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. 1996 Feb;70(2):898–904. doi: 10.1128/jvi.70.2.898-904.1996

Neutrophil-mediated suppression of virus replication after herpes simplex virus type 1 infection of the murine cornea.

T M Tumpey 1, S H Chen 1, J E Oakes 1, R N Lausch 1
PMCID: PMC189893  PMID: 8551629

Abstract

Herpes simplex virus type 1 (HSV-1) infection of the murine cornea induces the rapid infiltration of neutrophils. We investigated whether these cells could influence virus replication. BALB/c mice treated with monoclonal antibody (MAb) RB6-8C5 experienced a profound depletion of neutrophils in the bloodstream, spleen, and cornea. In these animals, virus titers in the eye were significantly higher than those in the immunoglobulin G-treated controls at 3 days postinfection. By day 9, virus was no longer detectable in the controls, whereas titers of 10(3) to 10(6) PFU were still present in the neutrophil-depleted hosts. Furthermore, virus spread more readily to the skin and brains of MAb RB6-8C5-treated animals, rendering them significantly more susceptible to HSV-1-induced blepharitis and encephalitis. Only 25% of the treated animals survived, whereas all of the controls lived. Although MAb RB6-8C5 treatment did not alter the CD4+ T-cell, B-cell, natural killer cell, or macrophage populations, the CD8+ T-cell population was partially reduced. Therefore, the experiments were repeated in severe combined immunodeficiency mice, which lack CD8+ T cells. Again virus growth was found to be significantly elevated in the eyes, trigeminal ganglia, and brains of the MAb RB6-8C5-treated hosts. These results strongly indicate that in both immunocompetent and immunodeficient mice, neutrophils play a significant role in helping to control the replication and spread of HSV-1 after corneal infection.

