Feline Coronavirus and Alpha-Herpesvirus Infections: Innate Immune Response and Immune Escape Mechanisms

Over time, feline viruses have acquired elaborateopportunistic properties, making their infections particularly difficult to prevent and treat. Feline coronavirus (FCoV) and feline herpesvirus-1 (FeHV-1), due to the involvement of host genetic factors and immune mechanisms in the development of the disease and more severe forms, are important examples of immune evasion of the host’s innate immune response by feline viruses.It is widely accepted that the innate immune system, which providesan initial universal form of the mammalian host protection from infectious diseases without pre-exposure, plays an essential role in determining the outcome of viral infection.The main components of this immune systembranchare represented by the internal sensors of the host cells that are able to perceive the presence of viral component, including nucleic acids, to start and trigger the production of first type interferon and to activate the cytotoxicity by Natural Killercells, often exploited by viruses for immune evasion.In this brief review, we providea general overview of the principal tools of innate immunity, focusing on the immunologic escape implemented byFCoVand FeHV-1 duringinfection.

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Tumour viruses and innate immunity

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0267 ◽

2017 ◽

Vol 372 (1732) ◽

pp. 20160267 ◽

Cited By ~ 13

Author(s):

Sharon E. Hopcraft ◽

Blossom Damania

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Viral Infection ◽

Innate Immune Response ◽

Innate Immune ◽

Host Cells ◽

Oncogenic Viruses ◽

Barr Virus ◽

Human T Cell ◽

Epstein Barr

Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRRs are localized to several different cellular compartments and are stimulated by viral proteins and nucleic acids. PRR activation initiates signal transduction events that ultimately result in an inflammatory response. Human tumour viruses, which include Kaposi's sarcoma-associated herpesvirus, Epstein–Barr virus, human papillomavirus, hepatitis C virus, hepatitis B virus, human T-cell lymphotropic virus type 1 and Merkel cell polyomavirus, are detected by several different PRRs. These viruses engage in a variety of mechanisms to evade the innate immune response, including downregulating PRRs, inhibiting PRR signalling, and disrupting the activation of transcription factors critical for mediating the inflammatory response, among others. This review will describe tumour virus PAMPs and the PRRs responsible for detecting viral infection, PRR signalling pathways, and the mechanisms by which tumour viruses evade the host innate immune system. This article is part of the themed issue ‘Human oncogenic viruses’.

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miR-26a Inhibits Feline Herpesvirus 1 Replication by Targeting SOCS5 and Promoting Type I Interferon Signaling

Viruses ◽

10.3390/v12010002 ◽

2019 ◽

Vol 12 (1) ◽

pp. 2 ◽

Cited By ~ 3

Author(s):

Jikai Zhang ◽

Zhijie Li ◽

Jiapei Huang ◽

Hang Yin ◽

Jin Tian ◽

...

Keyword(s):

Immune Response ◽

Viral Infection ◽

Innate Immune Response ◽

Antiviral Response ◽

Innate Immune ◽

Host Cells ◽

Type I ◽

Type I Ifn ◽

Feline Herpesvirus ◽

Herpesvirus 1

In response to viral infection, host cells activate various antiviral responses to inhibit virus replication. While feline herpesvirus 1 (FHV-1) manipulates the host early innate immune response in many different ways, the host could activate the antiviral response to counteract it through some unknown mechanisms. MicroRNAs (miRNAs) which serve as a class of regulatory factors in the host, participate in the regulation of the host innate immune response against virus infection. In this study, we found that the expression levels of miR-26a were significantly upregulated upon FHV-1 infection. Furthermore, FHV-1 infection induced the expression of miR-26a via a cGAS-dependent pathway, and knockdown of cellular cGAS significantly blocked the expression of miR-26a induced by poly (dA:dT) or FHV-1 infection. Next, we investigated the biological function of miR-26a during viral infection. miR-26a was able to increase the phosphorylation of STAT1 and promote type I IFN signaling, thus inhibiting viral replication. The mechanism study showed that miR-26a directly targeted host SOCS5. Knockdown of SOCS5 increased the phosphorylation of STAT1 and enhanced the type I IFN-mediated antiviral response, and overexpression of suppressor of the cytokine signalling 5 (SOCS5) decreased the phosphorylation of STAT1 and inhibited the type I IFN-mediated antiviral response. Meanwhile, with the knockdown of SOCS5, the upregulated expression of phosphorylated STAT1 and the anti-virus effect induced by miR-26a were significantly inhibited. Taken together, our data demonstrated a new strategy of host miRNAs against FHV-1 infection by enhancing IFN antiviral signaling.

