Navigating the Host Cell Response during Entry into Sites of Latent Cytomegalovirus Infection

The host cell represents a hostile environment that viruses must counter in order to establish infection. Human cytomegalovirus (HCMV) is no different and encodes a multitude of functions aimed at disabling, re-directing or hijacking cellular functions to promulgate infection. However, during the very early stages of infection the virus relies on the outcome of interactions between virion components, cell surface receptors and host signalling pathways to promote an environment that supports infection. In the context of latent infection—where the virus establishes an infection in an absence of many gene products specific for lytic infection—these initial interactions are crucial events. In this review, we will discuss key host responses triggered by viral infection and how, in turn, the virus ameliorates the impact on the establishment of non-lytic infections of cells. We will focus on strategies to evade intrinsic antiviral and innate immune responses and consider their impact on viral infection. Finally, we will consider the hypothesis that the very early events upon viral infection are important for dictating the outcome of infection and consider the possibility that events that occur during entry into non-permissive cells are unique and thus contribute to the establishment of latency.

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Immunologic Pathways in Protective versus Maladaptive Host Responses to Attenuated and Pathogenic Strains ofMycoplasma gallisepticum

Infection and Immunity ◽

10.1128/iai.00613-18 ◽

2018 ◽

Vol 87 (3) ◽

Cited By ~ 2

Author(s):

Jessica Beaudet ◽

Edan R. Tulman ◽

Katherine Pflaum ◽

Jessica A. Canter ◽

Lawrence K. Silbart ◽

...

Keyword(s):

Innate Immune ◽

Host Responses ◽

Immune Gene ◽

Avian Host ◽

Innate Immune Responses ◽

Content Type ◽

Mucosal Tissues ◽

Rapid Clearance ◽

Pathogen Clearance ◽

Host Genes

ABSTRACTMycoplasmas are small bacterial commensals or pathogens that commonly colonize host mucosal tissues and avoid rapid clearance, in part by stimulating inflammatory, immunopathogenic responses. We previously characterized a wide array of transcriptomic perturbations in avian host tracheal mucosae infected with virulent, immunopathologicMycoplasma gallisepticum; however, mechanisms delineating these from protective responses, such as those induced upon vaccination, have not been thoroughly explored. In this study, host transcriptomic responses to two experimentalM. gallisepticumvaccines were assessed during the first 2 days of infection. Relative to virulent infection, host metabolic and immune gene responses to both vaccines were greatly decreased, including early innate immune responses critical to disease development and subsequent adaptive immunity. These data specify host genes and potential mechanisms contributing to maladaptive versus beneficial host responses—information critical for design of vaccines efficacious in both limiting inflammation and enabling pathogen clearance.

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Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms

Frontiers in Immunology ◽

10.3389/fimmu.2021.644664 ◽

2021 ◽

Vol 12 ◽

Author(s):

Amanda L. Verzosa ◽

Lea A. McGeever ◽

Shun-Je Bhark ◽

Tracie Delgado ◽

Nicole Salazar ◽

...

Keyword(s):

Herpes Simplex ◽

Epithelial Cells ◽

Immune Responses ◽

Host Cell ◽

Signaling Pathways ◽

Sensory Neurons ◽

Immune Evasion ◽

Innate Immune ◽

Innate Immune Responses ◽

Hsv 1

Alphaherpesviruses (α-HV) are a large family of double-stranded DNA viruses which cause many human and animal diseases. There are three human α-HVs: Herpes Simplex Viruses (HSV-1 and HSV-2) and Varicella Zoster Virus (VZV). All α-HV have evolved multiple strategies to suppress or exploit host cell innate immune signaling pathways to aid in their infections. All α-HVs initially infect epithelial cells (primary site of infection), and later spread to infect innervating sensory neurons. As with all herpesviruses, α-HVs have both a lytic (productive) and latent (dormant) stage of infection. During the lytic stage, the virus rapidly replicates in epithelial cells before it is cleared by the immune system. In contrast, latent infection in host neurons is a life-long infection. Upon infection of mucosal epithelial cells, herpesviruses immediately employ a variety of cellular mechanisms to evade host detection during active replication. Next, infectious viral progeny bud from infected cells and fuse to neuronal axonal terminals. Here, the nucleocapsid is transported via sensory neuron axons to the ganglion cell body, where latency is established until viral reactivation. This review will primarily focus on how HSV-1 induces various innate immune responses, including host cell recognition of viral constituents by pattern-recognition receptors (PRRs), induction of IFN-mediated immune responses involving toll-like receptor (TLR) signaling pathways, and cyclic GMP‐AMP synthase stimulator of interferon genes (cGAS-STING). This review focuses on these pathways along with other mechanisms including autophagy and the complement system. We will summarize and discuss recent evidence which has revealed how HSV-1 is able to manipulate and evade host antiviral innate immune responses both in neuronal (sensory neurons of the trigeminal ganglia) and non-neuronal (epithelial) cells. Understanding the innate immune response mechanisms triggered by HSV-1 infection, and the mechanisms of innate immune evasion, will impact the development of future therapeutic treatments.