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Selected References

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  1. Bingham E. L., Fenger T. W., Sugar A., Smith J. W. Dependence on antibody for induction of chemiluminescence in polymorphonuclear leukocytes by herpes simplex virus. Invest Ophthalmol Vis Sci. 1985 Sep;26(9):1236–1243. [PubMed] [Google Scholar]
  2. Bonneau R. H., Jennings S. R. Modulation of acute and latent herpes simplex virus infection in C57BL/6 mice by adoptive transfer of immune lymphocytes with cytolytic activity. J Virol. 1989 Mar;63(3):1480–1484. doi: 10.1128/jvi.63.3.1480-1484.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bosma G. C., Custer R. P., Bosma M. J. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. doi: 10.1038/301527a0. [DOI] [PubMed] [Google Scholar]
  4. Cassatella M. A. The production of cytokines by polymorphonuclear neutrophils. Immunol Today. 1995 Jan;16(1):21–26. doi: 10.1016/0167-5699(95)80066-2. [DOI] [PubMed] [Google Scholar]
  5. Conlan J. W., North R. J. Neutrophils are essential for early anti-Listeria defense in the liver, but not in the spleen or peritoneal cavity, as revealed by a granulocyte-depleting monoclonal antibody. J Exp Med. 1994 Jan 1;179(1):259–268. doi: 10.1084/jem.179.1.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Custer R. P., Bosma G. C., Bosma M. J. Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms. Am J Pathol. 1985 Sep;120(3):464–477. [PMC free article] [PubMed] [Google Scholar]
  7. Czuprynski C. J., Brown J. F., Maroushek N., Wagner R. D., Steinberg H. Administration of anti-granulocyte mAb RB6-8C5 impairs the resistance of mice to Listeria monocytogenes infection. J Immunol. 1994 Feb 15;152(4):1836–1846. [PubMed] [Google Scholar]
  8. Dorshkind K., Keller G. M., Phillips R. A., Miller R. G., Bosma G. C., O'Toole M., Bosma M. J. Functional status of cells from lymphoid and myeloid tissues in mice with severe combined immunodeficiency disease. J Immunol. 1984 Apr;132(4):1804–1808. [PubMed] [Google Scholar]
  9. Dorshkind K., Pollack S. B., Bosma M. J., Phillips R. A. Natural killer (NK) cells are present in mice with severe combined immunodeficiency (scid). J Immunol. 1985 Jun;134(6):3798–3801. [PubMed] [Google Scholar]
  10. Douglas R. G., Jr, Alford R. H., Cate T. R., Couch R. B. The leukocyte response during viral respiratory illness in man. Ann Intern Med. 1966 Mar;64(3):521–530. doi: 10.7326/0003-4819-64-3-521. [DOI] [PubMed] [Google Scholar]
  11. Faden H., Hong J. J., Ogra P. L. Interaction of polymorphonuclear leukocytes and viruses in humans: adherence of polymorphonuclear leukocytes to respiratory syncytial virus-infected cells. J Virol. 1984 Oct;52(1):16–23. doi: 10.1128/jvi.52.1.16-23.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Faden H., Ogra P. Neutrophils and antiviral defense. Pediatr Infect Dis. 1986 Jan-Feb;5(1):86–92. doi: 10.1097/00006454-198601000-00015. [DOI] [PubMed] [Google Scholar]
  13. Feigin R. D., Shackelford P. G. Value of repeat lumbar puncture in the differential diagnosis of meningitis. N Engl J Med. 1973 Sep 13;289(11):571–574. doi: 10.1056/NEJM197309132891108. [DOI] [PubMed] [Google Scholar]
  14. Fleming T. J., Fleming M. L., Malek T. R. Selective expression of Ly-6G on myeloid lineage cells in mouse bone marrow. RB6-8C5 mAb to granulocyte-differentiation antigen (Gr-1) detects members of the Ly-6 family. J Immunol. 1993 Sep 1;151(5):2399–2408. [PubMed] [Google Scholar]
  15. Fujisawa H., Tsuru S., Taniguchi M., Zinnaka Y., Nomoto K. Protective mechanisms against pulmonary infection with influenza virus. I. Relative contribution of polymorphonuclear leukocytes and of alveolar macrophages to protection during the early phase of intranasal infection. J Gen Virol. 1987 Feb;68(Pt 2):425–432. doi: 10.1099/0022-1317-68-2-425. [DOI] [PubMed] [Google Scholar]
  16. Ganz T., Selsted M. E., Szklarek D., Harwig S. S., Daher K., Bainton D. F., Lehrer R. I. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985 Oct;76(4):1427–1435. doi: 10.1172/JCI112120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grewal A. S., Rouse B. T., Babiuk L. A. Mechanisms of resistant of herpesviruses: comparison of the effectiveness of different cell types in mediating antibody-dependent cell-mediated cytotoxicity. Infect Immun. 1977 Mar;15(3):698–703. doi: 10.1128/iai.15.3.698-703.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Habu S., Akamatsu K., Tamaoki N., Okumura K. In vivo significance of NK cell on resistance against virus (HSV-1) infections in mice. J Immunol. 1984 Nov;133(5):2743–2747. [PubMed] [Google Scholar]
  19. Hashimoto G., Wright P. F., Karzon D. T. Antibody-dependent cell-mediated cytotoxicity against influenza virus-infected cells. J Infect Dis. 1983 Nov;148(5):785–794. doi: 10.1093/infdis/148.5.785. [DOI] [PubMed] [Google Scholar]
