Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1988 Apr;56(4):779–784. doi: 10.1128/iai.56.4.779-784.1988

Lipid X protects mice against fatal Escherichia coli infection.

D T Golenbock 1, J E Leggett 1, P Rasmussen 1, W A Craig 1, C R Raetz 1, R A Proctor 1
PMCID: PMC259370  PMID: 3278981

Abstract

Lipid X, the major monosaccharide precursor of lipid A, is nontoxic and has previously been shown to protect mice and sheep from the harmful effects of endotoxin. To test the hypothesis that lipid X could be therapeutic against infections with gram-negative organisms, neutropenic ICR mice were infected by intramuscular inoculation of Escherichia coli and subsequently treated with lipid X alone or in combination with the antibiotic ticarcillin. Lipid X slightly prolonged survival; treated mice had a significantly improved rate of survival 18 h after intramuscular inoculation as compared with controls (P less than 0.025). By 24 h, however, this difference disappeared. When lipid X was combined with ticarcillin, survival differences were both significant and prolonged. Treatment of mice with one to two doses of lipid X for a total dose of 1 mg intravenously and with 1,200 mg of ticarcillin per kg every 6 h improved survival over a 48-h treatment period from 5 to 23% (P less than 0.0025). Treatment with lipid X and ticarcillin over a broad range of antibiotic dosages in 362 mice demonstrated improved survival of two- to fourfold (P less than 0.0001 at 24 h after inoculation, P less than or equal to 0.0005 at 48 h, and P less than or equal to 0.0001 at 5 days). Lipid X enabled the dose of ticarcillin necessary to protect 50% of mice from death to be reduced by two- to fivefold. Pretreatment with lipid X was not necessary to improve survival: 16 of 17 (94%) infected and visibly ill animals that received lipid X and ticarcillin 6 h after thigh inoculation survived versus 30 of 44 (68%) control animals treated with ticarcillin alone (P less than 0.0001). Lipid X had no antimicrobial activity in vitro. Lipid X is a novel agent that enhances survival in an animal model of severe infection with gram-negative organisms.

