Skip to main content

Advertisement

SpringerLink
Log in

Genetic susceptibility to sepsis: A possible role for mannose-binding lectin

  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Sepsis is an increasing problem in modern medicine and the leading cause of death in noncoronary intensive care unit patients. Over the past few years, several studies have provided data indicating that relatively common polymorphisms in genes encoding proteins of importance for innate immune recognition, the inflammatory response, and for coagulation and fibrinolysis, are associated with susceptibility for and outcome of sepsis. Recently, several studies have shed light on the importance of deficiency of mannose-binding lectin (MBL) as a susceptibility factor for sepsis. This review summarizes the evidence that critically ill patients carrying MBL-variant alleles may be at increased risk for severe sepsis. The prospect for the future is that genetic profiling may guide in identifying critically ill patients at increased risk for sepsis and poor outcome, and in tailoring a more individual and effective therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW: Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988, 318:727–732.

    Article  PubMed  CAS  Google Scholar 

  2. Rangel-Frausto MS, Pittet D, Costigan M, et al.: The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 1995, 273:117–123.

    Article  PubMed  CAS  Google Scholar 

  3. Bone RC, Sibbald WJ, Sprung CL: The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 1992, 101:1481–1483.

    PubMed  CAS  Google Scholar 

  4. Angus DC, Wax RS: Epidemiology of sepsis: an update. Crit Care Med 2001, 29:109–116.

    Article  Google Scholar 

  5. Holmes CL, Russell JA, Walley KR: Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. Chest 2003, 124:1103–1115.

    Article  PubMed  CAS  Google Scholar 

  6. Lin MT, Albertson TE: Genomic polymorphisms in sepsis. Crit Care Med 2004, 32:569–579.

    Article  PubMed  CAS  Google Scholar 

  7. Lorenz E, Mira JP, Cornish KL, et al.: A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 2000, 68:6398–6401.

    Article  PubMed  CAS  Google Scholar 

  8. Lorenz E, Mira JP, Frees KL, Schwartz DA: Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 2002, 162:1028–1032.

    Article  PubMed  CAS  Google Scholar 

  9. Hawn TR, Verbon A, Lettinga KD, et al.: A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J Exp Med 2003, 198:1563–1572.

    Article  PubMed  CAS  Google Scholar 

  10. Turner MW, Hamvas RMJ: Mannose-binding lectin: structure, function, genetics and disease associations. Rev Immunogenet 2000, 2:305–322.

    PubMed  CAS  Google Scholar 

  11. Palaniyar N, Nadesalingam J, Clark H, et al.: Nucleic acid is a novel ligand for innate immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. J Biol Chem 2004, 279:32728–32736.

    Article  PubMed  CAS  Google Scholar 

  12. Matsushita M, Fujita T: Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J Exp Med 1992, 176:1497–1503.

    Article  PubMed  CAS  Google Scholar 

  13. Thiel S, Vorup-Jensen T, Stover CM, et al.: A second serine protease associated with mannan-binding lectin that activates complement. Nature 1997, 386:506–510.

    Article  PubMed  CAS  Google Scholar 

  14. Dahl MR, Thiel S, Matsushita M, et al.: MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. Immunity 2001, 15:127–135.

    Article  PubMed  CAS  Google Scholar 

  15. Takahashi M, Endo Y, Fujita T, Matsushita M: A truncated form of mannose-binding lectin-associated serine protease (MASP)-2 expressed by alternative polyadenylation is a component of the lectin complement pathway. Int Immunol 1999, 11:859–863.

    Article  PubMed  CAS  Google Scholar 

  16. Gadjeva M, Thiel S, Jensenius JC: The mannan-binding-lectin pathway of the innate immune response. Curr Opin Immunol 2001, 13:74–78.

    Article  PubMed  CAS  Google Scholar 

  17. Ezekowitz RAB, Day LE, Herman GA: A human mannosebinding protein is an acute-phase reactant that shares sequence homology with other vertebrate lectins. J Exp Med 1988, 167:1034–1046.

