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. 1995 Feb;69(2):904–909. doi: 10.1128/jvi.69.2.904-909.1995

The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections.

M T Heise 1, H W Virgin 4th 1
PMCID: PMC188658  PMID: 7815559

Abstract

We defined the normal and innate (without functional B or T cells) inflammatory response to infection with mouse cytomegalovirus (MCMV) or herpes simplex virus (HSV). Intraperitoneal infection with MCMV or HSV induced an inflammatory infiltrate consisting largely of macrophages (M phi) in both normal CB17 and severe combined immunodeficient (SCID) mice (lacking functional B or T cells). M phi from infected mice were activated as shown by (i) spread morphology, (ii) increased expression of major histocompatibility complex (MHC) class II, MHC class I, and intercellular adhesion molecule-1 molecules, and (iii) downregulation of M phi-specific cell surface protein F4/80. In vivo administration of neutralizing antibodies specific for gamma interferon (IFN gamma) or tumor necrosis factor alpha (TNF alpha) inhibited MHC class II induction on infiltrating M phi in both normal and CB17 SCID mice. Anti-TNF alpha decreased the number of M phi in virus-induced inflammatory exudates. The MCMV titer increased in the spleen and liver of IFN gamma-depleted SCID mice, while TNF alpha depletion increased only splenic titers. MCMV-induced pathology was also increased in spleens of IFN gamma- and TNF alpha-depleted SCID mice. We conclude that (i) M phi activation is a prominent part of inflammatory responses to herpesvirus infection and (ii) IFN gamma and TNF alpha play a critical role in both virus-induced M phi activation and control of herpesvirus growth independent of T and B cells. This suggests that IFN gamma- and TNF alpha-mediated M phi activation is an important aspect of innate immunity to viral infection. As the M phi may be involved in MCMV latency, IFN gamma- and TNF alpha-dependent M phi activation during primary infection may be relevant to establishment of viral latency.

