αvβ3-integrin is a major sensor and activator of innate immunity to herpes simplex virus-1

Gianni, Tatiana; Leoni, Valerio; Chesnokova, Liudmila S.; Hutt-Fletcher, Lindsey; Campadelli-Fiume, Gabriella

doi:10.1073/pnas.1212597109

Cited by 60 publications

(112 citation statements)

References 51 publications

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“…This is supported by evidence that integrins can serve as specific receptors for EBV and HSV gH/gL and may provide the viral fusion trigger or promote viral endocytosis (64,(96)(97)(98)(99). Competition studies have revealed that cell surface expression of the PC, but not the gH/gL complex, the UL128/ UL130/UL131a complex, or gB, on the surfaces of epithelial cells can prevent CMV infection, implying that the PC may be involved in receptor binding by the virus (34) (Fig.…”

Section: Gh/gl Complexes Critical Determinants Of Tropismmentioning

confidence: 68%

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Gardner

Tortorella

2016

Microbiol Mol Biol Rev

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SUMMARYThe prototypic herpesvirus human cytomegalovirus (CMV) exhibits the extraordinary ability to establish latency and maintain a chronic infection throughout the life of its human host. This is even more remarkable considering the robust adaptive immune response elicited by infection and reactivation from latency. In addition to the ability of CMV to exist in a quiescent latent state, its persistence is enabled by a large repertoire of viral proteins that subvert immune defense mechanisms, such as NK cell activation and major histocompatibility complex antigen presentation, within the cell. However, dissemination outside the cell presents a unique existential challenge to the CMV virion, which is studded with antigenic glycoprotein complexes targeted by a potent neutralizing antibody response. The CMV virion envelope proteins, which are critical mediators of cell attachment and entry, possess various characteristics that can mitigate the humoral immune response and prevent viral clearance. Here we review the CMV glycoprotein complexes crucial for cell attachment and entry and propose inherent properties of these proteins involved in evading the CMV humoral immune response. These include viral glycoprotein polymorphism, epitope competition, Fc receptor-mediated endocytosis, glycan shielding, and cell-to-cell spread. The consequences of CMV virion glycoprotein-mediated immune evasion have a major impact on persistence of the virus in the population, and a comprehensive understanding of these evasion strategies will assist in designing effective CMV biologics and vaccines to limit CMV-associated disease.

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Section: Gh/gl Complexes Critical Determinants Of Tropismmentioning

confidence: 68%

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Gardner

Tortorella

2016

Microbiol Mol Biol Rev

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“…Importantly, these studies were performed with virus and human cells, rather than recombinant and/or tagged viral proteins, as the structure and function of individual components may be impacted by viruscell interactions and other envelope glycoproteins. Indeed, no interaction between gH and ␣v␤3 was detected by proximity ligation assay in response to ⌬gD or ⌬gB virus (expressing gH), although soluble gH-gL can bind to immobilized integrin ␣v␤3 (16).…”

Section: Discussionmentioning

confidence: 99%

“…However, other work also links the virusinduced Akt/integrin/Ca 2ϩ cascade to innate immune responses. For example, using 293T cells, Campadelli-Fiume and colleagues have shown that integrin ␣v␤3 relocates HSV-1 to cholesterol-rich membrane microdomains where the virus activates innate responses through Toll-like receptor 2 (TLR2)-dependent and TLR2-independent pathways (16). Moreover, HSV virus-like particles induced the expression of interferon-stimulated genes, including CXCL10 in dendritic cells, but the response was dependent on Akt activation, as drugs that blocked Akt phosphorylation prevented the CXCL10 response (38).…”

Section: Discussionmentioning

confidence: 99%

“…Glycoprotein H (which forms heteroligomers with gL) is also essential for viral entry and cell-to-cell spread and has been implicated in regulating the fusogenic activity of gB (12,13). Several studies suggest that gH-gL may interact with integrins at the plasma membrane, although the findings have been inconsistent (5,(14)(15)(16)(17)(18)(19)(20). Viruses can induce conformational changes and/or clustering of integrins to elicit cell signaling, cytoskeletal rearrangement, and viral internalization (21).…”

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confidence: 99%

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Herpes Simplex Virus Type 2 Glycoprotein H Interacts with Integrin αvβ3 To Facilitate Viral Entry and Calcium Signaling in Human Genital Tract Epithelial Cells

Cheshenko

Trépanier

González

et al. 2014

J Virol

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Herpes simplex virus (HSV) entry requires multiple interactions at the cell surface and activation of a complex calcium signaling cascade. Previous studies demonstrated that integrins participate in this process, but their precise role has not been determined. These studies were designed to test the hypothesis that integrin ␣v␤3 signaling promotes the release of intracellular calcium (Ca 2؉ ) stores and contributes to viral entry and cell-to-cell spread. Transfection of cells with small interfering RNA (siRNA) targeting integrin ␣v␤3, but not other integrin subunits, or treatment with cilengitide, an Arg-Gly-Asp (RGD) mimetic, impaired HSV-induced Ca 2؉ release, viral entry, plaque formation, and cell-to-cell spread of HSV-1 and HSV-2 in human cervical and primary genital tract epithelial cells. Coimmunoprecipitation studies and proximity ligation assays indicated that integrin ␣v␤3 interacts with glycoprotein H (gH). An HSV-2 gH-null virus was engineered to further assess the role of gH in the virus-induced signaling cascade. The gH-2-null virus bound to cells and activated Akt to induce a small Ca 2؉ response at the plasma membrane, but it failed to trigger the release of cytoplasmic Ca 2؉ stores and was impaired for entry and cell-to-cell spread. Silencing of integrin ␣v␤3 and deletion of gH prevented phosphorylation of focal adhesion kinase (FAK) and the transport of viral capsids to the nuclear pore. Together, these findings demonstrate that integrin signaling is activated downstream of virus-induced Akt signaling and facilitates viral entry through interactions with gH by activating the release of intracellular Ca 2؉ and FAK phosphorylation. These findings suggest a new target for HSV treatment and suppression. IMPORTANCEHerpes simplex viruses are the leading cause of genital disease worldwide, the most common infection associated with neonatal encephalitis, and a major cofactor for HIV acquisition and transmission. There is no effective vaccine. These epidemiological findings underscore the urgency to develop novel HSV treatment or prevention strategies. This study addresses this gap by further defining the signaling pathways the virus usurps to enter human genital tract epithelial cells. Specifically, the study defines the role played by integrins and by the viral envelope glycoprotein H in entry and cell-to-cell spread. This knowledge will facilitate the identification of new targets for the development of treatment and prevention.

