• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of iaiPermissionsJournals.ASM.orgJournalIAI ArticleJournal InfoAuthorsReviewers
Infect Immun. Aug 1989; 57(8): 2495–2501.
PMCID: PMC313476

Trehalose dimycolate enhances resistance to infection in neutropenic animals.

Abstract

Bacterial infections are lethal complications of neutropenia, and antibiotics alone are inadequate therapy for these infections. Irradiated mice become severely neutropenic and remain susceptible to infection for 2 to 3 weeks, depending on the dose and quality of radiation. Some bacterial cell wall derivatives stimulate nonspecific host defense mechanisms against a variety of microbes which might cause postirradiation infection. In this study we determined if the cell wall glycolipid trehalose dimycolate (TDM), derived from Mycobacterium phlei, or a synthetic preparation of TDM was able to (i) enhance survival in mice when given before or after lethal doses of 60Co radiation and (ii) increase nonspecific resistance to postirradiation infection. Treatment with TDM oil-in-water emulsions and with synthetic TDM significantly enhanced survival before and after lethal doses of 60Co irradiation. This result correlated with the ability of TDM to reduce the translocation of intestinal bacteria and to stimulate hematopoiesis. With respect to nonspecific resistance to infection, TDM injected 1 h after sublethal irradiation increased resistance to a lethal Klebsiella pneumoniae challenge (10 50% lethal doses of K. pneumoniae in 30 days [LD50/30]) 4 or 14 days later. Increasing the dose of K. pneumoniae to 5,000 LD50/30 on day 4 overwhelmed the ability of TDM-treated mice to overcome infection. However, TDM treatment 1 h postirradiation combined with ceftriaxone antibiotic therapy (days 5 through 14) enhanced survival, even when the higher dose of bacteria (5,000 LD50/30) was used. These results indicate that in irradiated mice, TDM can be used to enhance survival and, as a potent stimulant of nonspecific resistance to infection in neutropenic mice, can act synergistically with antibiotic therapy to reduce sepsis and mortality.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Alper T. Low oxygen enhancement ratios for radiosensitive bacterial strains, and the probable interaction of two types of primary lesion. Nature. 1968 Mar 2;217(5131):862–863. [PubMed]
  • Azuma I, Ribi EE, Meyer TJ, Zbar B. Biologically active components from mycobacterial cell walls. I. Isolation and composition of cell wall skeleton and component P3. J Natl Cancer Inst. 1974 Jan;52(1):95–101. [PubMed]
  • Batist G, Reynaud A, Katki AG, Travis EL, Shoemaker MC, Greene RF, Myers CE. Enzymatic defense against radiation damage in mice. Effect of selenium and vitamin E depletion. Biochem Pharmacol. 1986 Feb 15;35(4):601–606. [PubMed]
  • Cavanagh D, Knuppel RA, Shepherd JH, Anderson R, Rao PS. Septic shock and the obstetrician/gynecologist. South Med J. 1982 Jul;75(7):809–813. [PubMed]
  • Geiger B, Gallily R. Effect of X-irradiation on various functions of murine macrophages. Clin Exp Immunol. 1974 Apr;16(4):643–655. [PMC free article] [PubMed]
  • KAPLAN HS, SPECK RS, JAWETZ E. Impairment of antimicrobial defense following total body irradiation of mice. J Lab Clin Med. 1952 Nov;40(5):682–691. [PubMed]
  • Kierszenbaum F, Zenian A, Wirth JJ. Macrophage activation by cord factor (trehalose 6,6'-dimycolate): enhanced association with and intracellular killing of Trypanosoma cruzi. Infect Immun. 1984 Feb;43(2):531–535. [PMC free article] [PubMed]
  • Landauer MR, Davis HD, Dominitz JA, Weiss JF. Dose and time relationships of the radioprotector WR-2721 on locomotor activity in mice. Pharmacol Biochem Behav. 1987 Jul;27(3):573–576. [PubMed]
  • LEDNEY GD, WILSON R. PROTECTION INDUCED BY BACTERIAL ENDOTOXIN AGAINST WHOLE-BODY X-IRRADIATION IN GERMFREE AND CONVENTIONAL MICE. Proc Soc Exp Biol Med. 1965 Apr;118:1062–1065. [PubMed]