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Recent Advances on the Innate Immune Response to Coxiella burnetii

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.754455 ◽

2021 ◽

Vol 11 ◽

Author(s):

Guido Sireci ◽

Giusto Davide Badami ◽

Diana Di Liberto ◽

Valeria Blanda ◽

Francesca Grippi ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Coxiella Burnetii ◽

Q Fever ◽

Cell Types ◽

Innate Immune ◽

Host Cells ◽

Experimental Systems ◽

Monocytes And Macrophages ◽

Review Reports

Coxiella burnetii is an obligate intracellular Gram-negative bacterium and the causative agent of a worldwide zoonosis known as Q fever. The pathogen invades monocytes and macrophages, replicating within acidic phagolysosomes and evading host defenses through different immune evasion strategies that are mainly associated with the structure of its lipopolysaccharide. The main transmission routes are aerosols and ingestion of fomites from infected animals. The innate immune system provides the first host defense against the microorganism, and it is crucial to direct the infection towards a self-limiting respiratory disease or the chronic form. This review reports the advances in understanding the mechanisms of innate immunity acting during C. burnetii infection and the strategies that pathogen put in place to infect the host cells and to modify the expression of specific host cell genes in order to subvert cellular processes. The mechanisms through which different cell types with different genetic backgrounds are differently susceptible to C. burnetii intracellular growth are discussed. The subsets of cytokines induced following C. burnetii infection as well as the pathogen influence on an inflammasome-mediated response are also described. Finally, we discuss the use of animal experimental systems for studying the innate immune response against C. burnetii and discovering novel methods for prevention and treatment of disease in humans and livestock.

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Human Cytomegalovirus Immediate Early 86-kDa Protein Blocks Transcription and Induces Degradation of the Immature Interleukin-1β Protein during Virion-Mediated Activation of the AIM2 Inflammasome

mBio ◽

10.1128/mbio.02510-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 9

Author(s):

Sara Botto ◽

Jinu Abraham ◽

Nobuyo Mizuno ◽

Kara Pryke ◽

Bryan Gall ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Human Cytomegalovirus ◽