Full text

PDF
779

Selected References

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

  1. Berry L. J. Bacterial toxins. CRC Crit Rev Toxicol. 1977 Nov;5(3):239–318. doi: 10.3109/10408447709082601. [DOI] [PubMed] [Google Scholar]
  2. Braude A. I., Ziegler E. J., Douglas H., McCutchan J. A. Antibody to cell wall glycolipid of Gram-negative bacteria: induction of immunity to bacteremia and endotoxemia. J Infect Dis. 1977 Aug;136 (Suppl):S167–S173. doi: 10.1093/infdis/136.supplement.s167. [DOI] [PubMed] [Google Scholar]
  3. Burhop K. E., Proctor R. A., Helgerson R. B., Raetz C. H., Starling J. R., Will J. A. Pulmonary pathophysiological changes in sheep caused by endotoxin precursor, lipid X. J Appl Physiol (1985) 1985 Dec;59(6):1726–1732. doi: 10.1152/jappl.1985.59.6.1726. [DOI] [PubMed] [Google Scholar]
  4. Christy J. H. Treatment of gram-negative shock. Am J Med. 1971 Jan;50(1):77–88. doi: 10.1016/0002-9343(71)90207-5. [DOI] [PubMed] [Google Scholar]
  5. Cook J. A., Wise W. C., Halushka P. V. Elevated thromboxane levels in the rat during endotoxic shock: protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency. J Clin Invest. 1980 Jan;65(1):227–230. doi: 10.1172/JCI109655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Craig W. A., Turner J. H., Kunin C. M. Prevention of the generalized Shwartzman reaction and endotoxin lethality by polymyxin B localized in tissues. Infect Immun. 1974 Aug;10(2):287–292. doi: 10.1128/iai.10.2.287-292.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Davis C. E., Brown K. R., Douglas H., Tate W. J., 3rd, Braude A. I. Prevention of death from endotoxin with antisera. I. The risk of fatal anaphylaxis to endotoxin. J Immunol. 1969 Mar;102(3):563–572. [PubMed] [Google Scholar]
  8. DeMaria A., Carven D. E., Heffernan J. J., McIntosh T. K., Grindlinger G. A., McCabe W. R. Naloxone versus placebo in treatment of septic shock. Lancet. 1985 Jun 15;1(8442):1363–1365. doi: 10.1016/s0140-6736(85)91787-8. [DOI] [PubMed] [Google Scholar]
  9. Gerber A. U., Craig W. A., Brugger H. P., Feller C., Vastola A. P., Brandel J. Impact of dosing intervals on activity of gentamicin and ticarcillin against Pseudomonas aeruginosa in granulocytopenic mice. J Infect Dis. 1983 May;147(5):910–917. doi: 10.1093/infdis/147.5.910. [DOI] [PubMed] [Google Scholar]
  10. Golenbock D. T., Ebert S., Will J. A., Proctor R. A. Elimination and tissue distribution of the monosaccharide lipid A precursor, lipid X, in mice and sheep. Antimicrob Agents Chemother. 1988 Jan;32(1):37–41. doi: 10.1128/aac.32.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Golenbock D. T., Will J. A., Raetz C. R., Proctor R. A. Lipid X ameliorates pulmonary hypertension and protects sheep from death due to endotoxin. Infect Immun. 1987 Oct;55(10):2471–2476. doi: 10.1128/iai.55.10.2471-2476.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Guthrie L. A., McPhail L. C., Henson P. M., Johnston R. B., Jr Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharide. Evidence for increased activity of the superoxide-producing enzyme. J Exp Med. 1984 Dec 1;160(6):1656–1671. doi: 10.1084/jem.160.6.1656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hinshaw L. B., Archer L. T., Beller-Todd B. K., Benjamin B., Flournoy D. J., Passey R. Survival of primates in lethal septic shock following delayed treatment with steroid. Circ Shock. 1981;8(3):291–300. [PubMed] [Google Scholar]
  14. Hinshaw L. B., Beller-Todd B. K., Archer L. T., Benjamin B., Flournoy D. J., Passey R., Wilson M. F. Effectiveness of steroid/antibiotic treatment in primates administered LD100 Escherichia coli. Ann Surg. 1981 Jul;194(1):51–56. doi: 10.1097/00000658-198107000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Holaday J. W., Faden A. I. Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock. Nature. 1978 Oct 5;275(5679):450–451. doi: 10.1038/275450a0. [DOI] [PubMed] [Google Scholar]
  16. Jawetz E. Combined antibiotic action: some definitions and correlations between laboratory and clinical results. Antimicrob Agents Chemother (Bethesda) 1967;7:203–209. doi: 10.1128/AAC.7.2.203. [DOI] [PubMed] [Google Scholar]
  17. Johns M., Skehill A., McCabe W. R. Immunization with rough mutants of Salmonella minnesota. IV. Protection by antisera to O and rough antigens against endotoxin. J Infect Dis. 1983 Jan;147(1):57–67. doi: 10.1093/infdis/147.1.57. [DOI] [PubMed] [Google Scholar]