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The Roles of TRIMs in Antiviral Innate Immune Signaling

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.628275 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhou Shen ◽

Lin Wei ◽

Zhi-bo Yu ◽

Zhi-yan Yao ◽

Jing Cheng ◽

...

Keyword(s):

Immune Response ◽

Lupus Erythematosus ◽

Innate Immune ◽

Innate Immune Responses ◽

Cellular Functions ◽

Trim Protein ◽

Innate Immune Signaling ◽

Viral Lifecycle ◽

Trim Proteins ◽

Viral Components

The Tripartite motif (TRIM) protein family, which contains over 80 members in human sapiens, is the largest subfamily of the RING-type E3 ubiquitin ligase family. It is implicated in regulating various cellular functions, including cell cycle process, autophagy, and immune response. The dysfunction of TRIMs may lead to numerous diseases, such as systemic lupus erythematosus (SLE). Lots of studies in recent years have demonstrated that many TRIM proteins exert antiviral roles. TRIM proteins could affect viral replication by regulating the signaling pathways of antiviral innate immune responses. Besides, TRIM proteins can directly target viral components, which can lead to the degradation or functional inhibition of viral protein through degradative or non-degradative mechanisms and consequently interrupt the viral lifecycle. However, new evidence suggests that some viruses may manipulate TRIM proteins for their replication. Here, we summarize the latest discoveries on the interactions between TRIM protein and virus, especially TRIM proteins’ role in the signaling pathway of antiviral innate immune response and the direct “game” between them.

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Enterotoxigenic Escherichia coli Prevents Host NF-κB Activation by Targeting IκBα Polyubiquitination

Infection and Immunity ◽

10.1128/iai.00809-12 ◽

2012 ◽

Vol 80 (12) ◽

pp. 4417-4425 ◽

Cited By ~ 20

Author(s):

Xiaogang Wang ◽

Philip R. Hardwidge

Keyword(s):

Escherichia Coli ◽

Immune Responses ◽

Diarrheal Disease ◽

Innate Immune ◽

Host Cells ◽

Enterotoxigenic Escherichia Coli ◽

Host Responses ◽

Innate Immune Responses ◽

Content Type ◽

Heat Stable

ABSTRACTThe NF-κB pathway regulates innate immune responses to infection. NF-κB is activated after pathogen-associated molecular patterns are detected, leading to the induction of proinflammatory host responses. As a countermeasure, bacterial pathogens have evolved mechanisms to subvert NF-κB signaling. EnterotoxigenicEscherichia coli(ETEC) causes diarrheal disease and significant morbidity and mortality for humans in developing nations. The extent to which this important pathogen subverts innate immune responses by directly targeting the NF-κB pathway is an understudied topic. Here we report that ETEC secretes a heat-stable, proteinaceous factor that blocks NF-κB signaling normally induced by tumor necrosis factor (TNF), interleukin-1β, and flagellin. Pretreating intestinal epithelial cells with ETEC supernatant significantly blocked the degradation of the NF-κB inhibitor IκBα without affecting IκBα phosphorylation. Data from immunoprecipitation experiments suggest that the ETEC factor functions by preventing IκBα polyubiquitination. Inhibiting clathrin function blocked the activity of the secreted ETEC factor, suggesting that this yet-uncharacterized activity may utilize clathrin-dependent endocytosis to enter host cells. These data suggest that ETEC evades the host innate immune response by directly modulating NF-κB signaling.

