT In recent years, Asian lineage Zika virus (ZIKV) strains emerged to cause pandemic outbreaks associated with a high rate of congenital ZIKV syndrome (CZVS). The reasons for the enhanced spread and severe disease caused by newly emerging strains are not fully understood. Here we compared viral sequences, viral replication, and innate immune signaling induction of three different ZIKV strains derived from African and Asian lineages and West Nile virus, another flavivirus. We found pronounced differences in activation of innate immune signaling and inhibition of viral replication across ZIKV strains. The newly emerged Asian ZIKV strain Brazil Fortaleza 2015, which is associated with a higher rate of neurodevelopmental disorders like microcephaly, induced much weaker and delayed innate immune signaling in infected cells. However, superinfection studies to assess control of innate immune signaling induced by Sendai virus argue against an active block of IRF3 activation by the Brazilian strain of ZIKV and rather suggest an evasion of detection by host cell pattern recognition receptors. Compared to the Asian strain FSS13025 isolated in Cambodia, both ZIKV Uganda MR766 and ZIKV Brazil Fortaleza appear less sensitive to the interferon-induced antiviral response. ZIKV infection studies of cells lacking the different RIG-I-like receptors identified RIG-I as the major cytosolic pattern recognition receptor for detection of ZIKV. IMPORTANCE Zika Virus (ZIKV), discovered in 1947, is divided into African and Asian lineages. Pandemic outbreaks caused by currently emerging Asian lineage strains are accompanied by high rates of neurological disorders and exemplify the global health burden associated with this virus. Here we compared virological and innate immunological aspects of two ZIKV strains from the Asian lineage, an emerging Brazilian strain and a less-pathogenic Cambodian strain, and the prototypic African lineage ZIKV strain from Uganda. Compared to the replication of other ZIKV strains, the replication of ZIKV Brazil was less sensitive to the antiviral actions of interferon (IFN), while infection with this strain induced weaker and delayed innate immune responses in vitro. Our data suggest that ZIKV Brazil directs a passive strategy of innate immune evasion that is reminiscent of a stealth virus. Such strain-specific properties likely contribute to differential pathogenesis and should be taken into consideration when choosing virus strains for future molecular studies.

scholarly journals Human Nasal Turbinate Tissues in Organ Culture as a Model for Human Cytomegalovirus Infection at the Mucosal Entry Site

2020 ◽  
Vol 94 (19) ◽  
Author(s):  
Or Alfi ◽  
Ido From ◽  
Arkadi Yakirevitch ◽  
Michael Drendel ◽  
Michael Wolf ◽  
...  
Keyword(s):  
Organ Culture ◽  
Viral Infection ◽  
Human Cytomegalovirus ◽  
Viral Entry ◽  
Hcmv Infection ◽  
Horizontal Transmission ◽  
Innate Immune ◽  
Entry Site ◽  
Nasal Turbinate ◽  
Mucosal Tissues

ABSTRACT The initial events of viral infection at the primary mucosal entry site following horizontal person-to-person transmission have remained ill defined. Our limited understanding is further underscored by the absence of animal models in the case of human-restricted viruses, such as human cytomegalovirus (HCMV), a leading cause of congenital infection and a major pathogen in immunocompromised individuals. Here, we established a novel ex vivo model of HCMV infection in native human nasal turbinate tissues. Nasal turbinate tissue viability and physiological functionality were preserved for at least 7 days in culture. We found that nasal mucosal tissues were susceptible to HCMV infection, with predominant infection of ciliated respiratory epithelial cells. A limited viral spread was demonstrated, involving mainly stromal and vascular endothelial cells within the tissue. Importantly, functional antiviral and proleukocyte chemotactic signaling pathways were significantly upregulated in the nasal mucosa in response to infection. Conversely, HCMV downregulated the expression of nasal epithelial cell-related genes. We further revealed tissue-specific innate immune response patterns to HCMV, comparing infected human nasal mucosal and placental tissues, representing the viral entry and the maternal-to-fetal transmission sites, respectively. Taken together, our studies provide insights into the earliest stages of HCMV infection. Studies in this model could help evaluate new interventions against the horizontal transmission of HCMV. IMPORTANCE HCMV is a ubiquitous human pathogen causing neurodevelopmental disabilities in congenitally infected children and severe disease in immunocompromised patients. The earliest stages of HCMV infection in the human host have remained elusive in the absence of a model for the viral entry site. Here, we describe the establishment and use of a novel nasal turbinate organ culture to study the initial steps of viral infection and the consequent innate immune responses within the natural complexity and the full cellular repertoire of human nasal mucosal tissues. This model can be applied to examine new antiviral interventions against the horizontal transmission of HCMV and potentially that of other viruses.

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