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Selected References

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  1. Austyn J. M., Gordon S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur J Immunol. 1981 Oct;11(10):805–815. doi: 10.1002/eji.1830111013. [DOI] [PubMed] [Google Scholar]
  2. Bancroft G. J., Bosma M. J., Bosma G. C., Unanue E. R. Regulation of macrophage Ia expression in mice with severe combined immunodeficiency: induction of Ia expression by a T cell-independent mechanism. J Immunol. 1986 Jul 1;137(1):4–9. [PubMed] [Google Scholar]
  3. Bancroft G. J., Schreiber R. D., Bosma G. C., Bosma M. J., Unanue E. R. A T cell-independent mechanism of macrophage activation by interferon-gamma. J Immunol. 1987 Aug 15;139(4):1104–1107. [PubMed] [Google Scholar]
  4. Bancroft G. J., Sheehan K. C., Schreiber R. D., Unanue E. R. Tumor necrosis factor is involved in the T cell-independent pathway of macrophage activation in scid mice. J Immunol. 1989 Jul 1;143(1):127–130. [PubMed] [Google Scholar]
  5. Bancroft G. J., Shellam G. R., Chalmer J. E. Genetic influences on the augmentation of natural killer (NK) cells during murine cytomegalovirus infection: correlation with patterns of resistance. J Immunol. 1981 Mar;126(3):988–994. [PubMed] [Google Scholar]
  6. Beller D. I., Ho K. Regulation of macrophage populations. V. Evaluation of the control of macrophage Ia expression in vitro. J Immunol. 1982 Sep;129(3):971–976. [PubMed] [Google Scholar]
  7. Booss J., Dann P. R., Griffith B. P., Kim J. H. Host defense response to cytomegalovirus in the central nervous system. Predominance of the monocyte. Am J Pathol. 1989 Jan;134(1):71–78. [PMC free article] [PubMed] [Google Scholar]
  8. Bukowski J. F., Woda B. A., Welsh R. M. Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice. J Virol. 1984 Oct;52(1):119–128. doi: 10.1128/jvi.52.1.119-128.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chan S. H., Perussia B., Gupta J. W., Kobayashi M., Pospísil M., Young H. A., Wolf S. F., Young D., Clark S. C., Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991 Apr 1;173(4):869–879. doi: 10.1084/jem.173.4.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chong K. T., Gresser I., Mims C. A. Interferon as a defence mechanism in mouse cytomegalovirus infection. J Gen Virol. 1983 Feb;64(Pt 2):461–464. doi: 10.1099/0022-1317-64-2-461. [DOI] [PubMed] [Google Scholar]
  11. Einhorn L., Ost A. Cytomegalovirus infection of human blood cells. J Infect Dis. 1984 Feb;149(2):207–214. doi: 10.1093/infdis/149.2.207. [DOI] [PubMed] [Google Scholar]
  12. Fennie E. H., Lie Y. S., Low M. A., Gribling P., Anderson K. P. Reduced mortality in murine cytomegalovirus infected mice following prophylactic murine interferon-gamma treatment. Antiviral Res. 1988 Nov;10(1-3):27–39. doi: 10.1016/0166-3542(88)90012-5. [DOI] [PubMed] [Google Scholar]
  13. Haagmans B. L., Stals F. S., van der Meide P. H., Bruggeman C. A., Horzinek M. C., Schijns V. E. Tumor necrosis factor alpha promotes replication and pathogenicity of rat cytomegalovirus. J Virol. 1994 Apr;68(4):2297–2304. doi: 10.1128/jvi.68.4.2297-2304.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ibanez C. E., Schrier R., Ghazal P., Wiley C., Nelson J. A. Human cytomegalovirus productively infects primary differentiated macrophages. J Virol. 1991 Dec;65(12):6581–6588. doi: 10.1128/jvi.65.12.6581-6588.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jonjić S., Mutter W., Weiland F., Reddehase M. J., Koszinowski U. H. Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med. 1989 Apr 1;169(4):1199–1212. doi: 10.1084/jem.169.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jonjić S., Pavić I., Lucin P., Rukavina D., Koszinowski U. H. Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes. J Virol. 1990 Nov;64(11):5457–5464. doi: 10.1128/jvi.64.11.5457-5464.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lathey J. L., Spector S. A. Unrestricted replication of human cytomegalovirus in hydrocortisone-treated macrophages. J Virol. 1991 Nov;65(11):6371–6375. doi: 10.1128/jvi.65.11.6371-6375.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lewandowski G. A., Lo D., Bloom F. E. Interference with major histocompatibility complex class II-restricted antigen presentation in the brain by herpes simplex virus type 1: a possible mechanism of evasion of the immune response. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2005–2009. doi: 10.1073/pnas.90.5.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lucin P., Jonjić S., Messerle M., Polić B., Hengel H., Koszinowski U. H. Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor. J Gen Virol. 1994 Jan;75(Pt 1):101–110. doi: 10.1099/0022-1317-75-1-101. [DOI] [PubMed] [Google Scholar]
  20. Lucin P., Pavić I., Polić B., Jonjić S., Koszinowski U. H. Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands. J Virol. 1992 Apr;66(4):1977–1984. doi: 10.1128/jvi.66.4.1977-1984.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Maciejewski J. P., Bruening E. E., Donahue R. E., Mocarski E. S., Young N. S., St Jeor S. C. Infection of hematopoietic progenitor cells by human cytomegalovirus. Blood. 1992 Jul 1;80(1):170–178. [PubMed] [Google Scholar]
  22. Maciejewski J. P., Bruening E. E., Donahue R. E., Sellers S. E., Carter C., Young N. S., St Jeor S. Infection of mononucleated phagocytes with human cytomegalovirus. Virology. 1993 Aug;195(2):327–336. doi: 10.1006/viro.1993.1383. [DOI] [PubMed] [Google Scholar]
