• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jvirolPermissionsJournals.ASM.orgJournalJV ArticleJournal InfoAuthorsReviewers
J Virol. Feb 1996; 70(2): 898–904.
PMCID: PMC189893

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


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.

Full Text

The Full Text of this article is available as a PDF (485K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bingham EL, Fenger TW, Sugar A, Smith JW. 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]
  • Bonneau RH, Jennings SR. 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. [PMC free article] [PubMed]
  • Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. [PubMed]
  • Cassatella MA. The production of cytokines by polymorphonuclear neutrophils. Immunol Today. 1995 Jan;16(1):21–26. [PubMed]
  • Conlan JW, North RJ. 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. [PMC free article] [PubMed]
  • Czuprynski CJ, Brown JF, Maroushek N, Wagner RD, 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]
  • Custer RP, Bosma GC, Bosma MJ. Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms. Am J Pathol. 1985 Sep;120(3):464–477. [PMC free article] [PubMed]
  • Dorshkind K, Keller GM, Phillips RA, Miller RG, Bosma GC, O'Toole M, Bosma MJ. 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]
  • Dorshkind K, Pollack SB, Bosma MJ, Phillips RA. Natural killer (NK) cells are present in mice with severe combined immunodeficiency (scid). J Immunol. 1985 Jun;134(6):3798–3801. [PubMed]
  • Douglas RG, Jr, Alford RH, Cate TR, Couch RB. The leukocyte response during viral respiratory illness in man. Ann Intern Med. 1966 Mar;64(3):521–530. [PubMed]
  • Faden H, Hong JJ, Ogra PL. 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. [PMC free article] [PubMed]
  • Faden H, Ogra P. Neutrophils and antiviral defense. Pediatr Infect Dis. 1986 Jan-Feb;5(1):86–92. [PubMed]
  • Feigin RD, Shackelford PG. Value of repeat lumbar puncture in the differential diagnosis of meningitis. N Engl J Med. 1973 Sep 13;289(11):571–574. [PubMed]
  • Fleming TJ, Fleming ML, Malek TR. 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]
  • 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. [PubMed]
  • Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985 Oct;76(4):1427–1435. [PMC free article] [PubMed]
  • Grewal AS, Rouse BT, Babiuk LA. 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. [PMC free article] [PubMed]
  • 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]
  • Hashimoto G, Wright PF, Karzon DT. Antibody-dependent cell-mediated cytotoxicity against influenza virus-infected cells. J Infect Dis. 1983 Nov;148(5):785–794. [PubMed]
  • Hendricks RL, Epstein RJ, 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]
  • Hestdal K, Ruscetti FW, Ihle JN, Jacobsen SE, Dubois CM, Kopp WC, Longo DL, Keller JR. Characterization and regulation of RB6-8C5 antigen expression on murine bone marrow cells. J Immunol. 1991 Jul 1;147(1):22–28. [PubMed]
  • Holmes KL, Langdon WY, Fredrickson TN, Coffman RL, Hoffman PM, Hartley JW, Morse HC., 3rd Analysis of neoplasms induced by Cas-Br-M MuLV tumor extracts. J Immunol. 1986 Jul 15;137(2):679–688. [PubMed]
  • Ihara T, Starr SE, Ito M, Douglas SD, Arbeter AM. Human polymorphonuclear leukocyte-mediated cytotoxicity against varicella-zoster virus-infected fibroblasts. J Virol. 1984 Jul;51(1):110–116. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Kaul TN, Faden H, Baker R, Ogra PL. 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]
  • Larsen HS, Russell RG, Rouse BT. Recovery from lethal herpes simplex virus type 1 infection is mediated by cytotoxic T lymphocytes. Infect Immun. 1983 Jul;41(1):197–204. [PMC free article] [PubMed]
  • Lausch RN, Kleinschradt WR, Monteiro C, Kayes SG, Oakes JE. Resolution of HSV corneal infection in the absence of delayed-type hypersensitivity. Invest Ophthalmol Vis Sci. 1985 Nov;26(11):1509–1515. [PubMed]
  • Lausch RN, Oakes JE, Metcalf JF, Scimeca JM, Smith LA, Robertson SM. Quantitation of purified monoclonal antibody needed to prevent HSV-1 induced stromal keratitis in mice. Curr Eye Res. 1989 May;8(5):499–506. [PubMed]