Hcmv Infection ◽

Innate Immune ◽

Host Cells ◽

Interleukin 1Β ◽

Immediate Early ◽

Interferon Response ◽

Type I

ABSTRACTSecretion of interleukin-1β (IL-1β) represents a fundamental innate immune response to microbial infection that, at the molecular level, occurs following activation of proteolytic caspases that cleave the immature protein into a secretable form. Human cytomegalovirus (HCMV) is the archetypal betaherpesvirus that is invariably capable of lifelong infection through the activity of numerous virally encoded immune evasion phenotypes. Innate immune pathways responsive to cytoplasmic double-stranded DNA (dsDNA) are known to be activated in response to contact between HCMV and host cells. Here, we used clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9 (Cas9) genome editing to demonstrate that the dsDNA receptorabsentinmelanoma 2 (AIM2) is required for secretion of IL-1β following HCMV infection. Furthermore, dsDNA-responsive innate signaling induced by HCMV infection that leads to activation of the type I interferon response is also shown, unexpectedly, to play a contributory role in IL-1β secretion. Importantly, we also show that rendering virus particles inactive by UV exposure leads to substantially increased IL-1β processing and secretion and that live HCMV can inhibit this, suggesting the virus encodes factors that confer an inhibitory effect on this response. Further examination revealed that ectopic expression of the immediate early (IE) 86-kDa protein (IE86) is actually associated with a block in transcription of the pro-IL-1β gene and, independently, diminishment of the immature protein. Overall, these results reveal two new and distinct phenotypes conferred by the HCMV IE86 protein, as well as an unusual circumstance in which a single herpesviral protein exhibits inhibitory effects on multiple molecular processes within the same innate immune response.IMPORTANCEPersistent infection with HCMV is associated with the operation of diverse evasion phenotypes directed at antiviral immunity. Obstruction of intrinsic and innate immune responses is typically conferred by viral proteins either associated with the viral particle or expressed immediately after entry. In line with this, numerous phenotypes are attributed to the HCMV IE86 protein that involve interference with innate immune processes via transcriptional and protein-directed mechanisms. We describe novel IE86-mediated phenotypes aimed at virus-induced secretion of IL-1β. Intriguingly, while many viruses target the function of the molecular scaffold required for IL-1β maturation to prevent this response, we find that HCMV and IE86 target the IL-1β protein specifically. Moreover, we show that IE86 impairs both the synthesis of the IL-1β transcript and the stability of the immature protein. This indicates an unusual phenomenon in which a single viral protein exhibits two molecularly separate evasion phenotypes directed at a single innate cytokine.

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Innate Immune Responses to Herpesvirus Infection

Cells ◽

10.3390/cells10082122 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2122

Author(s):

Christine M. O’Connor ◽

Ganes C. Sen

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Defense Mechanisms ◽

Innate Immune ◽

Host Cells ◽

Innate Immune Responses ◽

Viral Pathogen ◽

Dna Viruses ◽

Host Innate Immune Response ◽

Human Herpesviruses

Infection of a host cell by an invading viral pathogen triggers a multifaceted antiviral response. One of the most potent defense mechanisms host cells possess is the interferon (IFN) system, which initiates a targeted, coordinated attack against various stages of viral infection. This immediate innate immune response provides the most proximal defense and includes the accumulation of antiviral proteins, such as IFN-stimulated genes (ISGs), as well as a variety of protective cytokines. However, viruses have co-evolved with their hosts, and as such, have devised distinct mechanisms to undermine host innate responses. As large, double-stranded DNA viruses, herpesviruses rely on a multitude of means by which to counter the antiviral attack. Herein, we review the various approaches the human herpesviruses employ as countermeasures to the host innate immune response.

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T6SS translocates a micropeptide to suppress STING-mediated innate immunity by sequestering manganese

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2103526118 ◽

2021 ◽

Vol 118 (42) ◽

pp. e2103526118

Author(s):

Lingfang Zhu ◽

Lei Xu ◽

Chenguang Wang ◽

Changfu Li ◽

Mengyuan Li ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Metal Ions ◽

Innate Immune Response ◽

Metal Ion ◽

Innate Immune ◽

Host Cells ◽

Host Innate Immune Response ◽

Host Innate Immunity

Cellular ionic concentrations are a central factor orchestrating host innate immunity, but no pathogenic mechanism that perturbs host innate immunity by directly targeting metal ions has yet been described. Here, we report a unique virulence strategy of Yersinia pseudotuberculosis (Yptb) involving modulation of the availability of Mn2+, an immunostimulatory metal ion in host cells. We showed that the Yptb type VI secretion system (T6SS) delivered a micropeptide, TssS, into host cells to enhance its virulence. The mutant strain lacking TssS (ΔtssS) showed substantially reduced virulence but induced a significantly stronger host innate immune response, indicating an antagonistic role of this effector in host antimicrobial immunity. Subsequent studies revealed that TssS is a Mn2+-chelating protein and that its Mn2+-chelating ability is essential for the disruption of host innate immunity. Moreover, we showed that Mn2+ enhances the host innate immune response to Yptb infection by activating the stimulator of interferon genes (STING)-mediated immune response. Furthermore, we demonstrated that TssS counteracted the cytoplasmic Mn2+ increase to inhibit the STING-mediated innate immune response by sequestering Mn2+. Finally, TssS-mediated STING inhibition sabotaged bacterial clearance in vivo. These results reveal a previously unrecognized bacterial immune evasion strategy involving modulation of the bioavailability of intracellular metal ions and provide a perspective on the role of the T6SS in pathogenesis.