    Article  PubMed  CAS  Google Scholar 

  18. Lu J, Thiel S, Wiedemann H, et al.: Binding of the pentamer/ hexamer forms of mannan-binding protein to zymosan activates the proenzyme C1r2C1s2 complex, of the classical pathway of complement, without involvement of C1q. J Immunol 1990, 144:2287–2294.

    PubMed  CAS  Google Scholar 

  19. Larsen F, Madsen HO, Sim RB, et al.: Disease-associated mutations in human mannose-binding lectin compromise oligomerisation and activity of the final protein. J Biol Chem 2004, 279:21302–21311.

    Article  PubMed  CAS  Google Scholar 

  20. Lipscombe RJ, Sumiya M, Summerfield JA, Turner MW: Distinct physicochemical characteristics of human mannose binding protein (MBP) expressed by individuals of differing genotype. Immunology 1995, 85:660–667.

    PubMed  CAS  Google Scholar 

  21. Miller ME, Seals J, Kaye R, Levitsky LC: A familial, plasma associated defect of phagocytosis: new cause of recurrent bacterial infection. Lancet 1968, 2:60–63.

    Article  Google Scholar 

  22. Garred P, Larsen F, Madsen HO, Koch C: Mannose-binding lectin deficiency-revisited. Mol Immunol 2003, 40:73–84.

    Article  PubMed  CAS  Google Scholar 

  23. Kawasaki N, Kawasaki T, Yamashina I: Isolation and characterization of mannan-binding protein from human serum. J Biochem (Tokyo) 1983, 94:937–947.

    CAS  Google Scholar 

  24. Ikeda K, Sannoh H, Kawasaki N, et al.: Serum lectin with known structure activates complement through the classical pathway. J Biol Chem 1987, 262:7451–7454.

    PubMed  CAS  Google Scholar 

  25. Super M, Thiel S, Lu J, et al.: Association of low levels of mannanbinding protein with a common defect in opsonisation. Lancet 1989, 2:1236–1239.

    Article  PubMed  CAS  Google Scholar 

  26. Taylor ME, Brickell PM, Craig RK, Summerfield JA: Structure and evolutionary origin of the gene encoding a human serum mannose-binding protein. Biochem J 1989, 262:763–771.

    PubMed  CAS  Google Scholar 

  27. Sastry K, Herman GA, Day L, et al.: The human mannose-binding protein gene. Exon structure reveals its evolutionary relationship to a human pulmonary surfactant gene and localization to chromosome 10. J Exp Med 1989, 170:1175–1189.

    Article  PubMed  CAS  Google Scholar 

  28. Guo N, Mogues T, Weremowicz S, et al.: The human ortholog of rhesus mannose-binding protein-A gene is an expressed pseudogene that localizes to chromosome 10. Mamm Genome 1998, 9:246–249.

    Article  PubMed  CAS  Google Scholar 

  29. Naito H, Ikeda A, Hasegawa K, et al.: Characterization of human serum mannan-binding protein promoter. J Biochem (Tokyo) 1999, 126:1004–1012.

    CAS  Google Scholar 

  30. Sumiya M, Super M, Tabona P, et al.: Molecular basis of opsonic defect in immunodeficient children. Lancet 1991, 337:1569–1570.

    Article  PubMed  CAS  Google Scholar 

  31. Lipscombe RJ, Sumiya M, Hill AV, et al.: High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene. Hum Mol Genet 1992, 1:709–715.

    Article  PubMed  CAS  Google Scholar 

  32. Madsen HO, Garred P, Kurtzhals JAL, et al.: A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein. Immunogenetics 1994, 40:37–44.

    Article  PubMed  CAS  Google Scholar 

  33. Madsen HO, Garred P, Thiel S, et al.: Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol 1995, 155:3013–3020.

    PubMed  CAS  Google Scholar 

  34. Madsen HO, Satz ML, Hogh B, et al.: Different molecular events result in low protein levels of mannan-binding lectin in populations from Southeast Africa and South America. J Immunol 1998, 161:3169–3175.

    PubMed  CAS  Google Scholar 

  35. Terai I, Kobayashi K, Matsushita M, et al.: Relationship between gene polymorphisms of mannose-binding lectin (MBL) and two molecular forms of MBL. Eur J Immunol 2003, 33:2755–2763.

