Herpes Simplex Virus 1 Infection Induces Activation and Subsequent Inhibition of the IFI16 and NLRP3 Inflammasomes
TL;DR: The results suggest that though the host cell responds to HSV-1 infection by IFI16 and NLRP3 inflammasomes early during infection, HSv-1 has evolved mechanisms to shut down these responses to evade the proinflammatory consequences.
Abstract: Inflammasomes are multiprotein complexes that recognize pathogens and pathogen- or danger-associated molecular patterns. They induce the maturation and secretion of powerful proinflammatory interleukin-1B (IL-1β), IL-18, and IL-33 cytokines, which in turn activate expression of other immune genes and lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Inflammasomes are comprised of cytoplasmic sensor molecules, such as NLRP3 and AIM2 or nuclear sensor IFI16, the adaptor protein ASC (apoptosis-associated speck-like protein containing CARD), and the effector protein procaspase-1. Herpes simplex virus 1 (HSV-1), a ubiquitous virus that infects humans and establishes life-long latency, has evolved numerous mechanisms to evade host detection and immune responses. Here, we show that early during in vitro infection of human foreskin fibroblasts (2 to 4 h), HSV-1 induced the activation of the IFI16 and NLRP3 inflammasomes and maturation of IL-1β. Independent of viral gene expression, IFI16 recognized the HSV-1 genome in infected cell nuclei, relocalized, and colocalized with ASC in the cytoplasm. However, HSV-1 specifically targeted IFI16 for rapid proteasomic degradation at later times postinfection, which was dependent on the expression of ICP0, an immediate early protein of HSV-1. In contrast, NLRP3, AIM2, and ASC levels were not decreased. Also, caspase-1 was "trapped" in actin clusters at later time points that likely blocked the NLRP3/IFI16 inflammasome activity. In addition, the secretion of mature IL-1β was inhibited. These results suggest that though the host cell responds to HSV-1 infection by IFI16 and NLRP3 inflammasomes early during infection, HSV-1 has evolved mechanisms to shut down these responses to evade the proinflammatory consequences.
Citations
More filters
TL;DR: Genetic studies indicate that mutations in NLRP1, NLRP3, NLRC4, and AIM2 are linked with the development of auto‐inflammatory diseases, enterocolitis, and cancer and transform the understanding of the basic biology and clinical relevance of inflammasomes.
Abstract: Inflammasome biology is one of the most exciting and rapidly growing areas in immunology. Over the past 10 years, inflammasomes have been recognized for their roles in the host defense against invading pathogens and in the development of cancer, autoinflammatory, metabolic, and neurodegenerative diseases. Assembly of an inflammasome complex requires cytosolic sensing of pathogen-associated molecular patterns or danger-associated molecular patterns by a nucleotide-binding domain and leucine-rich repeat receptor (NLR) or absent in melanoma 2-like receptor (ALR). NLRs and ALRs engage caspase-1, in most cases requiring the adapter protein apoptosis-associated speck-like protein containing a CARD (ASC), to catalyze proteolytic cleavage of pro-interleukin-1β (pro-IL-1β) and pro-IL-18 and drive pyroptosis. Recent studies indicate that caspase-8, caspase-11, IL-1R–associated kinases (IRAK), and receptor-interacting protein (RIP) kinases contribute to inflammasome functions. In addition, post-translational modifications, including ubiquitination, deubiquitination, phosphorylation, and degradation, control almost every aspect of inflammasome activities. Genetic studies indicate that mutations in NLRP1, NLRP3, NLRC4, and AIM2 are linked to the development of autoinflammatory diseases, enterocolitis, and cancer. Overall, these findings transform our understanding of the basic biology and clinical relevance of inflammasomes. In this review, we provide an overview of the latest development of inflammasome research and discuss how inflammasome activities govern health and disease.
736 citations
Cites background from "Herpes Simplex Virus 1 Infection In..."
...IFI16 initiates inflammasome activities in response to Kaposi sarcoma-associated herpesvirus (212), Epstein–Barr virus (213), and herpes simplex virus-1 (HSV-1) (214)....
[...]
...Intriguingly, IFI16 also activates the STING and TBK1 signaling axis to drive IFN-b induction in cells infected with HSV-1 and human CMV (211, 215)....
[...]
...IFI16 initiates inflammasome activities in response to Kaposi sarcoma-associated herpesvirus (212), Epstein–Barr virus (213), and herpes simplex virus-1 (HSV-1) (214)....
[...]
TL;DR: Recent findings that provide fresh insights on the role of inflammasomes across cell types and disease states in the brain are discussed.