  20. Hendricks R. L., Epstein R. J., Tumpey T. The effect of cellular immune tolerance to HSV-1 antigens on the immunopathology of HSV-1 keratitis. Invest Ophthalmol Vis Sci. 1989 Jan;30(1):105–115. [PubMed] [Google Scholar]
  21. Hestdal K., Ruscetti F. W., Ihle J. N., Jacobsen S. E., Dubois C. M., Kopp W. C., Longo D. L., Keller J. R. Characterization and regulation of RB6-8C5 antigen expression on murine bone marrow cells. J Immunol. 1991 Jul 1;147(1):22–28. [PubMed] [Google Scholar]
  22. Holmes K. L., Langdon W. Y., Fredrickson T. N., Coffman R. L., Hoffman P. M., Hartley J. W., Morse H. C., 3rd Analysis of neoplasms induced by Cas-Br-M MuLV tumor extracts. J Immunol. 1986 Jul 15;137(2):679–688. [PubMed] [Google Scholar]
  23. Ihara T., Starr S. E., Ito M., Douglas S. D., Arbeter A. M. Human polymorphonuclear leukocyte-mediated cytotoxicity against varicella-zoster virus-infected fibroblasts. J Virol. 1984 Jul;51(1):110–116. doi: 10.1128/jvi.51.1.110-116.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. JOHNSON R. T. THE PATHOGENESIS OF HERPES VIRUS ENCEPHALITIS. II. A CELLULAR BASIS FOR THE DEVELOPMENT OF RESISTANCE WITH AGE. J Exp Med. 1964 Sep 1;120:359–374. doi: 10.1084/jem.120.3.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jensen J., Warner T., Balish E. Resistance of SCID mice to Candida albicans administered intravenously or colonizing the gut: role of polymorphonuclear leukocytes and macrophages. J Infect Dis. 1993 Apr;167(4):912–919. doi: 10.1093/infdis/167.4.912. [DOI] [PubMed] [Google Scholar]
  26. Kaul T. N., Faden H., Baker R., Ogra P. L. Virus-induced complement activation and neutrophil-mediated cytotoxicity against respiratory syncytial virus (RSV). Clin Exp Immunol. 1984 Jun;56(3):501–508. [PMC free article] [PubMed] [Google Scholar]
  27. Larsen H. S., Russell R. G., Rouse B. T. Recovery from lethal herpes simplex virus type 1 infection is mediated by cytotoxic T lymphocytes. Infect Immun. 1983 Jul;41(1):197–204. doi: 10.1128/iai.41.1.197-204.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lausch R. N., Kleinschradt W. R., Monteiro C., Kayes S. G., Oakes J. E. Resolution of HSV corneal infection in the absence of delayed-type hypersensitivity. Invest Ophthalmol Vis Sci. 1985 Nov;26(11):1509–1515. [PubMed] [Google Scholar]
  29. Lausch R. N., Oakes J. E., Metcalf J. F., Scimeca J. M., Smith L. A., Robertson S. M. Quantitation of purified monoclonal antibody needed to prevent HSV-1 induced stromal keratitis in mice. Curr Eye Res. 1989 May;8(5):499–506. doi: 10.3109/02713688909000030. [DOI] [PubMed] [Google Scholar]
  30. Lausch R. N., Staats H., Metcalf J. F., Oakes J. E. Effective antibody therapy in herpes simplex virus ocular infection. Characterization of recipient immune response. Intervirology. 1990;31(2-4):159–165. doi: 10.1159/000150150. [DOI] [PubMed] [Google Scholar]
  31. Lloyd A. R., Oppenheim J. J. Poly's lament: the neglected role of the polymorphonuclear neutrophil in the afferent limb of the immune response. Immunol Today. 1992 May;13(5):169–172. doi: 10.1016/0167-5699(92)90121-M. [DOI] [PubMed] [Google Scholar]
  32. MacGregor R. R., Friedman H. M., Macarak E. J., Kefalides N. A. Virus infection of endothelial cells increases granulocyte adherence. J Clin Invest. 1980 Jun;65(6):1469–1477. doi: 10.1172/JCI109811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Malech H. L., Gallin J. I. Current concepts: immunology. Neutrophils in human diseases. N Engl J Med. 1987 Sep 10;317(11):687–694. doi: 10.1056/NEJM198709103171107. [DOI] [PubMed] [Google Scholar]
  34. Metcalf J. F., Hamilton D. S., Reichert R. W. Herpetic keratitis in athymic (nude) mice. Infect Immun. 1979 Dec;26(3):1164–1171. doi: 10.1128/iai.26.3.1164-1171.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Metcalf J. F., Koga J., Chatterjee S., Whitley R. J. Passive immunization with monoclonal antibodies against herpes simplex virus glycoproteins protects mice against herpetic ocular disease. Curr Eye Res. 1987 Jan;6(1):173–177. doi: 10.3109/02713688709020086. [DOI] [PubMed] [Google Scholar]
  36. Metcalf J. F., Reichert R. W. Histological and electron microscopic studies of experimental herpetic keratitis in the rabbit. Invest Ophthalmol Vis Sci. 1979 Nov;18(11):1123–1138. [PubMed] [Google Scholar]
  37. Meyers-Elliott R. H., Chitjian P. A. Immunopathogenesis of corneal inflammation in herpes simplex virus stromal keratitis: role of the polymorphonuclear leukocyte. Invest Ophthalmol Vis Sci. 1981 Jun;20(6):784–798. [PubMed] [Google Scholar]
  38. Newell C. K., Martin S., Sendele D., Mercadal C. M., Rouse B. T. Herpes simplex virus-induced stromal keratitis: role of T-lymphocyte subsets in immunopathology. J Virol. 1989 Feb;63(2):769–775. doi: 10.1128/jvi.63.2.769-775.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ratcliffe D. R., Nolin S. L., Cramer E. B. Neutrophil interaction with influenza-infected epithelial cells. Blood. 1988 Jul;72(1):142–149. [PubMed] [Google Scholar]