  • Lemaire G, Tenu JP, Petit JF, Lederer E. Natural and synthetic trehalose diesters as immunomodulators. Med Res Rev. 1986 Jul-Sep;6(3):243–274. [PubMed]
  • Madonna GS, Peterson JE, Ribi EE, Vogel SN. Early-phase endotoxin tolerance: induction by a detoxified lipid A derivative, monophosphoryl lipid A. Infect Immun. 1986 Apr;52(1):6–11. [PMC free article] [PubMed]
  • Masihi KN, Lange W, Brehmer W, Ribi E. Immunobiological activities of nontoxic lipid A: enhancement of nonspecific resistance in combination with trehalose dimycolate against viral infection and adjuvant effects. Int J Immunopharmacol. 1986;8(3):339–345. [PubMed]
  • Numata F, Nishimura K, Ishida H, Ukei S, Tone Y, Ishihara C, Saiki I, Sekikawa I, Azuma I. Lethal and adjuvant activities of cord factor (trehalose-6,6'-dimycolate) and synthetic analogs in mice. Chem Pharm Bull (Tokyo) 1985 Oct;33(10):4544–4555. [PubMed]
  • Olds GR, Chedid L, Lederer E, Mahmoud AA. Induction of resistance to Schistosoma mansoni by natural cord factor and synthetic lower homologues. J Infect Dis. 1980 Apr;141(4):473–478. [PubMed]
  • Parant M, Parant F, Chedid L, Drapier JC, Petit JF, Wietzerbin J, Lederer Enhancement of nonspecific immunity to bacterial infection by cord factor (6,6'-trehalose dimycolate). J Infect Dis. 1977 May;135(5):771–777. [PubMed]
  • Patchen ML, D'Alesandro MM, Brook I, Blakely WF, MacVittie TJ. Glucan: mechanisms involved in its "radioprotective" effect. J Leukoc Biol. 1987 Aug;42(2):95–105. [PubMed]
  • Patchen ML, MacVittie TJ, Wathen LM. Effects of pre- and post-irradiation glucan treatment on pluripotent stem cells, granulocyte, macrophage and erythroid progenitor cells, and hemopoietic stromal cells. Experientia. 1984 Nov 15;40(11):1240–1244. [PubMed]
  • Qureshi N, Takayama K, Ribi E. Purification and structural determination of nontoxic lipid A obtained from the lipopolysaccharide of Salmonella typhimurium. J Biol Chem. 1982 Oct 10;257(19):11808–11815. [PubMed]
  • Ribi E, Cantrell JL, Takayama K, Qureshi N, Peterson J, Ribi HO. Lipid A and immunotherapy. Rev Infect Dis. 1984 Jul-Aug;6(4):567–572. [PubMed]
  • SMITH WW, ALDERMAN IM, GILLESPIE RE. Hematopoietic recovery induced by bacterial endotoxin in irradiated mice. Am J Physiol. 1958 Mar;192(3):549–556. [PubMed]
  • Stewart DA, Ledney GD, Baker WH, Daxon EG, Sheehy PA. Bone marrow transplantation of mice exposed to a modified fission neutron (N/G-30:1) field. Radiat Res. 1982 Nov;92(2):268–279. [PubMed]
  • Takayama K, Qureshi N, Ribi E, Cantrell JL. Separation and characterization of toxic and nontoxic forms of lipid A. Rev Infect Dis. 1984 Jul-Aug;6(4):439–443. [PubMed]
  • Tenu JP, Lederer E, Petit JF. Stimulation of thymocyte mitogenic protein secretion and of cytostatic activity of mouse peritoneal macrophages by trehalose dimycolate and muramyldipeptide. Eur J Immunol. 1980 Aug;10(8):647–653. [PubMed]
  • TILL JE, McCULLOCH EA. Early repair processes in marrow cells irradiated and proliferating in vivo. Radiat Res. 1963 Jan;18:96–105. [PubMed]
  • Vosika GJ, Gray GR. Phase I study of iv mycobacterial cell wall skeleton and cell wall skeleton combined with trehalose dimycolate. Cancer Treat Rep. 1983 Sep;67(9):785–790. [PubMed]
  • Walker RI, Ledney GD, Galley CB. Aseptic endotoxemia in radiation injury and graft-vs-host diesease. Radiat Res. 1975 May;62(2):242–249. [PubMed]
  • Yarkoni E, Bekierkunst A. Nonspecific resistance against infection with Salmonella typhi and Salmonella typhimurium induced in mice by cord factor (trehalose-6,6'-dimycolate) and its analogues. Infect Immun. 1976 Nov;14(5):1125–1129. [PMC free article] [PubMed]
  • Yarkoni E, Wang L, Bekierkunst A. Stimulation of macrophages by cord factor and by heat-killed and living BCG. Infect Immun. 1977 Apr;16(1):1–8. [PMC free article] [PubMed]
  • Zimmerman JJ, Dietrich KA. Current perspectives on septic shock. Pediatr Clin North Am. 1987 Feb;34(1):131–163. [PubMed]

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

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...