Skip to main content
PMC home page
Infection and Immunity logoLink to Infection and Immunity
. 1995 May;63(5):1820–1826. doi: 10.1128/iai.63.5.1820-1826.1995

Regulation of macrophage activation and human immunodeficiency virus production by invasive Salmonella strains.

S B Mizel 1, L S Kucera 1, S H Richardson 1, F Ciacci 1, N P Iyer 1
PMCID: PMC173230  PMID: 7729890

Abstract

Salmonellae possess the ability to adhere to and invade macrophages and in so doing trigger a number of intracellular events that are associated with cellular activation. As an initial approach to defining the mechanisms by which invasive salmonellae alter macrophage function, we have explored the impact of Salmonella infection on the production of human immunodeficiency virus (HIV) in U1 cells, a promonocytic cell line latently infected with the virus. Infection of U1 cells with a pathogenic strain of Salmonella enteritidis resulted in a marked induction of macrophage activation and HIV production. The stimulatory effect of salmonellae was mediated by signals other than lipopolysaccharide. Salmonella mutants with specific defects in invasion or intracellular survival were markedly less effective in the induction of HIV production. In contrast to S. enteritidis, strains of Yersinia enterocolitica, Legionella pneumophila, and Escherichia coli did not induce HIV production. However, all of these bacteria induced comparable levels of gene expression mediated by the HIV long terminal repeat. The results of this study are consistent with the notion that invasive salmonellae possess the ability to activate the macrophage by at least one mechanism that is not shared with several other species of gram-negative bacteria. Furthermore, the expression of this unique property is maximal with Salmonella strains that are not only invasive but also capable of prolonged survival within the macrophage. Our results indicate that the U1 cell line may be a very useful model system with which to examine the biochemical pathways by which internalized salmonellae modulate the activation state of the macrophage.

Full Text

The Full Text of this article is available as a PDF (268.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abshire K. Z., Neidhardt F. C. Growth rate paradox of Salmonella typhimurium within host macrophages. J Bacteriol. 1993 Jun;175(12):3744–3748. doi: 10.1128/jb.175.12.3744-3748.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alpuche-Aranda C. M., Racoosin E. L., Swanson J. A., Miller S. I. Salmonella stimulate macrophage macropinocytosis and persist within spacious phagosomes. J Exp Med. 1994 Feb 1;179(2):601–608. doi: 10.1084/jem.179.2.601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Andreana A., Gollapudi S., Kim C. H., Gupta S. Salmonella typhimurium activates human immunodeficiency virus type 1 in chronically infected promonocytic cells by inducing tumor necrosis factor-alpha production. Biochem Biophys Res Commun. 1994 May 30;201(1):16–23. doi: 10.1006/bbrc.1994.1663. [DOI] [PubMed] [Google Scholar]
  4. Antoni B. A., Stein S. B., Rabson A. B. Regulation of human immunodeficiency virus infection: implications for pathogenesis. Adv Virus Res. 1994;43:53–145. doi: 10.1016/s0065-3527(08)60047-0. [DOI] [PubMed] [Google Scholar]
  5. Bagasra O., Wright S. D., Seshamma T., Oakes J. W., Pomerantz R. J. CD14 is involved in control of human immunodeficiency virus type 1 expression in latently infected cells by lipopolysaccharide. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6285–6289. doi: 10.1073/pnas.89.14.6285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barnett S. W., Barboza A., Wilcox C. M., Forsmark C. E., Levy J. A. Characterization of human immunodeficiency virus type 1 strains recovered from the bowel of infected individuals. Virology. 1991 Jun;182(2):802–809. doi: 10.1016/0042-6822(91)90621-h. [DOI] [PubMed] [Google Scholar]