  40. Roberts R. L., Ank B. J., Stiehm E. R. Antiviral properties of neonatal and adult human neutrophils. Pediatr Res. 1994 Dec;36(6):792–798. doi: 10.1203/00006450-199412000-00018. [DOI] [PubMed] [Google Scholar]
  41. Rogers H. W., Unanue E. R. Neutrophils are involved in acute, nonspecific resistance to Listeria monocytogenes in mice. Infect Immun. 1993 Dec;61(12):5090–5096. doi: 10.1128/iai.61.12.5090-5096.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rouse B. T., Babiuk L. A., Henson P. M. Neutrophils in antiviral immunity: inhibition of virus replication by a mediator produced by bovine neutrophils. J Infect Dis. 1980 Feb;141(2):223–232. doi: 10.1093/infdis/141.2.223. [DOI] [PubMed] [Google Scholar]
  43. Russell R. G., Nasisse M. P., Larsen H. S., Rouse B. T. Role of T-lymphocytes in the pathogenesis of herpetic stromal keratitis. Invest Ophthalmol Vis Sci. 1984 Aug;25(8):938–944. [PubMed] [Google Scholar]
  44. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  45. Siebens H., Tevethia S. S., Babior B. M. Neutrophil-mediated antibody-dependent killing of herpes-simplex-virus-infected cells. Blood. 1979 Jul;54(1):88–94. [PubMed] [Google Scholar]
  46. Smith J. A. Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol. 1994 Dec;56(6):672–686. doi: 10.1002/jlb.56.6.672. [DOI] [PubMed] [Google Scholar]
  47. Smith J. W., Jachimowicz J. R., Bingham E. L. Binding and internalization of herpes simplex virus-antibody complexes by polymorphonuclear leukocytes. J Med Virol. 1986 Oct;20(2):151–163. doi: 10.1002/jmv.1890200207. [DOI] [PubMed] [Google Scholar]
  48. Staats H. F., Oakes J. E., Lausch R. N. Anti-glycoprotein D monoclonal antibody protects against herpes simplex virus type 1-induced diseases in mice functionally depleted of selected T-cell subsets or asialo GM1+ cells. J Virol. 1991 Nov;65(11):6008–6014. doi: 10.1128/jvi.65.11.6008-6014.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Stevens D. A., Ferrington R. A., Jordan G. W., Merigan T. C. Cellular events in zoster vesicles: relation to clinical course and immune parameters. J Infect Dis. 1975 May;131(5):509–515. doi: 10.1093/infdis/131.5.509. [DOI] [PubMed] [Google Scholar]
  50. Su Y. H., Oakes J. E., Lausch R. N. Ocular avirulence of a herpes simplex virus type 1 strain is associated with heightened sensitivity to alpha/beta interferon. J Virol. 1990 May;64(5):2187–2192. doi: 10.1128/jvi.64.5.2187-2192.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tepper R. I., Coffman R. L., Leder P. An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science. 1992 Jul 24;257(5069):548–551. doi: 10.1126/science.1636093. [DOI] [PubMed] [Google Scholar]
  52. Tsuru S., Fujisawa H., Taniguchi M., Zinnaka Y., Nomoto K. Mechanism of protection during the early phase of a generalized viral infection. II. Contribution of polymorphonuclear leukocytes to protection against intravenous infection with influenza virus. J Gen Virol. 1987 Feb;68(Pt 2):419–424. doi: 10.1099/0022-1317-68-2-419. [DOI] [PubMed] [Google Scholar]
  53. Van Strijp J. A., Van Kessel K. P., van der Tol M. E., Fluit A. C., Snippe H., Verhoef J. Phagocytosis of herpes simplex virus by human granulocytes and monocytes. Arch Virol. 1989;104(3-4):287–298. doi: 10.1007/BF01315550. [DOI] [PubMed] [Google Scholar]
  54. Van Strijp J. A., Van Kessel K. P., van der Tol M. E., Verhoef J. Complement-mediated phagocytosis of herpes simplex virus by granulocytes. Binding or ingestion. J Clin Invest. 1989 Jul;84(1):107–112. doi: 10.1172/JCI114129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wang H. M., Sheu M. M., Stulting R. D., Kaplan H. J. Immunohistochemical evaluation of murine HSV-1 keratouveitis. Curr Eye Res. 1989 Jan;8(1):37–46. doi: 10.3109/02713688909013892. [DOI] [PubMed] [Google Scholar]
  56. Zawatzky R., Gresser I., DeMaeyer E., Kirchner H. The role of interferon in the resistance of C57BL/6 mice to various doses of herpes simplex virus type 1. J Infect Dis. 1982 Sep;146(3):405–410. doi: 10.1093/infdis/146.3.405. [DOI] [PubMed] [Google Scholar]
  57. Zisman B., Hirsch M. S., Allison A. C. Selective effects of anti-macrophage serum, silica and anti-lymphocyte serum on pathogenesis of herpes virus infection of young adult mice. J Immunol. 1970 May;104(5):1155–1159. [PubMed] [Google Scholar]
  58. van Strijp J. A., van Kessel K. P., Miltenburg L. A., Fluit A. C., Verhoef J. Attachment of human polymorphonuclear leukocytes to herpes simplex virus-infected fibroblasts mediated by antibody-independent complement activation. J Virol. 1988 Mar;62(3):847–850. doi: 10.1128/jvi.62.3.847-850.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]

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