Abstract
We reported that administration of anti-tumor necrosis factor alpha (anti-TNF-alpha) antibodies exacerbates the course of a Salmonella infection in both susceptible and resistant mice by preventing the suppression of bacterial growth in the reticuloendothelial system. In the present study, we evaluated the effect of in vivo neutralization of TNF-alpha on the histopathology of primary Salmonella infections. We show that in primary infections, the suppression of bacterial growth in the reticuloendothelial system coincides with granuloma formation in the spleen and liver. Administration of anti-TNF-alpha globulins on day -1 of salmonellosis affected neither the histological picture nor the course of the infection in the early stages of the disease (days 1 to 3), with splenic and hepatic lesions consisting mainly of polymorphonuclear leukocytes (PMNs); conversely, later in infection (days 3 to 7), the treatment inhibited the formation of granulomas. When the anti-TNF-alpha treatment was started well after the suppression of bacterial growth in the reticuloendothelial system and the formation of granulomatous lesions in the spleen and liver, a prompt relapse of the infection and regression of already established granulomas were seen. In anti-TNF-alpha-treated mice, salmonellae were found inside macrophages and PMNs and extracellularly in the necrotic tissue of the spleen, while in the liver the organisms were seen mainly in inflammatory mononuclear cells, resident Kupffer cells, and hepatocytes and occasionally in the extracellular compartment within necrotic lesions. The bacteria appeared most often in clusters, being morphologically intact when in the extracellular space or within hepatocytes, while undergoing various degrees of degeneration when inside phagocytes. The results suggest that TNF-alpha is required for granuloma formation in salmonellosis and that its neutralization does not completely abrogate the bactericidal activity of macrophages and PMNs. Salmonellae were observed to grow within both hepatocytes and phagocytes but were killed only in the latter.
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- Amiri P., Locksley R. M., Parslow T. G., Sadick M., Rector E., Ritter D., McKerrow J. H. Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature. 1992 Apr 16;356(6370):604–607. doi: 10.1038/356604a0. [DOI] [PubMed] [Google Scholar]
- Collins F. M. Vaccines and cell-mediated immunity. Bacteriol Rev. 1974 Dec;38(4):371–402. doi: 10.1128/br.38.4.371-402.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Conlan J. W., North R. J. Early pathogenesis of infection in the liver with the facultative intracellular bacteria Listeria monocytogenes, Francisella tularensis, and Salmonella typhimurium involves lysis of infected hepatocytes by leukocytes. Infect Immun. 1992 Dec;60(12):5164–5171. doi: 10.1128/iai.60.12.5164-5171.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dunlap N. E., Benjamin W. H., Jr, Berry A. K., Eldridge J. H., Briles D. E. A 'safe-site' for Salmonella typhimurium is within splenic polymorphonuclear cells. Microb Pathog. 1992 Sep;13(3):181–190. doi: 10.1016/0882-4010(92)90019-k. [DOI] [PubMed] [Google Scholar]
- Dunlap N. E., Benjamin W. H., Jr, McCall R. D., Jr, Tilden A. B., Briles D. E. A 'safe-site' for Salmonella typhimurium is within splenic cells during the early phase of infection in mice. Microb Pathog. 1991 Apr;10(4):297–310. doi: 10.1016/0882-4010(91)90013-z. [DOI] [PubMed] [Google Scholar]
- Hauser T., Frei K., Zinkernagel R. M., Leist T. P. Role of tumor necrosis factor in Listeria resistance of nude mice. Med Microbiol Immunol. 1990;179(2):95–104. doi: 10.1007/BF00198530. [DOI] [PubMed] [Google Scholar]
- Hormaeche C. E., Mastroeni P., Arena A., Uddin J., Joysey H. S. T cells do not mediate the initial suppression of a Salmonella infection in the RES. Immunology. 1990 Jun;70(2):247–250. [PMC free article] [PubMed] [Google Scholar]
- Hormaeche C. E. Natural resistance to Salmonella typhimurium in different inbred mouse strains. Immunology. 1979 Jun;37(2):311–318. [PMC free article] [PubMed] [Google Scholar]
- Hsu H. S. Pathogenesis and immunity in murine salmonellosis. Microbiol Rev. 1989 Dec;53(4):390–409. doi: 10.1128/mr.53.4.390-409.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Killar L. M., Eisenstein T. K. Immunity to Salmonella typhimurium infection in C3H/HeJ and C3H/HeNCrlBR mice: studies with an aromatic-dependent live S. typhimurium strain as a vaccine. Infect Immun. 1985 Mar;47(3):605–612. doi: 10.1128/iai.47.3.605-612.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kindler V., Sappino A. P., Grau G. E., Piguet P. F., Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989 Mar 10;56(5):731–740. doi: 10.1016/0092-8674(89)90676-4. [DOI] [PubMed] [Google Scholar]
- Lin F. R., Wang X. M., Hsu H. S., Mumaw V. R., Nakoneczna I. Electron microscopic studies on the location of bacterial proliferation in the liver in murine salmonellosis. Br J Exp Pathol. 1987 Aug;68(4):539–550. [PMC free article] [PubMed] [Google Scholar]
- Maskell D. J., Hormaeche C. E., Harrington K. A., Joysey H. S., Liew F. Y. The initial suppression of bacterial growth in a salmonella infection is mediated by a localized rather than a systemic response. Microb Pathog. 1987 Apr;2(4):295–305. doi: 10.1016/0882-4010(87)90127-6. [DOI] [PubMed] [Google Scholar]
- Mastroeni P., Arena A., Costa G. B., Liberto M. C., Bonina L., Hormaeche C. E. Serum TNF alpha in mouse typhoid and enhancement of a Salmonella infection by anti-TNF alpha antibodies. Microb Pathog. 1991 Jul;11(1):33–38. doi: 10.1016/0882-4010(91)90091-n. [DOI] [PubMed] [Google Scholar]
- Mastroeni P., Villarreal-Ramos B., Hormaeche C. E. Effect of late administration of anti-TNF alpha antibodies on a Salmonella infection in the mouse model. Microb Pathog. 1993 Jun;14(6):473–480. doi: 10.1006/mpat.1993.1046. [DOI] [PubMed] [Google Scholar]
- Mastroeni P., Villarreal B., Demarco de Hormaeche R., Hormaeche C. E. Serum TNF alpha inhibitor in mouse typhoid. Microb Pathog. 1992 May;12(5):343–349. doi: 10.1016/0882-4010(92)90097-8. [DOI] [PubMed] [Google Scholar]
- Ming W. J., Bersani L., Mantovani A. Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J Immunol. 1987 Mar 1;138(5):1469–1474. [PubMed] [Google Scholar]
- Muotiala A., Mäkelä P. H. The role of IFN-gamma in murine Salmonella typhimurium infection. Microb Pathog. 1990 Feb;8(2):135–141. doi: 10.1016/0882-4010(90)90077-4. [DOI] [PubMed] [Google Scholar]
- Nakoneczna I., Hsu H. S. The comparative histopathology of primary and secondary lesions in murine salmonellosis. Br J Exp Pathol. 1980 Feb;61(1):76–84. [PMC free article] [PubMed] [Google Scholar]
- Nauciel C., Espinasse-Maes F. Role of gamma interferon and tumor necrosis factor alpha in resistance to Salmonella typhimurium infection. Infect Immun. 1992 Feb;60(2):450–454. doi: 10.1128/iai.60.2.450-454.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tite J. P., Dougan G., Chatfield S. N. The involvement of tumor necrosis factor in immunity to Salmonella infection. J Immunol. 1991 Nov 1;147(9):3161–3164. [PubMed] [Google Scholar]