  18. McCabe W. R. Immunization with R mutants of S. Minnesota. I. Protection against challenge with heterologous gram-negative bacilli. J Immunol. 1972 Mar;108(3):601–610. [PubMed] [Google Scholar]
  19. Nishijima M., Amano F., Akamatsu Y., Akagawa K., Tokunaga T., Raetz C. R. Macrophage activation by monosaccharide precursors of Escherichia coli lipid A. Proc Natl Acad Sci U S A. 1985 Jan;82(2):282–286. doi: 10.1073/pnas.82.2.282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Proctor R. A., Textor J. A. Activation and inhibition of Limulus amebocyte lysate coagulation by chemically defined substructures of lipid A. Infect Immun. 1985 Aug;49(2):286–290. doi: 10.1128/iai.49.2.286-290.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Proctor R. A., Will J. A., Burhop K. E., Raetz C. R. Protection of mice against lethal endotoxemia by a lipid A precursor. Infect Immun. 1986 Jun;52(3):905–907. doi: 10.1128/iai.52.3.905-907.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Raetz C. R., Purcell S., Takayama K. Molecular requirements for B-lymphocyte activation by Escherichia coli lipopolysaccharide. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4624–4628. doi: 10.1073/pnas.80.15.4624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Raetz C. R. The enzymatic synthesis of lipid A: molecular structure and biologic function of monosaccharide precursors. Rev Infect Dis. 1984 Jul-Aug;6(4):463–471. doi: 10.1093/clinids/6.4.463. [DOI] [PubMed] [Google Scholar]
  24. Sakulramrung R., Domingue G. J. Cross-reactive immunoprotective antibodies to Escherichia coli O111 rough mutant J5. J Infect Dis. 1985 Jun;151(6):995–1004. doi: 10.1093/infdis/151.6.995. [DOI] [PubMed] [Google Scholar]
  25. Sheagren J. N. Septic shock and corticosteroids. N Engl J Med. 1981 Aug 20;305(8):456–458. doi: 10.1056/NEJM198108203050810. [DOI] [PubMed] [Google Scholar]
  26. Shenep J. L., Barton R. P., Mogan K. A. Role of antibiotic class in the rate of liberation of endotoxin during therapy for experimental gram-negative bacterial sepsis. J Infect Dis. 1985 Jun;151(6):1012–1018. doi: 10.1093/infdis/151.6.1012. [DOI] [PubMed] [Google Scholar]
  27. Shenep J. L., Mogan K. A. Kinetics of endotoxin release during antibiotic therapy for experimental gram-negative bacterial sepsis. J Infect Dis. 1984 Sep;150(3):380–388. doi: 10.1093/infdis/150.3.380. [DOI] [PubMed] [Google Scholar]
  28. Sprung C. L., Caralis P. V., Marcial E. H., Pierce M., Gelbard M. A., Long W. M., Duncan R. C., Tendler M. D., Karpf M. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984 Nov 1;311(18):1137–1143. doi: 10.1056/NEJM198411013111801. [DOI] [PubMed] [Google Scholar]
  29. Takayama K., Qureshi N., Raetz C. R., Ribi E., Peterson J., Cantrell J. L., Pearson F. C., Wiggins J., Johnson A. G. Influence of fine structure of lipid A on Limulus amebocyte lysate clotting and toxic activities. Infect Immun. 1984 Aug;45(2):350–355. doi: 10.1128/iai.45.2.350-355.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Weil M. H., Shubin H., Carlson R. Treatment of circulatory shock. Use of sympathomimetic and related vasoactive agents. JAMA. 1975 Mar 24;231(12):1280–1286. [PubMed] [Google Scholar]
  31. Wightman P. D., Raetz C. R. The activation of protein kinase C by biologically active lipid moieties of lipopolysaccharide. J Biol Chem. 1984 Aug 25;259(16):10048–10052. [PubMed] [Google Scholar]
  32. Ziegler E. J., Douglas H., Sherman J. E., Davis C. E., Braude A. I. Treatment of E. coli and klebsiella bacteremia in agranulocytic animals with antiserum to a UDP-gal epimerase-deficient mutant. J Immunol. 1973 Aug;111(2):433–438. [PubMed] [Google Scholar]
  33. Ziegler E. J., McCutchan J. A., Douglas H., Braude A. I. Prevention of lethal pseudomonas bacteremia with epimerase-deficient E. coli antiserum. Trans Assoc Am Physicians. 1975;88:101–108. [PubMed] [Google Scholar]
  34. Ziegler E. J., McCutchan J. A., Fierer J., Glauser M. P., Sadoff J. C., Douglas H., Braude A. I. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med. 1982 Nov 11;307(20):1225–1230. doi: 10.1056/NEJM198211113072001. [DOI] [PubMed] [Google Scholar]

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

RESOURCES