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Structure of interferon-stimulated gene product 15 (ISG15) from the bat species Myotis davidii and the impact of interdomain ISG15 interactions on viral protein engagement

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798318015322 ◽

2019 ◽

Vol 75 (1) ◽

pp. 21-31 ◽

Cited By ~ 6

Author(s):

Caroline Langley ◽

Octavia Goodwin ◽

John V. Dzimianski ◽

Courtney M. Daczkowski ◽

Scott D. Pegan

Keyword(s):

Gene Product ◽

Species Differences ◽

Viral Proteins ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Host Proteins ◽

Post Translational Modifications ◽

Interferon Responses ◽

The Impact

Bats have long been observed to be the hosts and the origin of numerous human diseases. Bats, like all mammals, rely on a number of innate immune mechanisms to combat invading pathogens, including the interferon type I, II and III responses. Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of these interferon responses. Within these pathways, ISG15 can serve to stabilize host proteins modulating innate immune responses and act as a cytokine. Post-translational modifications of viral proteins introduced by ISG15 have also been observed to directly affect the function of numerous viral proteins. Unlike ubiquitin, which is virtually identical across all animals, comparison of ISG15s across species reveals that they are relatively divergent, with sequence identity dropping to as low as ∼58% among mammals. In addition to serving as an obstacle to the zoonotic transmission of influenza, these ISG15 species–species differences have also long been shown to have an impact on the function of viral deISGylases. Recently, the structure of the first nonhuman ISG15, originating from mouse, suggested that the structures of human ISG15 may not be reflective of other species. Here, the structure of ISG15 from the bat species Myotis davidii solved to 1.37 Å resolution is reported. Comparison of this ISG15 structure with those from human and mouse not only underscores the structural impact of ISG15 species–species differences, but also highlights a conserved hydrophobic motif formed between the two domains of ISG15. Using the papain-like deISGylase from Severe acute respiratory syndrome coronavirus as a probe, the biochemical importance of this motif in ISG15–protein engagements was illuminated.

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Innate Immune Responses of Skin Mucosa in Common Carp (Cyprinus Carpio) Fed a Diet Supplemented with Galactooligosaccharides

Animals ◽

10.3390/ani10030438 ◽

2020 ◽

Vol 10 (3) ◽

pp. 438 ◽

Cited By ~ 3

Author(s):

Elzbieta Pietrzak ◽

Jan Mazurkiewicz ◽

Anna Slawinska

Keyword(s):

Gene Expression ◽

Immune Responses ◽

Common Carp ◽

Geometric Mean ◽

Juvenile Fish ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Related Genes ◽

The Impact ◽

Skin Mucosa

Galactooligosaccharides (GOS) are well-known immunomodulatory prebiotics. We hypothesize that GOS supplemented in feed modulates innate immune responses in the skin-associated lymphoid tissue (SALT) of common carp. The aim of this study was to determine the impact of GOS on mRNA expression of the immune-related genes in skin mucosa. During the feeding trial, the juvenile fish (bodyweight 180 ± 5 g) were fed two types of diet for 50 days: control and supplemented with 2% GOS. At the end of the trial, a subset of fish was euthanized (n = 8). Skin mucosa was collected, and RNA was extracted. Gene expression analysis was performed with RT-qPCR to determine the mRNA abundance of the genes associated with innate immune responses in SALT, i.e., acute-phase protein (CRP), antimicrobial proteins (His2Av and GGGT5L), cytokines (IL1β, IL4, IL8, IL10, and IFNγ), lectin (CLEC4M), lyzosymes (LyzC and LyzG), mucin (M5ACL), peroxidase (MPO), proteases (CTSB and CTSD), and oxidoreductase (TXNL). The geometric mean of 40s s11 and ACTB was used to normalize the data. Relative quantification of the gene expression was calculated with ∆∆Ct. GOS upregulated INFγ (p ≤ 0.05) and LyzG (p ≤ 0.05), and downregulated CRP (p ≤ 0.01). We conclude that GOS modulates innate immune responses in the skin mucosa of common carp.

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Viral miRNAs Alter Host Cell miRNA Profiles and Modulate Innate Immune Responses

Frontiers in Immunology ◽

10.3389/fimmu.2018.00433 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 20

Author(s):

Afsar R. Naqvi ◽

Jennifer Shango ◽

Alexandra Seal ◽

Deepak Shukla ◽

Salvador Nares

Keyword(s):

Immune Responses ◽

Host Cell ◽

Innate Immune ◽

Innate Immune Responses ◽

Viral Mirnas

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Mycobacterium PPE31 Contributes to Host Cell Death

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.629836 ◽

2021 ◽

Vol 11 ◽

Author(s):

Siyuan Feng ◽

Zhongsi Hong ◽

Guoliang Zhang ◽

Jiachen Li ◽

Guo-Bao Tian ◽

...

