Herpes Simplex Virus 1 VP22 Inhibits AIM2-Dependent Inflammasome Activation to Enable Efficient Viral Replication

Maruzuru, Yuhei; Ichinohe, Takeshi; Sato, Ryota; Miyake, Kensuke; Okano, Tokuju; Suzuki, Toshihiko; Koshiba, Takumi; Koyanagi, Naoto; Tsuda, Shumpei; Watanabe, Mizuki; Arii, Jun; Kato, Akihisa; Kawaguchi, Yasushi

doi:10.1016/j.chom.2017.12.014

Cited by 114 publications

(108 citation statements)

References 40 publications

(52 reference statements)

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“…The HSV-1 tegument protein VP22 blocks activation of the AIM2 inflammasome [21] and; therefore, it is unsurprising that we failed to find a dependence on AIM2. However, it is possible that HSV-1 has evolved multiple mechanisms to alter inflammasome activation.…”

Section: Resultsmentioning

confidence: 98%

“…HSV-1 is known to activate the inflammasome in THP-1 cells, but the mechanisms is unknown and it has not been studied extensively in primary human macrophages [20,21]. To determine if HSV-1 is capable of activating the inflammasome in primary human monocyte derived macrophages (MDM), we inoculated both unstimulated macrophages (referred to as M0) and macrophages incubated for 24 hours with IFNγ (referred to as M1) [22,23] with HSV-1, media alone, or nigericin and LPS (a potent activator of the NLRP3 inflammasome [24]) and then measured IL-18 in supernatants 24 hours later.…”

Section: Resultsmentioning

confidence: 99%

“…Although CMV, a closely related herpesvirus, was recently discovered to activate the inflammasome through AIM2 [33], initial studies on HSV-1 inflammasome activation in macrophages did not find a dependence on AIM2 [20]. This finding was explained by the discovery that VP22 specifically inhibits the interaction between AIM2 and the HSV genome [21]. In agreement with these studies, our current investigation found that AIM2 was not required for HSV-1 to activate the inflammasome in THP-1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, understanding how HSV-1 activates the inflammasome in these cells is key to developing a comprehensive view of HSV-1 pathogenesis. A previous study demonstrated that the HSV-1 viral tegument protein VP22 specifically blocks AIM2 inflammasome activation and signaling in the THP-1 monocyte/macrophage cell line despite production of IL-1β, leaving the mechanism of HSV-1 activation of the inflammasome in these cells to be defined [20,21]. Thus, it remains unclear which adapters are required for HSV-1 induction of inflammasome activation in macrophages.…”

Section: Introductionmentioning

confidence: 99%

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Herpes Simplex Virus type 1 Inflammasome Activation in Human Macrophages is Dependent on NLRP3, ASC, and Caspase-1