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“…To investigate whether ␣v␤3 integrin acts in concert with plasma membrane TLRs other than TLR2, we made use of a 293T-derivative cell line in which ␤3 integrin was stably silenced by means of a lentivirus encoding a short hairpin RNA (shRNA; herein called 293Tsh␤3 cells). Depletion of ␤3 integrin was ascertained through a 70% reduction in both ␤3 mRNA and ␤3 protein compared to those in cells transduced with a control shRNA (14,15). We measured the NF-B activation in 293T and 293Tsh␤3 cells transfected with the appropriate TLRs and exposed to HSV or bacterial PAMPs.…”

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confidence: 99%

αvβ3 Integrin Boosts the Innate Immune Response Elicited in Epithelial Cells through Plasma Membrane and Endosomal Toll-Like Receptors

Casiraghi

Gianni

Campadelli-Fiume

2016

J Virol

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We report that ␣v␤3 integrin strongly affects the innate immune response in epithelial cells. ␣v␤3 integrin greatly increased the response elicited via plasma membrane Toll-like receptors (TLRs) by herpes simplex virus or bacterial ligands. The endosomal TLR3, not the cytosolic sensor interferon gamma-inducible protein 16 (IFI16), was also boosted by ␣v␤3 integrin. The boosting was exerted specifically by ␣v␤3 integrin but not by ␣v␤6 or ␣v␤8 integrin. Current and previous work indicates that integrin-TLR cooperation occurs in epithelial and monocytic cells. The TLR response should be considered an integrin-TLR response. The Toll-like receptors (TLRs) constitute the first line of defense against invading pathogens (1). They include TLR1, TLR2, and TLR4 to TLR6, which are localized at the plasma membrane, and TLR3, TLR7, and TLR9, which are localized at endosomal membranes (1). TLR2 can be expressed as a homodimer or as a heterodimer with TLR1 or TLR6. The plasma membrane TLRs recognize pathogen-associated molecular patterns (PAMPs) present on the surfaces of bacteria (e.g., lipopolysaccharide [LPS], flagellin) or of viruses (e.g., virion envelope glycoproteins). The endosomal TLRs recognize viral or bacterial DNA or RNA.Integrins are cell surface glycoproteins involved in cell-cell and cell-matrix interactions. They are composed of an ␣ and a ␤ subunit (2-4). They serve as receptors for several viruses, including some herpesviruses (5-10). Our laboratory investigated the role played by integrins in herpes simplex virus (HSV) entry and found that ␣v␤6 and ␣v␤8 integrins serve as interchangeable receptors for HSV entry into epithelial and neuronal cells (11). They bind the envelope glycoproteins gH and gL (gH/gL), a heterodimeric component of the fusion machinery, with high affinity (11). Their interaction with gH/gL promotes virion endocytosis and the displacement of gL from gH, most likely as part of the process of gH activation (12). An additional integrin involved in HSV entry is ␣v␤3, which serves two functions. It binds gH/gL at low affinity and routes HSV to lipid rafts and an acidic endosomal pathway of entry and thus serves as a routing factor (13). Importantly, it contributes to the innate immune response through a concerted action with TLR2 (14-16). In epithelial cell lines, including keratinocytic and neuronal cells, interferon alpha (IFN-␣) and IFN-␤, interleukin 2, and interleukin 10 are upregulated, and NF-B is activated in response to HSV or to LPS (14). This response is strongly impaired in the absence of TLR2 or upon ␤3-integrin depletion. The HSV PAMP is gH/gL, which simultaneously binds ␣v␤3 integrin and TLR2 and thus cross-links the two receptors (14). The basis of the concerted ␣v␤3 integrin-TLR2 response rests in boosting by ␣v␤3 integrin of MYD88-dependent TLR2 signaling (16).Here, we asked whether the concerted integrin-TLR response is a broader phenomenon that involves epithelial integrins other than ␣v␤3 (e.g., ␣v␤6 and ␣v␤8) or additional TLRs. To address this question, 293T cells and t...

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αvβ3-integrin is a major sensor and activator of innate immunity to herpes simplex virus-1

Cited by 60 publications

References 51 publications

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

Herpes Simplex Virus Type 2 Glycoprotein H Interacts with Integrin αvβ3 To Facilitate Viral Entry and Calcium Signaling in Human Genital Tract Epithelial Cells

αvβ3 Integrin Boosts the Innate Immune Response Elicited in Epithelial Cells through Plasma Membrane and Endosomal Toll-Like Receptors

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