Keyword(s):

Cell Death ◽

Host Cell ◽

Acid Medium ◽

Mutant Strain ◽

Mycobacterial Infection ◽

Innate Immune ◽

Innate Immune Responses ◽

Jnk Signaling ◽

Host Cell Death ◽

Genome Scale

Genome scale mutagenesis identifies many genes required for mycobacterial infectivity and survival, but their contributions and mechanisms of action within the host are poorly understood. Using CRISPR interference, we created a knockdown of ppe31Mm gene in Mycobacterium marinum (M. marinum), which reduced the resistance to acid medium. To further explore the function of PPE31, the ppe31 mutant strain was generated in M. marinum and Mycobacterium tuberculosis (M. tuberculosis), respectively. Macrophages infected with the ppe31Mm mutant strain caused a reduced inflammatory mediator expressions. In addition, macrophages infected with M. marinum Δppe31Mm had decreased host cell death dependent on JNK signaling. Consistent with these results, deletion of ppe31Mtb from M. tuberculosis increased the sensitivity to acid medium and reduced cell death in macrophages. Furthermore, we demonstrate that both ppe31 mutants from M. marinum and M. tuberculosis resulted in reduced survival in macrophages, and the survivability of M. marinum was deceased in zebrafish due to loss of ppe31Mm. Our findings confirm that PPE31 as a virulence associated factor that modulates innate immune responses to mycobacterial infection.

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SARS-CoV-2-Indigenous Microbiota Nexus: Does Gut Microbiota Contribute to Inflammation and Disease Severity in COVID-19?

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.590874 ◽

2021 ◽

Vol 11 ◽

Author(s):

Indranil Chattopadhyay ◽

Esaki M. Shankar

Keyword(s):

Gut Microbiota ◽

Immune Responses ◽

Gut Microbiome ◽

Innate Immune ◽

Innate Immune Responses ◽

Targeted Interventions ◽

Promising Therapeutic Approach ◽

Indigenous Microbiota ◽

The Impact ◽

Microbiome Profiling

Gut microbiome alterations may play a paramount role in determining the clinical outcome of clinical COVID-19 with underlying comorbid conditions like T2D, cardiovascular disorders, obesity, etc. Research is warranted to manipulate the profile of gut microbiota in COVID-19 by employing combinatorial approaches such as the use of prebiotics, probiotics and symbiotics. Prediction of gut microbiome alterations in SARS-CoV-2 infection may likely permit the development of effective therapeutic strategies. Novel and targeted interventions by manipulating gut microbiota indeed represent a promising therapeutic approach against COVID-19 immunopathogenesis and associated co-morbidities. The impact of SARS-CoV-2 on host innate immune responses associated with gut microbiome profiling is likely to contribute to the development of key strategies for application and has seldom been attempted, especially in the context of symptomatic as well as asymptomatic COVID-19 disease.

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Organotypic modeling of SARS-CoV-2 lung and brainstem infection

10.21203/rs.3.rs-122126/v1 ◽

2020 ◽

Author(s):

Marion Ferren ◽

Valérie Favede ◽

Didier Decimo ◽

Mathieu Iampietro ◽

Nicole A. P. Lieberman ◽

...

Keyword(s):

Central Nervous System ◽

Immune Responses ◽

Viral Infection ◽

Central Nervous System Infection ◽

Tissue Level ◽

Innate Immune ◽

Innate Immune Responses ◽

Organotypic Cultures ◽

Neurological Sequelae ◽

Global Pandemic

Abstract SARS-CoV-2 has caused a global pandemic of Covid-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also lead to central nervous system infection and neurological sequelae. We developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer the unique opportunity to study the early steps of the pathogenesis and screening of antivirals. Using these models, we validated the early tropism of the virus in the lung and demonstrated that SARS-CoV2 can infect brainstem and cerebellum, mainly by targeting granular neurons. Viral infection induced specific interferon and innate immune responses with patterns specific to each organ along with apoptotic, necroptotic, and pyroptotic cell death. Overall, our data illustrate the potential of rapidly modeling complex tissue level interactions of viral infection in a newly emerged virus.

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