Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

Guo, Chunhe; Zhu, Zhenbang; Guo, Yang; Wang, Xiaoying; Yu, Pengpeng; Xiao, Shuqi; Chen, Yaosheng; Cao, Yongchang; Liu, Xiaohong

doi:10.1128/jvi.00625-17

Cited by 34 publications

(35 citation statements)

References 40 publications

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“…We suspect that inhibition of viral HPSE upregulation or removal of the protein altogether will produce large reductions in virulence and manifestations of disease. Recently, HPSE has been shown to be upregulated and activated in multiple viral infections (Hadigal et al, 2015; Puerta-Guardo et al, 2016; Guo et al, 2017), suggesting that our findings will likely also apply to other pathogens outside of the herpesvirus family. With several HPSE-blocking agents currently in phase 1 and 2 clinical trials for various cancers, targeting HPSE in infection could be an effective and attainable strategy for which there already exists a wealth of clinical information.…”

Section: Resultsmentioning

confidence: 76%

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

et al. 2017

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Summary Herpes simplex virus type-1 (HSV-1) causes lifelong recurrent pathologies without a cure. How infection by HSV-1 triggers disease processes, especially in the immune-privileged avascular human cornea, remains a major unresolved puzzle. It has been speculated that a cornea-resident molecule must tip the balance in favor of pro-inflammatory and pro-angiogenic conditions observed with herpetic as well as non-herpetic ailments of the cornea. Here, we demonstrate that heparanase (HPSE), a host enzyme, is the molecular trigger for multiple pathologies associated with HSV-1 infection. In human corneal epithelial cells, HSV-1 infection upregulates HPSE in a manner dependent on HSV-1 infected cell protein 34.5. HPSE then relocates to the nucleus to regulate cytokine production, inhibits wound closure, enhances viral spread, and thus generates a toxic local environment. Overall, our findings implicate activated HPSE as a driver of viral pathogenesis, and call for further attention to this host protein in infection and other inflammatory disorders.

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Section: Resultsmentioning

confidence: 76%

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

et al. 2017

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“…HSV-2 encodes two envelope glycoproteins, gB and gC, which bind HS at the cell surface and initiate viral entry (17)(18)(19). We first reported that host-encoded HPSE is upregulated and required for the release of viral progeny from parent cells after HSV-1 infection, and subsequently, similar findings were reported for porcine reproductive and respiratory syndrome virus (PRRSV) infection (20,21).…”

mentioning

confidence: 70%

“…In this regard, HSV-2 does not have any known viral proteins that can cleave cell surface HS. HSV-2 may have found the ability to cleave HS nevertheless from a host enzyme (20,21). Given that HPSE is the only known mam- malian enzyme capable of cleaving HS chains (9-11), we hypothesized and then demonstrated that its upregulation during infection may be beneficial for HSV-2 release from host cells.…”

Section: Discussionmentioning

confidence: 96%

Host Enzymes Heparanase and Cathepsin L Promote Herpes Simplex Virus 2 Release from Cells

Hopkins

Yadavalli

Agelidis

et al. 2018

J Virol

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Herpes simplex virus 2 (HSV-2) can productively infect many different cell types of human and nonhuman origin. Here we demonstrate interconnected roles for two host enzymes, heparanase (HPSE) and cathepsin L, in HSV-2 release from cells. In vaginal epithelial cells, HSV-2 causes heparan sulfate shedding and upregulation in HPSE levels during the productive phase of infection. We also noted increased levels of cathepsin L and show that regulation of HPSE by cathepsin L via cleavage of HPSE proenzyme is important for infection. Furthermore, inhibition of HPSE by a specific inhibitor, OGT 2115, dramatically reduces HSV-2 release from vaginal epithelial cells. Likewise, we show evidence that the inhibition of cathepsin L is detrimental to the infection. The HPSE increase after infection is mediated by an increased NF-κB nuclear localization and a resultant activation of HPSE transcription. Together these mechanisms contribute to the removal of heparan sulfate from the cell surface and thus facilitate virus release from cells. Genital infections by HSV-2 represent one of the most common sexually transmitted viral infections. The virus causes painful lesions and sores around the genitals or rectum. Intermittent release of the virus from infected tissues during sexual activities is the most common cause of transmission. At the molecular level, cell surface heparan sulfate (HS) is known to provide attachment sites for HSV-2. While the removal of HS during HSV-1 release has been shown, not much is known about the host factors and their regulators that contribute to HSV-2 release from natural target cell types. Here we suggest a role for the host enzyme heparanase in HSV-2 release. Our work reveals that in addition to the regulation of transcription by NF-κB, HPSE is also regulated posttranslationally by cathepsin L and that inhibition of heparanase activity directly affects HSV-2 release. We provide unique insights into the host mechanisms controlling HSV-2 egress and spread.

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“…HSV-2 encodes for two envelop glycoproteins, gB and gC, which bind HS at the cell surface and initiate viral entry (17-19). We first reported that host-encoded HPSE is upregulated and required for the release of viral progeny from parent cells after HSV-1 infection and subsequently similar findings were reported for porcine reproductive and respiratory syndrome virus (PRRSV) infection(20, 21).…”

Section: Introductionmentioning

confidence: 52%

“…In this regard, HSV-2 does not have any known viral proteins that can cleave cell surface HS. HSV-2 may have found the ability to cleave HS nevertheless from a host enzyme (20, 21). Given that HPSE is the only known mammalian enzyme capable of cleaving HS chains (9), we hypothesized and then demonstrated that its upregulation during infection may be beneficial for HSV-2 release from host cells.…”

Section: Discussionmentioning

confidence: 99%

Host Enzymes Heparanase and Cathepsin L Promote Herpes Simplex Virus-2 Release from Cells

Hopkins

Yadavalli

Agelidis

et al. 2018

Preprint

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15Herpes simplex virus-2 (HSV-2) can productively infect many different cell types of human and 16 non-human origin. Here we demonstrate interconnected roles for two host enzymes, heparanase 17 (HPSE) and cathepsin L in HSV-2 release from cells. In vaginal epithelial cells and other cell lines 18 tested, HSV-2 causes heparan sulfate shedding and upregulation in HPSE levels during the 19 productive phase of infection. We also noted increased levels of cathepsin L and show that 20 regulation of HPSE by cathepsin L via cleavage of HPSE proenzyme is important for infection. 21 Furthermore, inhibition of HPSE by a specific inhibitor, OGT 2115, dramatically reduces HSV-2 22 release from vaginal epithelial cells. Likewise, we show evidence that the inhibition of cathepsin 23 L is detrimental to the infection. The HPSE increase after infection is mediated by an increased 24 NF-kB nuclear localization and a resultant activation of HPSE transcription. Together these 25 mechanisms contribute to the removal of heparan sulfate from the cell surface, and thus facilitate 26 virus release from cells. 27 Importance 28Genital infections by HSV-2 represent one of the most common sexually transmitted viral 29 infections. The virus causes painful lesions, and sores around the genitals or rectum. Intermittent 30 release of the virus from infected tissues during sexual activities is the most common cause of 31 transmission. At the molecular level, cell surface heparan sulfate (HS) is known to provide 32 attachment sites for HSV-2. While the removal of HS during HSV-1 release has been shown, not 33 much is known about the host factors and their regulators that contribute to HSV-2 release from 34 natural target cell types. Here we suggest a role for the host enzyme heparanase in HSV-2 release. 35 Our work reveals that in addition to the regulation of transcription by NF-kB, HPSE is also 36 3 regulated post-translationally by cathepsin L and that inhibition of heparanase activity directly 37 affects HSV-2 release. We provide unique insights into the host mechanisms controlling HSV-2 38 egress and spread. 39 Introduction 40 Genital herpes is one of the most common, persistent and highly infectious sexually transmitted 41 disease caused by herpes simplex virus type-2 (HSV-2) and in many emerging first-time cases, by 42 herpes simplex virus type-1 (HSV-1)(1-4). Primarily, the sites of infection include the vulva and 43 the vagina, with some cases involving the cervix and perianal region in women and typically on 44 the glans or the shaft of the penis in heterosexual men, whereas anal infection has also been 45 reported with homosexual men (5-7). Primary and recurrent genital herpes infections result in 46 lesions and inflammation around the genital area which are painful and cause distress (4). While 47 there is no vaccination or cure against HSV-2, resistance against current therapies, such as 48 Acyclovir, have been reported (8). Furthermore, these therapies are more than a decade old and 49 work on a single aspect of the viral life ...

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Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

Cited by 34 publications

References 40 publications

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

Viral Activation of Heparanase Drives Pathogenesis of Herpes Simplex Virus-1

Host Enzymes Heparanase and Cathepsin L Promote Herpes Simplex Virus 2 Release from Cells

Host Enzymes Heparanase and Cathepsin L Promote Herpes Simplex Virus-2 Release from Cells

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