  7. Behlau I., Miller S. I. A PhoP-repressed gene promotes Salmonella typhimurium invasion of epithelial cells. J Bacteriol. 1993 Jul;175(14):4475–4484. doi: 10.1128/jb.175.14.4475-4484.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bliska J. B., Galán J. E., Falkow S. Signal transduction in the mammalian cell during bacterial attachment and entry. Cell. 1993 Jun 4;73(5):903–920. doi: 10.1016/0092-8674(93)90270-z. [DOI] [PubMed] [Google Scholar]
  9. Buchmeier N. A., Heffron F. Intracellular survival of wild-type Salmonella typhimurium and macrophage-sensitive mutants in diverse populations of macrophages. Infect Immun. 1989 Jan;57(1):1–7. doi: 10.1128/iai.57.1.1-7.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Buchmüller-Rouiller Y., Mauël J. Macrophage activation for intracellular killing as induced by calcium ionophore. Correlation with biologic and biochemical events. J Immunol. 1991 Jan 1;146(1):217–223. [PubMed] [Google Scholar]
  11. Bäumler A. J., Kusters J. G., Stojiljkovic I., Heffron F. Salmonella typhimurium loci involved in survival within macrophages. Infect Immun. 1994 May;62(5):1623–1630. doi: 10.1128/iai.62.5.1623-1630.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cannon P., Kim S. H., Ulich C., Kim S. Analysis of Tat function in human immunodeficiency virus type 1-infected low-level-expression cell lines U1 and ACH-2. J Virol. 1994 Mar;68(3):1993–1997. doi: 10.1128/jvi.68.3.1993-1997.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chedid M., Yoza B. K., Brooks J. W., Mizel S. B. Activation of AP-1 by IL-1 and phorbol esters in T cells. Role of protein kinase A and protein phosphatases. J Immunol. 1991 Aug 1;147(3):867–873. [PubMed] [Google Scholar]
  14. Christman M. F., Morgan R. W., Jacobson F. S., Ames B. N. Positive control of a regulon for defenses against oxidative stress and some heat-shock proteins in Salmonella typhimurium. Cell. 1985 Jul;41(3):753–762. doi: 10.1016/s0092-8674(85)80056-8. [DOI] [PubMed] [Google Scholar]
  15. Cullen B. R. Regulation of human immunodeficiency virus replication. Annu Rev Microbiol. 1991;45:219–250. doi: 10.1146/annurev.mi.45.100191.001251. [DOI] [PubMed] [Google Scholar]
  16. Dong Z., Qi X., Fidler I. J. Tyrosine phosphorylation of mitogen-activated protein kinases is necessary for activation of murine macrophages by natural and synthetic bacterial products. J Exp Med. 1993 Apr 1;177(4):1071–1077. doi: 10.1084/jem.177.4.1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Duan L., Oakes J. W., Ferraro A., Bagasra O., Pomerantz R. J. Tat and rev differentially affect restricted replication of human immunodeficiency virus type 1 in various cells. Virology. 1994 Mar;199(2):474–478. doi: 10.1006/viro.1994.1148. [DOI] [PubMed] [Google Scholar]
  18. Elsinghorst E. A., Baron L. S., Kopecko D. J. Penetration of human intestinal epithelial cells by Salmonella: molecular cloning and expression of Salmonella typhi invasion determinants in Escherichia coli. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5173–5177. doi: 10.1073/pnas.86.13.5173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Felber B. K., Pavlakis G. N. A quantitative bioassay for HIV-1 based on trans-activation. Science. 1988 Jan 8;239(4836):184–187. doi: 10.1126/science.3422113. [DOI] [PubMed] [Google Scholar]
  20. Fields P. I., Groisman E. A., Heffron F. A Salmonella locus that controls resistance to microbicidal proteins from phagocytic cells. Science. 1989 Feb 24;243(4894 Pt 1):1059–1062. doi: 10.1126/science.2646710. [DOI] [PubMed] [Google Scholar]
  21. Fields P. I., Swanson R. V., Haidaris C. G., Heffron F. Mutants of Salmonella typhimurium that cannot survive within the macrophage are avirulent. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5189–5193. doi: 10.1073/pnas.83.14.5189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Folks T. M., Justement J., Kinter A., Dinarello C. A., Fauci A. S. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987 Nov 6;238(4828):800–802. doi: 10.1126/science.3313729. [DOI] [PubMed] [Google Scholar]