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Enterohaemorrhagic Escherichia coli serogroup O111 inhibits NF-κB-dependent innate responses in a manner independent of a type III secreted OspG orthologue

Microbiology ◽

10.1099/mic.0.030759-0 ◽

2009 ◽

Vol 155 (10) ◽

pp. 3214-3225 ◽

Cited By ~ 16

Author(s):

Rika Nobe ◽

Jean-Philippe Nougayrède ◽

Frédéric Taieb ◽

Marjorie Bardiau ◽

Dominique Cassart ◽

...

Keyword(s):

Escherichia Coli ◽

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Host Cells ◽

Effector Protein ◽

Intestinal Loop ◽

Loop Model ◽

Type Iii ◽

Enterohaemorrhagic Escherichia Coli

Enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) inject a repertoire of effector proteins into host cells via a type III secretion system (T3SS) encoded by the locus of enterocyte effacement (LEE). OspG is an effector protein initially identified in Shigella that was shown to inhibit the host innate immune response. In this study, we found ospG homologues in EHEC (mainly of serogroup O111) and in Yersinia enterocolitica. The T3SS encoded by the LEE was able to inject these different OspG homologues into host cells. Infection of HeLa cells with EHEC O111 inhibited the NF-κB-dependent innate immune response via a T3SS-dependent mechanism. However, an EHEC O111 ospG mutant was still able to inhibit NF-κB p65 transfer to the nucleus in infected cells stimulated by tumour necrosis factor α (TNF-α). In addition, no difference in the inflammatory response was observed between wild-type EHEC O111 and the isogenic ospG mutant in the rabbit ligated intestinal loop model. These results suggest that OspG is not the sole effector protein involved in the inactivation of the host innate immune system during EHEC O111 infection.

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Innate Immune Response to Tick-Borne Pathogens: Cellular and Molecular Mechanisms Induced in the Hosts

International Journal of Molecular Sciences ◽

10.3390/ijms21155437 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5437 ◽

Cited By ~ 4

Author(s):

Alessandra Torina ◽

Sara Villari ◽

Valeria Blanda ◽

Stefano Vullo ◽

Marco Pio La Manna ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Infectious Diseases ◽

Innate Immune Response ◽

Molecular Mechanisms ◽

Defense Mechanism ◽

Innate Immune ◽

Bioactive Molecules ◽

Host Cells ◽

Ongoing Research

Many pathogens are transmitted by tick bites, including Anaplasma spp., Ehrlichia spp., Rickettsia spp., Babesia and Theileria sensu stricto species. These pathogens cause infectious diseases both in animals and humans. Different types of immune effector mechanisms could be induced in hosts by these microorganisms, triggered either directly by pathogen-derived antigens or indirectly by molecules released by host cells binding to these antigens. The components of innate immunity, such as natural killer cells, complement proteins, macrophages, dendritic cells and tumor necrosis factor alpha, cause a rapid and intense protection for the acute phase of infectious diseases. Moreover, the onset of a pro-inflammatory state occurs upon the activation of the inflammasome, a protein scaffold with a key-role in host defense mechanism, regulating the action of caspase-1 and the maturation of interleukin-1β and IL-18 into bioactive molecules. During the infection caused by different microbial agents, very similar profiles of the human innate immune response are observed including secretion of IL-1α, IL-8, and IFN-α, and suppression of superoxide dismutase, IL-1Ra and IL-17A release. Innate immunity is activated immediately after the infection and inflammasome-mediated changes in the pro-inflammatory cytokines at systemic and intracellular levels can be detected as early as on days 2–5 after tick bite. The ongoing research field of “inflammasome biology” focuses on the interactions among molecules and cells of innate immune response that could be responsible for triggering a protective adaptive immunity. The knowledge of the innate immunity mechanisms, as well as the new targets of investigation arising by bioinformatics analysis, could lead to the development of new methods of emergency diagnosis and prevention of tick-borne infections.