Abstract: The mammalian CNS is an intricate and fragile structure, which on one hand is open to change in order to store information, but on the other hand is vulnerable to damage from injury, pathogen invasion or neurodegeneration. During senescence and neurodegeneration, activation of the innate immune system can occur. Inflammasomes are signalling complexes that regulate cells of the immune system, which in the brain mainly includes microglial cells. In microglia, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome becomes activated when these cells sense proteins such as misfolded or aggregated amyloid-β, α-synuclein and prion protein or superoxide dismutase, ATP and members of the complement pathway. Several other inflammasomes have been described in microglia and the other cells of the brain, including astrocytes and neurons, where their activation and subsequent caspase 1 cleavage contribute to disease development and progression.
460 citations
TL;DR: One of the most exciting developments in the field of bacterial pathogenesis in recent years is the discovery that many pathogens utilize complex nanomachines to deliver bacterially encoded effector proteins into target eukaryotic cells.
Abstract: One of the most exciting developments in the field of bacterial pathogenesis in recent years is the discovery that many pathogens utilize complex nanomachines to deliver bacterially encoded effector proteins into target eukaryotic cells. These effector proteins modulate a variety of cellular functions for the pathogen's benefit. One of these protein-delivery machines is the type III secretion system (T3SS). T3SSs are widespread in nature and are encoded not only by bacteria pathogenic to vertebrates or plants but also by bacteria that are symbiotic to plants or insects. A central component of T3SSs is the needle complex, a supramolecular structure that mediates the passage of the secreted proteins across the bacterial envelope. Working in conjunction with several cytoplasmic components, the needle complex engages specific substrates in sequential order, moves them across the bacterial envelope, and ultimately delivers them into eukaryotic cells. The central role of T3SSs in pathogenesis makes them great targets for novel antimicrobial strategies.
437 citations
Cites background from "Herpes Simplex Virus 1 Infection In..."
...HSV-1 ICP0 promotes the degradation of IFI16 in normal human fibroblasts (33, 57)....
[...]
...IFI16-dependent activation of inflammasome signaling has also been demonstrated in human fibroblasts during HSV-1 infection (33)....
[...]
TL;DR: Direct evidence is provided that SARS-CoV 3a protein activates the NLRP3 inflammasome in lipopolysaccharide-primed macrophages, highlighting the importance of viroporins, transmembrane pore-forming viral proteins, in virus-induced NLRP2 inflammaome activation.
Abstract: Nod-like receptor family, pyrin domain-containing 3 (NLRP3) regulates the secretion of proinflammatory cytokines interleukin 1 beta (IL-1β) and IL-18. We previously showed that influenza virus M2 or encephalomyocarditis virus (EMCV) 2B proteins stimulate IL-1β secretion following activation of the NLRP3 inflammasome. However, the mechanism by which severe acute respiratory syndrome coronavirus (SARS-CoV) activates the NLRP3 inflammasome remains unknown. Here, we provide direct evidence that SARS-CoV 3a protein activates the NLRP3 inflammasome in lipopolysaccharide-primed macrophages. SARS-CoV 3a was sufficient to cause the NLRP3 inflammasome activation. The ion channel activity of the 3a protein was essential for 3a-mediated IL-1β secretion. While cells uninfected or infected with a lentivirus expressing a 3a protein defective in ion channel activity expressed NLRP3 uniformly throughout the cytoplasm, NLRP3 was redistributed to the perinuclear space in cells infected with a lentivirus expressing the 3a protein. K+ efflux and mitochondrial reactive oxygen species were important for SARS-CoV 3a-induced NLRP3 inflammasome activation. These results highlight the importance of viroporins, transmembrane pore-forming viral proteins, in virus-induced NLRP3 inflammasome activation.
409 citations
Cites background from "Herpes Simplex Virus 1 Infection In..."
...Activation of the NLRP3 inflammasome led to a redistribution from the cytosol to the perinuclear space, a process considered as a hallmark of NLRP3 activation (Zhou et al., 2011; Ito et al., 2012; Johnson et al., 2013; Moriyama et al., 2016)....
[...]
TL;DR: The balance between host immune control and viral immune evasion is pivotal to viral pathogenesis, and the balance is discussed in the context of the cGAS-STING innate immune pathway.
282 citations
Cites background from "Herpes Simplex Virus 1 Infection In..."
...For example, IFI16 has been described as a nuclear viral DNA sensor that is important for HSV-1 triggered IRF3 C signaling and induction of inflammasomes (Johnson et al., 2013; Morrone et al., 2014; Orzalli et al., 2012)....
[...]
References
More filters
TL;DR: A member of theIL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T( H)2 cells is reported.
3,306 citations
TL;DR: Using mouse and human cells, the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) is identified as a receptor for cytosolic DNA, which regulates caspase-1.