  23. Frankel A. D., Pabo C. O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988 Dec 23;55(6):1189–1193. doi: 10.1016/0092-8674(88)90263-2. [DOI] [PubMed] [Google Scholar]
  24. Galyov E. E., Håkansson S., Forsberg A., Wolf-Watz H. A secreted protein kinase of Yersinia pseudotuberculosis is an indispensable virulence determinant. Nature. 1993 Feb 25;361(6414):730–732. doi: 10.1038/361730a0. [DOI] [PubMed] [Google Scholar]
  25. Galán J. E., Curtiss R., 3rd Cloning and molecular characterization of genes whose products allow Salmonella typhimurium to penetrate tissue culture cells. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6383–6387. doi: 10.1073/pnas.86.16.6383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Gartner S., Popovic M. Macrophage tropism of HIV-1. AIDS Res Hum Retroviruses. 1990 Aug;6(8):1017–1021. doi: 10.1089/aid.1990.6.1017. [DOI] [PubMed] [Google Scholar]
  27. Gendelman H. E., Orenstein J. M., Baca L. M., Weiser B., Burger H., Kalter D. C., Meltzer M. S. The macrophage in the persistence and pathogenesis of HIV infection. AIDS. 1989 Aug;3(8):475–495. doi: 10.1097/00002030-198908000-00001. [DOI] [PubMed] [Google Scholar]
  28. Groisman E. A., Ochman H. Cognate gene clusters govern invasion of host epithelial cells by Salmonella typhimurium and Shigella flexneri. EMBO J. 1993 Oct;12(10):3779–3787. doi: 10.1002/j.1460-2075.1993.tb06056.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jones B. D., Falkow S. Identification and characterization of a Salmonella typhimurium oxygen-regulated gene required for bacterial internalization. Infect Immun. 1994 Sep;62(9):3745–3752. doi: 10.1128/iai.62.9.3745-3752.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Jones B. D., Paterson H. F., Hall A., Falkow S. Salmonella typhimurium induces membrane ruffling by a growth factor-receptor-independent mechanism. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10390–10394. doi: 10.1073/pnas.90.21.10390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kucera L. S., Iyer N., Leake E., Raben A., Modest E. J., Daniel L. W., Piantadosi C. Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation. AIDS Res Hum Retroviruses. 1990 Apr;6(4):491–501. doi: 10.1089/aid.1990.6.491. [DOI] [PubMed] [Google Scholar]
  32. Letari O., Nicosia S., Chiavaroli C., Vacher P., Schlegel W. Activation by bacterial lipopolysaccharide causes changes in the cytosolic free calcium concentration in single peritoneal macrophages. J Immunol. 1991 Aug 1;147(3):980–983. [PubMed] [Google Scholar]
  33. Levy J. A. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993 Mar;57(1):183–289. doi: 10.1128/mr.57.1.183-289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Libby S. J., Goebel W., Ludwig A., Buchmeier N., Bowe F., Fang F. C., Guiney D. G., Songer J. G., Heffron F. A cytolysin encoded by Salmonella is required for survival within macrophages. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):489–493. doi: 10.1073/pnas.91.2.489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Manak J. R., de Bisschop N., Kris R. M., Prywes R. Casein kinase II enhances the DNA binding activity of serum response factor. Genes Dev. 1990 Jun;4(6):955–967. doi: 10.1101/gad.4.6.955. [DOI] [PubMed] [Google Scholar]
  36. Mellors J. W., Griffith B. P., Ortiz M. A., Landry M. L., Ryan J. L. Tumor necrosis factor-alpha/cachectin enhances human immunodeficiency virus type 1 replication in primary macrophages. J Infect Dis. 1991 Jan;163(1):78–82. doi: 10.1093/infdis/163.1.78. [DOI] [PubMed] [Google Scholar]
  37. Miller S. I., Kukral A. M., Mekalanos J. J. A two-component regulatory system (phoP phoQ) controls Salmonella typhimurium virulence. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5054–5058. doi: 10.1073/pnas.86.13.5054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Miller S. I., Mekalanos J. J. Constitutive expression of the phoP regulon attenuates Salmonella virulence and survival within macrophages. J Bacteriol. 1990 May;172(5):2485–2490. doi: 10.1128/jb.172.5.2485-2490.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Miller S. I. PhoP/PhoQ: macrophage-specific modulators of Salmonella virulence? Mol Microbiol. 1991 Sep;5(9):2073–2078. doi: 10.1111/j.1365-2958.1991.tb02135.x. [DOI] [PubMed] [Google Scholar]