  23. Mercadal C. M., Bouley D. M., DeStephano D., Rouse B. T. Herpetic stromal keratitis in the reconstituted scid mouse model. J Virol. 1993 Jun;67(6):3404–3408. doi: 10.1128/jvi.67.6.3404-3408.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mims C. A., Gould J. The role of macrophages in mice infected with murine cytomegalovirus. J Gen Virol. 1978 Oct;41(1):143–153. doi: 10.1099/0022-1317-41-1-143. [DOI] [PubMed] [Google Scholar]
  25. Minton E. J., Tysoe C., Sinclair J. H., Sissons J. G. Human cytomegalovirus infection of the monocyte/macrophage lineage in bone marrow. J Virol. 1994 Jun;68(6):4017–4021. doi: 10.1128/jvi.68.6.4017-4021.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pavić I., Polić B., Crnković I., Lucin P., Jonjić S., Koszinowski U. H. Participation of endogenous tumour necrosis factor alpha in host resistance to cytomegalovirus infection. J Gen Virol. 1993 Oct;74(Pt 10):2215–2223. doi: 10.1099/0022-1317-74-10-2215. [DOI] [PubMed] [Google Scholar]
  27. Price P., Winter J. G., Nikoletti S., Hudson J. B., Shellam G. R. Functional changes in murine macrophages infected with cytomegalovirus relate to H-2-determined sensitivity to infection. J Virol. 1987 Nov;61(11):3602–3606. doi: 10.1128/jvi.61.11.3602-3606.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Price P., Winter J. G., Shellam G. R. Genetically determined resistance to murine cytomegalovirus: a role for lymphocytostatic macrophages. J Gen Virol. 1987 Dec;68(Pt 12):2997–3008. doi: 10.1099/0022-1317-68-12-2997. [DOI] [PubMed] [Google Scholar]
  29. Rice G. P., Schrier R. D., Oldstone M. B. Cytomegalovirus infects human lymphocytes and monocytes: virus expression is restricted to immediate-early gene products. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6134–6138. doi: 10.1073/pnas.81.19.6134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rogers H. W., Sheehan K. C., Brunt L. M., Dower S. K., Unanue E. R., Schreiber R. D. Interleukin 1 participates in the development of anti-Listeria responses in normal and SCID mice. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1011–1015. doi: 10.1073/pnas.89.3.1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rubin R. H. Impact of cytomegalovirus infection on organ transplant recipients. Rev Infect Dis. 1990 Sep-Oct;12 (Suppl 7):S754–S766. doi: 10.1093/clinids/12.supplement_7.s754. [DOI] [PubMed] [Google Scholar]
  32. SMITH M. G. Propagation of salivary gland virus of the mouse in tissue cultures. Proc Soc Exp Biol Med. 1954 Jul;86(3):435–440. doi: 10.3181/00379727-86-21123. [DOI] [PubMed] [Google Scholar]
  33. Schooley R. T. Cytomegalovirus in the setting of infection with human immunodeficiency virus. Rev Infect Dis. 1990 Sep-Oct;12 (Suppl 7):S811–S819. doi: 10.1093/clinids/12.supplement_7.s811. [DOI] [PubMed] [Google Scholar]
  34. Schreiber R. D., Hicks L. J., Celada A., Buchmeier N. A., Gray P. W. Monoclonal antibodies to murine gamma-interferon which differentially modulate macrophage activation and antiviral activity. J Immunol. 1985 Mar;134(3):1609–1618. [PubMed] [Google Scholar]
  35. Shanley J. D. In vivo administration of monoclonal antibody to the NK 1.1 antigen of natural killer cells: effect on acute murine cytomegalovirus infection. J Med Virol. 1990 Jan;30(1):58–60. doi: 10.1002/jmv.1890300113. [DOI] [PubMed] [Google Scholar]
  36. Shanley J. D., Pesanti E. L. Murine peritoneal macrophages support murine cytomegalovirus replication. Infect Immun. 1983 Sep;41(3):1352–1359. doi: 10.1128/iai.41.3.1352-1359.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sheehan K. C., Ruddle N. H., Schreiber R. D. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed] [Google Scholar]
  38. Stoddart C. A., Cardin R. D., Boname J. M., Manning W. C., Abenes G. B., Mocarski E. S. Peripheral blood mononuclear phagocytes mediate dissemination of murine cytomegalovirus. J Virol. 1994 Oct;68(10):6243–6253. doi: 10.1128/jvi.68.10.6243-6253.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Taylor-Wiedeman J., Sissons J. G., Borysiewicz L. K., Sinclair J. H. Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol. 1991 Sep;72(Pt 9):2059–2064. doi: 10.1099/0022-1317-72-9-2059. [DOI] [PubMed] [Google Scholar]
  40. Taylor-Wiedeman J., Sissons P., Sinclair J. Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. J Virol. 1994 Mar;68(3):1597–1604. doi: 10.1128/jvi.68.3.1597-1604.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tegtmeyer P. J., Craighead J. E. Infection of adult mouse macrophages in vitro with cytomegalovirus. Proc Soc Exp Biol Med. 1968 Dec;129(3):690–694. doi: 10.3181/00379727-129-33399. [DOI] [PubMed] [Google Scholar]
  42. Virgin H. W., 4th, Mann M. A., Fields B. N., Tyler K. L. Monoclonal antibodies to reovirus reveal structure/function relationships between capsid proteins and genetics of susceptibility to antibody action. J Virol. 1991 Dec;65(12):6772–6781. doi: 10.1128/jvi.65.12.6772-6781.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Weigent D. A., Stanton G. J., Johnson H. M. Interleukin 2 enhances natural killer cell activity through induction of gamma interferon. Infect Immun. 1983 Sep;41(3):992–997. doi: 10.1128/iai.41.3.992-997.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Welsh R. M., Brubaker J. O., Vargas-Cortes M., O'Donnell C. L. Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell function. J Exp Med. 1991 May 1;173(5):1053–1063. doi: 10.1084/jem.173.5.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]

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