Abstract: The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIH1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes. A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1beta and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-kappaB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.
2,174 citations
"Herpes Simplex Virus 1 Infection In..." refers background in this paper
...IFI16 is typically localized to the nucleus (28) but translocates to the cytoplasm in association with ASC following KSHV infection of endothelial cells (25)....
[...]
TL;DR: A model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS) is suggested.
Abstract: This Opinion article discusses the evidence for and the limitations of the three main models of inflammasome activation. The authors propose that the production of reactive oxygen species might be a common factor downstream of many types of inflammasome activator. The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that activates caspase 1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. The NLRP3 inflammasome is activated by a wide range of danger signals that derive not only from microorganisms but also from metabolic dysregulation. It is unclear how these highly varied stress signals can be detected by a single inflammasome. In this Opinion article, we review the different signalling pathways that have been proposed to engage the NLRP3 inflammasome and suggest a model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS).
1,492 citations
"Herpes Simplex Virus 1 Infection In..." refers background in this paper
...The mechanisms of the second step of NLRP3 inflammasome activation are unknown as of yet (12)....
[...]
...Because of the range of stimuli that activate the NLRP3 inflammasome, it is hypothesized that NLRP3 does not directly recognize all of its agonists but, instead, senses a change or changes in its direct environment that is a shared result of the stimuli (12)....
[...]
TL;DR: This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.
Abstract: Host- and pathogen-associated cytoplasmic double-stranded DNA triggers the activation of a NALP3 (also known as cryopyrin and NLRP3)-independent inflammasome, which activates caspase-1 leading to maturation of pro-interleukin-1beta and inflammation. The nature of the cytoplasmic-DNA-sensing inflammasome is currently unknown. Here we show that AIM2 (absent in melanoma 2), an interferon-inducible HIN-200 family member that contains an amino-terminal pyrin domain and a carboxy-terminal oligonucleotide/oligosaccharide-binding domain, senses cytoplasmic DNA by means of its oligonucleotide/oligosaccharide-binding domain and interacts with ASC (apoptosis-associated speck-like protein containing a CARD) through its pyrin domain to activate caspase-1. The interaction of AIM2 with ASC also leads to the formation of the ASC pyroptosome, which induces pyroptotic cell death in cells containing caspase-1. Knockdown of AIM2 by short interfering RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in human and mouse macrophages, whereas stable expression of AIM2 in the non-responsive human embryonic kidney 293T cell line conferred responsiveness to cytoplasmic DNA. Our results show that cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization. This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.
1,471 citations
TL;DR: IFI16 (p204) is the first PYHIN protein to their knowledge shown to be involved in IFN-β induction and forms a new family of innate DNA sensors the authors call 'AIM2-like receptors' (ALRs).
Abstract: The detection of intracellular microbial DNA is critical to appropriate innate immune responses; however, knowledge of how such DNA is sensed is limited. Here we identify IFI16, a PYHIN protein, as an intracellular DNA sensor that mediates the induction of interferon-β (IFN-β). IFI16 directly associated with IFN-β-inducing viral DNA motifs. STING, a critical mediator of IFN-β responses to DNA, was recruited to IFI16 after DNA stimulation. Lowering the expression of IFI16 or its mouse ortholog p204 by RNA-mediated interference inhibited gene induction and activation of the transcription factors IRF3 and NF-κB induced by DNA and herpes simplex virus type 1 (HSV-1). IFI16 (p204) is the first PYHIN protein to our knowledge shown to be involved in IFN-β induction. Thus, the PYHIN proteins IFI16 and AIM2 form a new family of innate DNA sensors we call 'AIM2-like receptors' (ALRs).
1,440 citations
"Herpes Simplex Virus 1 Infection In..." refers background in this paper
...recognize HSV-1 infection and activate IRF3 to stimulate IFNexpression (34, 52)....
[...]
...Though IFI16 has been shown to interact with HSV-1 DNA in two recent studies, the authors of these studies used overexpressed IFI16 or a transfected 60-mer DNA sequence from the HSV-1 genome to detect the interaction (26, 52, 54)....
[...]
...The restriction of IFI16 on HSV-1 could be due to a similar mechanism, to the induction of interferon transcription through the IFI16-STING signaling pathway (34, 52), to activation of the inflammasome, or, very likely, to a combination of the three....
[...]
...The capacity of IFI16 to localize to the cytoplasm has been demonstrated previously (25, 26, 52)....
[...]
...IFI16 has been shown to May 2013 Volume 87 Number 9 jvi.asm.org 5007 recognize HSV-1 infection and activate IRF3 to stimulate IFNexpression (34, 52)....
[...]