    Article  PubMed  CAS  Google Scholar 

  36. Butler GS, Sim D, Tam E, et al.: Mannose-binding lectin (MBL) mutants are susceptible to matrix metalloproteinase proteolysis: potential role in human MBL deficiency. J Biol Chem 2002, 277:17511–17519.

    Article  PubMed  CAS  Google Scholar 

  37. Koch A, Melbye M, Sorensen P, et al.: Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood. JAMA 2001, 285:1316–1321.

    Article  PubMed  CAS  Google Scholar 

  38. Garred P, Harboe M, Oettinger T, et al.: Dual role of mannanbinding protein in infections: another case of heterosis? Eur J Immunogenet 1994, 21:125–131.

    Article  PubMed  CAS  Google Scholar 

  39. Garred P, Pressler T, Madsen HO, et al.: Association of mannosebinding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest 1999, 104:431–437.

    Article  PubMed  CAS  Google Scholar 

  40. Gabolde M, Guilloud-Bataile M, Feingold J, Besmond C: Association of variant alleles of mannose binding lectin with severity of pulmonary disease in cystic fibrosis: cohort study. BMJ 1999, 319:1166–1167.

    PubMed  CAS  Google Scholar 

  41. Garred P, Madsen HO, Halberg P, et al.: Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 1999, 42:2145–2152.

    Article  PubMed  CAS  Google Scholar 

  42. Volhenschlæger T, Garred P, Madsen HO, Jacobsen S: Mannosebinding lectin variant alleles and the risk of arterial thrombosis in systemic lupus erythematosus. N Engl J Med 2004, 351:260–267.

    Article  Google Scholar 

  43. Garred P, Strom JJ, Quist L, et al.: Association of mannosebinding lectin polymorphisms with sepsis and fatal outcome in patients with systemic inflammatory response syndrome. J Infect Dis 2003, 188:1394–1403. This is an epidemiologic study indicating that in particular, homozygosity for MBL-variant alleles confers increased risk for septic shock and adverse outcome in adult ICU patients.

    Article  PubMed  CAS  Google Scholar 

  44. Fidler KJ, Wilson P, Davies JC, et al.: Increased incidence and severity of the systemic inflammatory response syndrome in patients deficient in mannose-binding lectin. Intensive Care Med 2004, 30:1438–1445. This is an epidemiologic study indicating that presence of MBLvariant alleles confers increased risk for SIRS and sepsis in children admitted to the ICU.

    Article  PubMed  Google Scholar 

  45. Hansen TK, Thiel S, Wouters PJ, et al.: Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 2003, 88:1082–1088. Important study.

    Article  PubMed  CAS  Google Scholar 

  46. Shi L, Takahashi K, Dundee J, et al.: Mannose-binding lectindeficient mice are susceptible to infection with Staphylococcus aureus. J Exp Med 2004, 199:1379–1390. This is a mouse MBL knock out model showing that MBL-deficient mice are more susceptible to sepsis when challenged with S. aureus into the bloodstream than are wild-type littermates.

    Article  PubMed  CAS  Google Scholar 

  47. Takahashi K, Gordon J, Liu H, et al.: Lack of mannose-binding lectin-A enhances survival in a mouse model of acute septic peritonitis. Microbes Infect 2002, 4:773–784.

    Article  PubMed  CAS  Google Scholar 

  48. Uemura K, Saka M, Nakagawa T, et al.: L-MBP is expressed in epithelial cells of mouse small intestine. J Immunol 2002, 169:6945–6950.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Immunology, Tissue Typing Laboratory-7631, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen O, Denmark

    Peter Garred MD, DMSci

Authors
  1. Peter Garred MD, DMSci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans O. Madsen PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garred, P., Madsen, H.O. Genetic susceptibility to sepsis: A possible role for mannose-binding lectin. Curr Infect Dis Rep 6, 367–373 (2004). https://doi.org/10.1007/s11908-004-0035-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-004-0035-0

Keywords

Search

Navigation