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TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

Viruses ◽

10.3390/v13020279 ◽

2021 ◽

Vol 13 (2) ◽

pp. 279

Author(s):

Ling Wang ◽

Shunbin Ning

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Stress Responses ◽

Viral Infections ◽

Immune Escape ◽

E3 Ligase ◽

Innate Immune ◽

Type I ◽

Antiviral Immune Response ◽

Wide Range

The tripartite motif (TRIM) family comprises at least 80 members in humans, with most having ubiquitin or SUMO E3 ligase activity conferred by their N-terminal RING domain. TRIMs regulate a wide range of processes in ubiquitination- or sumoylation-dependent manners in most cases, and fewer as adaptors. Their roles in the regulation of viral infections, autophagy, cell cycle progression, DNA damage and other stress responses, and carcinogenesis are being increasingly appreciated, and their E3 ligase activities are attractive targets for developing specific immunotherapeutic strategies for immune diseases and cancers. Given their importance in antiviral immune response, viruses have evolved sophisticated immune escape strategies to subvert TRIM-mediated mechanisms. In this review, we focus on their regulation of IFN-I-mediated innate immune response, which plays key roles in antiviral and antitumor defense.

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Zoonotic Visceral Leishmaniasis: New Insights on Innate Immune Response by Blood Macrophages and Liver Kupffer Cells to Leishmania infantum Parasites

Biology ◽

10.3390/biology11010100 ◽

2022 ◽

Vol 11 (1) ◽

pp. 100

Author(s):

Armanda Viana Rodrigues ◽

Ana Valério-Bolas ◽

Graça Alexandre-Pires ◽

Maria Aires-Pereira ◽

Telmo Nunes ◽

...

Keyword(s):

Immune Response ◽

Visceral Leishmaniasis ◽

Innate Immune Response ◽

Kupffer Cells ◽

Immune Activation ◽

Innate Immune ◽

Host Cells ◽

Leishmania Infection ◽

Phagocytic Cells ◽

Zoonotic Visceral Leishmaniasis

L. infantum is the aetiological agent of zoonotic visceral leishmaniasis (ZVL), a disease that affects humans and dogs. Leishmania parasites are well adapted to aggressive conditions inside the phagolysosome and can control the immune activation of macrophages (MØs). Although MØs are highly active phagocytic cells with the capacity to destroy pathogens, they additionally comprise the host cells for Leishmania infection, replication, and stable establishment in the mammal host. The present study compares, for the first time, the innate immune response to L. infantum infection of two different macrophage lineages: the blood macrophages and the liver macrophages (Kupffer cells, KC). Our findings showed that L. infantum takes advantage of the natural predisposition of blood-MØs to phagocyte pathogens. However, parasites rapidly subvert the mechanisms of MØs immune activation. On the other hand, KCs, which are primed for immune tolerance, are not extensively activated and can overcome the dormancy induced by the parasite, exhibiting a selection of immune mechanisms, such as extracellular trap formation. Altogether, KCs reveal a different pattern of response in contrast with blood-MØs when confronting L. infantum parasites. In addition, KCs response appears to be more efficient in managing parasite infection, thus contributing to the ability of the liver to naturally restrain Leishmania dissemination.

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