  • Lausch RN, Staats H, Metcalf JF, Oakes JE. Effective antibody therapy in herpes simplex virus ocular infection. Characterization of recipient immune response. Intervirology. 1990;31(2-4):159–165. [PubMed]
  • Lloyd AR, Oppenheim JJ. 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. [PubMed]
  • MacGregor RR, Friedman HM, Macarak EJ, Kefalides NA. Virus infection of endothelial cells increases granulocyte adherence. J Clin Invest. 1980 Jun;65(6):1469–1477. [PMC free article] [PubMed]
  • Malech HL, Gallin JI. Current concepts: immunology. Neutrophils in human diseases. N Engl J Med. 1987 Sep 10;317(11):687–694. [PubMed]
  • Metcalf JF, Hamilton DS, Reichert RW. Herpetic keratitis in athymic (nude) mice. Infect Immun. 1979 Dec;26(3):1164–1171. [PMC free article] [PubMed]
  • Metcalf JF, Koga J, Chatterjee S, Whitley RJ. 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. [PubMed]
  • Metcalf JF, Reichert RW. Histological and electron microscopic studies of experimental herpetic keratitis in the rabbit. Invest Ophthalmol Vis Sci. 1979 Nov;18(11):1123–1138. [PubMed]
  • Meyers-Elliott RH, Chitjian PA. 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]
  • Newell CK, Martin S, Sendele D, Mercadal CM, Rouse BT. Herpes simplex virus-induced stromal keratitis: role of T-lymphocyte subsets in immunopathology. J Virol. 1989 Feb;63(2):769–775. [PMC free article] [PubMed]
  • Ratcliffe DR, Nolin SL, Cramer EB. Neutrophil interaction with influenza-infected epithelial cells. Blood. 1988 Jul;72(1):142–149. [PubMed]
  • Roberts RL, Ank BJ, Stiehm ER. Antiviral properties of neonatal and adult human neutrophils. Pediatr Res. 1994 Dec;36(6):792–798. [PubMed]
  • Rogers HW, Unanue ER. Neutrophils are involved in acute, nonspecific resistance to Listeria monocytogenes in mice. Infect Immun. 1993 Dec;61(12):5090–5096. [PMC free article] [PubMed]
  • Rouse BT, Babiuk LA, Henson PM. Neutrophils in antiviral immunity: inhibition of virus replication by a mediator produced by bovine neutrophils. J Infect Dis. 1980 Feb;141(2):223–232. [PubMed]
  • Russell RG, Nasisse MP, Larsen HS, Rouse BT. Role of T-lymphocytes in the pathogenesis of herpetic stromal keratitis. Invest Ophthalmol Vis Sci. 1984 Aug;25(8):938–944. [PubMed]
  • Sarmiento M, Glasebrook AL, Fitch FW. 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]
  • Siebens H, Tevethia SS, Babior BM. Neutrophil-mediated antibody-dependent killing of herpes-simplex-virus-infected cells. Blood. 1979 Jul;54(1):88–94. [PubMed]
  • Smith JA. Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol. 1994 Dec;56(6):672–686. [PubMed]
  • Smith JW, Jachimowicz JR, Bingham EL. Binding and internalization of herpes simplex virus-antibody complexes by polymorphonuclear leukocytes. J Med Virol. 1986 Oct;20(2):151–163. [PubMed]
  • Staats HF, Oakes JE, Lausch RN. 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. [PMC free article] [PubMed]
  • Stevens DA, Ferrington RA, Jordan GW, Merigan TC. Cellular events in zoster vesicles: relation to clinical course and immune parameters. J Infect Dis. 1975 May;131(5):509–515. [PubMed]
  • Su YH, Oakes JE, Lausch RN. 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. [PMC free article] [PubMed]
  • Tepper RI, Coffman RL, Leder P. An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science. 1992 Jul 24;257(5069):548–551. [PubMed]
  • 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. [PubMed]
  • van Strijp JA, van Kessel KP, Miltenburg LA, Fluit AC, 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. [PMC free article] [PubMed]
  • Van Strijp JA, Van Kessel KP, van der Tol ME, Fluit AC, Snippe H, Verhoef J. Phagocytosis of herpes simplex virus by human granulocytes and monocytes. Arch Virol. 1989;104(3-4):287–298. [PubMed]
  • Van Strijp JA, Van Kessel KP, van der Tol ME, Verhoef J. Complement-mediated phagocytosis of herpes simplex virus by granulocytes. Binding or ingestion. J Clin Invest. 1989 Jul;84(1):107–112. [PMC free article] [PubMed]
  • Wang HM, Sheu MM, Stulting RD, Kaplan HJ. Immunohistochemical evaluation of murine HSV-1 keratouveitis. Curr Eye Res. 1989 Jan;8(1):37–46. [PubMed]
  • 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. [PubMed]
  • Zisman B, Hirsch MS, Allison AC. 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]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...