Karaba

Figueroa

Massaccesi

et al. 2019

Preprint

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20 Review and Editing 21 22 23 Abstract:24 The pro-inflammatory cytokines interleukin (IL)-1 and IL-18 are products of activation of the 25 inflammasome, an innate sensing system, and important in the pathogenesis of herpes simplex 26 type 1 (HSV-1). The release of IL-18 and IL-1 from monocytes/macrophages is critical for 27 protection from HSV-1 based on animal models of encephalitis and genital infection, yet if and 28 how HSV-1 activates inflammasomes in human macrophages is unknown. To investigate this, 29 we utilized both primary human monocyte derived macrophages and human monocytic cell 30 lines (THP-1 cells) with various inflammasome components knocked-out. We found that HSV-1 31 activates inflammasome signaling in pro-inflammatory primary human macrophages.32 Additionally, HSV-1 inflammasome activation is dependent on nucleotide-binding domain and 33 leucine-rich repeat-containing receptor 3 (NLRP3), apoptosis-associated speck-like molecule 34 containing a caspase recruitment domain (ASC), and caspase-1, but not on absent in melanoma 35 2 (AIM2), or gamma interferon-inducible protein 16 (IFI16). Ultraviolet irradiation of HSV-1 36 enhanced inflammasome activation, demonstrating that viral replication suppresses 37 inflammasome activation. These results confirm that HSV-1 is capable of activating the 38 inflammasome in human macrophages through an NLRP3 dependent process and that the virus 39 has an NLRP3 specific mechanism to inhibit inflammasome activation in monocytes and 40 macrophages. 41 42 43 44 3 45 Author Summary: 46The inflammasome is a multi-protein complex that forms in response to pathogens and 47 cellular damage. Active inflammasomes recruit pro-caspase-1 via ASC and cleave the cytokine 48 precursors pro-IL-1 and pro-IL-18 into mature IL-1 and IL-18. These cytokines serve to 49 activate other immune cells that either repair the damage or attempt to clear the invading 50 pathogen. Upon activation, the inflammasome also promotes an inflammatory form of cell 51 death called pyroptosis. Herpes simplex virus type 1 (HSV-1) is a common human pathogen that 52 can cause cold sores, genital ulcers, encephalitis, and blindness. HSV-1 infection leads to 53 induction of IL-1 and IL-18, but whether it is capable of activating inflammasomes in 54 macrophages, which play a role in severe forms of HSV-1 infection, was unclear. Here, we 55 infected both primary human macrophages and a macrophage/monocytic cell line, THP-1 cells, 56 with HSV-1. We found that HSV-1 does activate inflammasome signaling in macrophages in a 57 process dependent on NLRP3, ASC, and caspase-1. This is important because it illustrates the 58 mechanism by which HSV-1 infection leads to inflammasome activation in macrophages, known 59 to be crucial for protection from severe disease in mouse models. 60 61 62 63 64 65 66 4 67 Introduction: 68 The ability to quickly recognize and respond to pathogens is essential to host survival. 69 The first opportunity to do so lies in the innate immune response. One of the most essential 70 aspe...

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Herpes Simplex Virus type 1 Inflammasome Activation in Human Macrophages is Dependent on NLRP3, ASC, and Caspase-1

Karaba

Figueroa

Massaccesi

et al. 2019

Preprint

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show abstract

“…Activated caspase-1 then cleaves pro-IL-1β or pro-IL-18 enabling the release of the mature active cytokines IL-1β and IL-18 (Fernandes-Alnemri et al, 2009;Hornung et al, 2009;Roberts et al, 2009). AIM2 also has a crucial role in the development of the innate immune response against pathogen infections that include Francisella tularensis (Fernandes-Alnemri et al, 2010), HSV-1 (Maruzuru et al, 2018) and human papillomavirus (Reinholz et al, 2013). IFI16 is also a member of the ALR family.…”

Section: Alrsmentioning

confidence: 99%

Discrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System

Kawasaki

Kawai

2019

International Review of Cell and Molecular Biology

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During viral and bacterial infections, the innate immune system recognizes various types of pathogen-associated molecular patterns (PAMPs), such as nucleic acids, via a series of membrane-bound or cytosolic pattern-recognition receptors. These include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), AIM2-like receptors (ALRs), and cytosolic DNA sensors. The binding of PAMPs to these receptors triggers the production of type I interferon (IFN) and inflammatory cytokines. Type I IFN induces the expression of interferon stimulated genes (ISGs), which protect surrounding cells from infection. Some ISGs are nucleic acids-binding proteins that bind viral nucleic acids and suppress their replication. As nucleic acids are essential components that store and transmit genetic information in every species, infectious pathogens have developed systems to escape from the host nucleic acid recognition system. Host cells also have their own nucleic acids that are frequently released to the extracellular milieu or the cytoplasm during cell death or stress responses, which, if able to bind pattern-recognition receptors, would induce autoimmunity and inflammation. Therefore, host cells have acquired mechanisms to protect themselves from contact with their own nucleic acids. In this review, we describe recent research progress into the nucleic acid recognition mechanism and the molecular bases of discrimination between self and non-self-nucleic acids.

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Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

2019

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AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.Keywords: AIM2 r cell death r gasdermin r inflammasome r pyroptosis

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Herpes Simplex Virus 1 VP22 Inhibits AIM2-Dependent Inflammasome Activation to Enable Efficient Viral Replication

Cited by 114 publications

References 40 publications

Herpes Simplex Virus type 1 Inflammasome Activation in Human Macrophages is Dependent on NLRP3, ASC, and Caspase-1

Herpes Simplex Virus type 1 Inflammasome Activation in Human Macrophages is Dependent on NLRP3, ASC, and Caspase-1

Discrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

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