  40. Miller V. L., Beer K. B., Loomis W. P., Olson J. A., Miller S. I. An unusual pagC::TnphoA mutation leads to an invasion- and virulence-defective phenotype in Salmonellae. Infect Immun. 1992 Sep;60(9):3763–3770. doi: 10.1128/iai.60.9.3763-3770.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Nakano M., Saito S., Nakano Y., Yamasu H., Matsuura M., Shinomiya H. Intracellular protein phosphorylation in murine peritoneal macrophages in response to bacterial lipopolysaccharide (LPS): effects of kinase-inhibitors and LPS-induced tolerance. Immunobiology. 1993 Apr;187(3-5):272–282. doi: 10.1016/S0171-2985(11)80344-X. [DOI] [PubMed] [Google Scholar]
  42. Pace J., Hayman M. J., Galán J. E. Signal transduction and invasion of epithelial cells by S. typhimurium. Cell. 1993 Feb 26;72(4):505–514. doi: 10.1016/0092-8674(93)90070-7. [DOI] [PubMed] [Google Scholar]
  43. Pomerantz R. J., Feinberg M. B., Trono D., Baltimore D. Lipopolysaccharide is a potent monocyte/macrophage-specific stimulator of human immunodeficiency virus type 1 expression. J Exp Med. 1990 Jul 1;172(1):253–261. doi: 10.1084/jem.172.1.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Pomerantz R. J., Trono D., Feinberg M. B., Baltimore D. Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency. Cell. 1990 Jun 29;61(7):1271–1276. doi: 10.1016/0092-8674(90)90691-7. [DOI] [PubMed] [Google Scholar]
  45. Portnoy D. A., Moseley S. L., Falkow S. Characterization of plasmids and plasmid-associated determinants of Yersinia enterocolitica pathogenesis. Infect Immun. 1981 Feb;31(2):775–782. doi: 10.1128/iai.31.2.775-782.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Raybourne R. B., Bunning V. K. Bacterium-host cell interactions at the cellular level: fluorescent labeling of bacteria and analysis of short-term bacterium-phagocyte interaction by flow cytometry. Infect Immun. 1994 Feb;62(2):665–672. doi: 10.1128/iai.62.2.665-672.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Saito S., Shinomiya H., Nakano M. Protein phosphorylation in murine peritoneal macrophages induced by infection with Salmonella species. Infect Immun. 1994 May;62(5):1551–1556. doi: 10.1128/iai.62.5.1551-1556.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Shirakawa F., Mizel S. B. In vitro activation and nuclear translocation of NF-kappa B catalyzed by cyclic AMP-dependent protein kinase and protein kinase C. Mol Cell Biol. 1989 Jun;9(6):2424–2430. doi: 10.1128/mcb.9.6.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Stone B. J., Garcia C. M., Badger J. L., Hassett T., Smith R. I., Miller V. L. Identification of novel loci affecting entry of Salmonella enteritidis into eukaryotic cells. J Bacteriol. 1992 Jun;174(12):3945–3952. doi: 10.1128/jb.174.12.3945-3952.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Suzuki T. Signal transduction mechanisms through Fc gamma receptors on the mouse macrophage surface. FASEB J. 1991 Feb;5(2):187–193. doi: 10.1096/fasebj.5.2.1706281. [DOI] [PubMed] [Google Scholar]
  51. Vaishnav Y. N., Wong-Staal F. The biochemistry of AIDS. Annu Rev Biochem. 1991;60:577–630. doi: 10.1146/annurev.bi.60.070191.003045. [DOI] [PubMed] [Google Scholar]
  52. Valentin A., Von Gegerfelt A., Matsuda S., Nilsson K., Asjö B. In vitro maturation of mononuclear phagocytes and susceptibility to HIV-1 infection. J Acquir Immune Defic Syndr. 1991;4(8):751–759. [PubMed] [Google Scholar]
  53. Yamamoto K. K., Gonzalez G. A., Biggs W. H., 3rd, Montminy M. R. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature. 1988 Aug 11;334(6182):494–498. doi: 10.1038/334494a0. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES