Cathelicidin LL-37 and HSV-1 Corneal Infection

Peptide Versus Gene Therapy

Chyan-Jang Lee, Oleksiy Buznyk, Lucia Kuffova, Vijayalakshmi Rajendran, John V Forrester, Jaywant Phopase, Mohammad M Islam, Mårten Skog, Jenny Ahlqvist, May Griffith

Research output: Contribution to journalArticle

Abstract

PURPOSE: To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37.

METHODS: We tested the ability of collagen-phosphorylcholine implants to tolerate the adverse microenvironment of herpetic murine corneas. Then, we investigated the efficacy of LL-37 peptides delivered through nanoparticles incorporated within the corneal implants to block HSV-1 viral activity. In addition, LL-37 complementary DNA (cDNA) was transferred into HCECs to confer viral resistance, and their response to HSV-1 infection was examined.

RESULTS: Our implants remained in herpetic murine corneas 7 days longer than allografts. LL-37 released from the implants blocked HSV-1 infection of HCECs by interfering with viral binding. However, in pre-infected HCECs, LL-37 delayed but could not prevent viral spreading nor clear viruses from the infected cells. HCECs transfected with the LL-37 expressed and secreted the peptide. Secreted LL-37 inhibited viral binding in vitro but was insufficient to protect cells completely from HSV-1 infection. Nevertheless, secreted LL-37 reduced both the incidence of plaque formation and plaque size.

CONCLUSION: LL-37 released from composite nanoparticle-hydrogel corneal implants and HCEC-produced peptide, both showed anti-HSV-1 activity by blocking binding. However, while both slowed down virus spread, neither was able on its own to completely inhibit the viruses.

TRANSLATIONAL RELEVANCE: LL-37 releasing hydrogels may have potential utility as corneal substitutes for grafting in HSV-1 infected corneas, possibly in combination with LL-37 producing therapeutic cells.

Original languageEnglish
Pages (from-to)4
JournalTranslational vision science & technology
Volume3
Issue number3
DOIs
Publication statusPublished - May 2014

Fingerprint

Gene therapy
Human Herpesvirus 1
Viruses
Genetic Therapy
Peptides
Epithelial Cells
Infection
Virus Diseases
Nanoparticles
Cornea
Collagen
Hydrogels
Corneal Transplantation
Phosphorylcholine
Hydrogel
CAP18 lipopolysaccharide-binding protein
Allografts
Complementary DNA
DNA
Incidence

Keywords

  • cornea
  • HSV-1
  • antiviral peptides
  • nanoparticles
  • gene transfer

Cite this

Cathelicidin LL-37 and HSV-1 Corneal Infection : Peptide Versus Gene Therapy. / Lee, Chyan-Jang; Buznyk, Oleksiy; Kuffova, Lucia; Rajendran, Vijayalakshmi; Forrester, John V; Phopase, Jaywant; Islam, Mohammad M; Skog, Mårten; Ahlqvist, Jenny; Griffith, May.

In: Translational vision science & technology, Vol. 3, No. 3, 05.2014, p. 4.

Research output: Contribution to journalArticle

Lee, C-J, Buznyk, O, Kuffova, L, Rajendran, V, Forrester, JV, Phopase, J, Islam, MM, Skog, M, Ahlqvist, J & Griffith, M 2014, 'Cathelicidin LL-37 and HSV-1 Corneal Infection: Peptide Versus Gene Therapy', Translational vision science & technology, vol. 3, no. 3, pp. 4. https://doi.org/10.1167/tvst.3.3.4
Lee, Chyan-Jang ; Buznyk, Oleksiy ; Kuffova, Lucia ; Rajendran, Vijayalakshmi ; Forrester, John V ; Phopase, Jaywant ; Islam, Mohammad M ; Skog, Mårten ; Ahlqvist, Jenny ; Griffith, May. / Cathelicidin LL-37 and HSV-1 Corneal Infection : Peptide Versus Gene Therapy. In: Translational vision science & technology. 2014 ; Vol. 3, No. 3. pp. 4.
@article{0bf01a7e3a9a49cea2d05c412e688b07,
title = "Cathelicidin LL-37 and HSV-1 Corneal Infection: Peptide Versus Gene Therapy",
abstract = "PURPOSE: To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37.METHODS: We tested the ability of collagen-phosphorylcholine implants to tolerate the adverse microenvironment of herpetic murine corneas. Then, we investigated the efficacy of LL-37 peptides delivered through nanoparticles incorporated within the corneal implants to block HSV-1 viral activity. In addition, LL-37 complementary DNA (cDNA) was transferred into HCECs to confer viral resistance, and their response to HSV-1 infection was examined.RESULTS: Our implants remained in herpetic murine corneas 7 days longer than allografts. LL-37 released from the implants blocked HSV-1 infection of HCECs by interfering with viral binding. However, in pre-infected HCECs, LL-37 delayed but could not prevent viral spreading nor clear viruses from the infected cells. HCECs transfected with the LL-37 expressed and secreted the peptide. Secreted LL-37 inhibited viral binding in vitro but was insufficient to protect cells completely from HSV-1 infection. Nevertheless, secreted LL-37 reduced both the incidence of plaque formation and plaque size.CONCLUSION: LL-37 released from composite nanoparticle-hydrogel corneal implants and HCEC-produced peptide, both showed anti-HSV-1 activity by blocking binding. However, while both slowed down virus spread, neither was able on its own to completely inhibit the viruses.TRANSLATIONAL RELEVANCE: LL-37 releasing hydrogels may have potential utility as corneal substitutes for grafting in HSV-1 infected corneas, possibly in combination with LL-37 producing therapeutic cells.",
keywords = "cornea, HSV-1, antiviral peptides, nanoparticles, gene transfer",
author = "Chyan-Jang Lee and Oleksiy Buznyk and Lucia Kuffova and Vijayalakshmi Rajendran and Forrester, {John V} and Jaywant Phopase and Islam, {Mohammad M} and M{\aa}rten Skog and Jenny Ahlqvist and May Griffith",
note = "Acknowledgments The authors thank Martin Mak for technical assistance. Supported by an EU ERAnet Nanomedicine project grant “I-CARE” (funded by the Swedish Research Council and Vinnova [MG, BL]), and Vironova AB (JA) ; in vivo work was supported by grants from National Health Science Grampian Endowment grant, Saving Sight in Grampian and the IGEN Centre, Link{\"o}ping University (LK, VR, JVF); and by a post-doctoral fellowship from the Swedish Institute (OB).",
year = "2014",
month = "5",
doi = "10.1167/tvst.3.3.4",
language = "English",
volume = "3",
pages = "4",
journal = "Translational vision science & technology",
issn = "2164-2591",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "3",

}

TY - JOUR

T1 - Cathelicidin LL-37 and HSV-1 Corneal Infection

T2 - Peptide Versus Gene Therapy

AU - Lee, Chyan-Jang

AU - Buznyk, Oleksiy

AU - Kuffova, Lucia

AU - Rajendran, Vijayalakshmi

AU - Forrester, John V

AU - Phopase, Jaywant

AU - Islam, Mohammad M

AU - Skog, Mårten

AU - Ahlqvist, Jenny

AU - Griffith, May

N1 - Acknowledgments The authors thank Martin Mak for technical assistance. Supported by an EU ERAnet Nanomedicine project grant “I-CARE” (funded by the Swedish Research Council and Vinnova [MG, BL]), and Vironova AB (JA) ; in vivo work was supported by grants from National Health Science Grampian Endowment grant, Saving Sight in Grampian and the IGEN Centre, Linköping University (LK, VR, JVF); and by a post-doctoral fellowship from the Swedish Institute (OB).

PY - 2014/5

Y1 - 2014/5

N2 - PURPOSE: To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37.METHODS: We tested the ability of collagen-phosphorylcholine implants to tolerate the adverse microenvironment of herpetic murine corneas. Then, we investigated the efficacy of LL-37 peptides delivered through nanoparticles incorporated within the corneal implants to block HSV-1 viral activity. In addition, LL-37 complementary DNA (cDNA) was transferred into HCECs to confer viral resistance, and their response to HSV-1 infection was examined.RESULTS: Our implants remained in herpetic murine corneas 7 days longer than allografts. LL-37 released from the implants blocked HSV-1 infection of HCECs by interfering with viral binding. However, in pre-infected HCECs, LL-37 delayed but could not prevent viral spreading nor clear viruses from the infected cells. HCECs transfected with the LL-37 expressed and secreted the peptide. Secreted LL-37 inhibited viral binding in vitro but was insufficient to protect cells completely from HSV-1 infection. Nevertheless, secreted LL-37 reduced both the incidence of plaque formation and plaque size.CONCLUSION: LL-37 released from composite nanoparticle-hydrogel corneal implants and HCEC-produced peptide, both showed anti-HSV-1 activity by blocking binding. However, while both slowed down virus spread, neither was able on its own to completely inhibit the viruses.TRANSLATIONAL RELEVANCE: LL-37 releasing hydrogels may have potential utility as corneal substitutes for grafting in HSV-1 infected corneas, possibly in combination with LL-37 producing therapeutic cells.

AB - PURPOSE: To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37.METHODS: We tested the ability of collagen-phosphorylcholine implants to tolerate the adverse microenvironment of herpetic murine corneas. Then, we investigated the efficacy of LL-37 peptides delivered through nanoparticles incorporated within the corneal implants to block HSV-1 viral activity. In addition, LL-37 complementary DNA (cDNA) was transferred into HCECs to confer viral resistance, and their response to HSV-1 infection was examined.RESULTS: Our implants remained in herpetic murine corneas 7 days longer than allografts. LL-37 released from the implants blocked HSV-1 infection of HCECs by interfering with viral binding. However, in pre-infected HCECs, LL-37 delayed but could not prevent viral spreading nor clear viruses from the infected cells. HCECs transfected with the LL-37 expressed and secreted the peptide. Secreted LL-37 inhibited viral binding in vitro but was insufficient to protect cells completely from HSV-1 infection. Nevertheless, secreted LL-37 reduced both the incidence of plaque formation and plaque size.CONCLUSION: LL-37 released from composite nanoparticle-hydrogel corneal implants and HCEC-produced peptide, both showed anti-HSV-1 activity by blocking binding. However, while both slowed down virus spread, neither was able on its own to completely inhibit the viruses.TRANSLATIONAL RELEVANCE: LL-37 releasing hydrogels may have potential utility as corneal substitutes for grafting in HSV-1 infected corneas, possibly in combination with LL-37 producing therapeutic cells.

KW - cornea

KW - HSV-1

KW - antiviral peptides

KW - nanoparticles

KW - gene transfer

U2 - 10.1167/tvst.3.3.4

DO - 10.1167/tvst.3.3.4

M3 - Article

VL - 3

SP - 4

JO - Translational vision science & technology

JF - Translational vision science & technology

SN - 2164-2591

IS - 3

ER -