Diabetes mellitus und Immunantwort bei pyogenen Infektionen

Leitthema
  • 16 Downloads

Zusammenfassung

Hintergrund

Diabetes mellitus prädisponiert für eine Vielzahl von Infektionserkrankungen. Das Risiko für pyogene Infektionen ist etwa 2‑ bis 4‑fach erhöht, wobei Staphylococcus aureus einer der wichtigsten Erreger ist. Neben Komorbiditäten führen v. a. Dysfunktionen des Immunsystems zu einer erhöhten Infektanfälligkeit.

Ergebnisse

Trotz teils widersprüchlicher Ergebnisse ist insgesamt eine Reihe von Immundysfunktionen beschrieben. Beeinträchtigungen der Funktion der Granulozyten umfassen reduzierte Chemotaxis, Phagozytose und Bakterizidie mit verringertem oxidativem Burst. Eine erniedrigte pathogeninduzierte Apoptose bei Granulozyten geht mit einer längeren Entzündungsreaktion und Zytokinproduktion einher. Auf Seiten der humoralen Immunantwort sind erniedrigte IgG-Spiegel (Ig: Immunglobulin) sowie eine Inhibition der Komplementaktivierung und Opsonisation beschrieben. Eine gestörte Prostaglandin-E2-Produktion ist mit einer verminderten Reifung dendritischer Zellen und einer erniedrigten TH17-Antwort (TH17: Typ-17-T-Helferzelle) assoziiert. Zusätzlich gibt es Hinweise, dass auf Seiten der Pathogene erhöhte Glukosekonzentrationen zu Adaptationen mit veränderter Genexpression und teils erhöhter Virulenz führen.

Schlussfolgerung

Zusammenfassend ist von einer multifaktoriellen Genese des erhöhten Infektionsrisikos bei Diabetespatienten auszugehen. Neben prädisponierenden Begleiterkrankungen sind v. a. eine Beeinträchtigung der angeborenen Immunantwort in Kombination mit der Virulenz typischer Erreger Ursache der erhöhten Inzidenz pyogener Infektionen.

Schlüsselwörter

Zuckerstoffwechselstörungen Staphylococcus aureus Granulozyten Angeborenes Immunsystem Anfälligkeit für Erkrankungen 

Diabetes mellitus and the immune response to pyogenic infections

Abstract

Background

Diabetes mellitus predisposes to variety of infectious diseases. The risk for pyogenic infections is increased 2‑ to 4‑fold, with Staphylococcus aureus being among the most important pathogens. Apart from comorbidities, dysfunction of the immune system leads to an increased susceptibility to infections.

Results

Despite conflicting results, several disturbances of the immune system have been described. Impairments of granulocyte function comprise reduced chemotaxis, phagocytosis, and bacterial killing with reduced oxidative burst. Decreased pathogen-induced granulocyte apoptosis leads to prolonged inflammation and production of inflammatory cytokines. Lower IgG (Ig: immunoglobulin) levels and inhibition of complement activation and opsonization are found on the side of the humoral immune response. Disturbed prostaglandin E2 production leads to a reduced maturation of dendritic cells and a lower Th17 response (Th17: T helper 17 cell). Additionally, evidence suggests that pathogens adapt to increased glucose concentrations with altered gene expression and increased virulence.

Conclusions

A multifactorial genesis of the increased susceptibility to infections observed in patients with diabetes mellitus is assumed. Besides predisposing comorbidities mainly disturbances of the innate immune system in combination with the virulence of typical pathogens form the basis of the increased incidence of pyogenic infections.

Keywords

Glucose metabolism disorders Staphylococcus aureus Granulocytes Immunity, innate  Disease susceptibility 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

F. Hanses gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine vom Autor durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Ackerman AL, Parameshwar PS, Anger JT (2018) Diagnosis and treatment of patients with prostatic abscess in the post-antibiotic era. Int J Urol 25(2):103–110.  https://doi.org/10.1111/iju.13451 CrossRefPubMedGoogle Scholar
  2. 2.
    Alba-Loureiro TC, Hirabara SM, Mendonca JR, Curi R, Pithon-Curi TC (2006) Diabetes causes marked changes in function and metabolism of rat neutrophils. J Endocrinol 188(2):295–303.  https://doi.org/10.1677/joe.1.06438 CrossRefPubMedGoogle Scholar
  3. 3.
    Alexiewicz JM, Kumar D, Smogorzewski M, Klin M, Massry SG (1995) Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: abnormalities in metabolism and function. Ann Intern Med 123(12):919–924CrossRefPubMedGoogle Scholar
  4. 4.
    Bischoff M, Wonnenberg B, Nippe N, Nyffenegger-Jann NJ, Voss M, Beisswenger C, Sunderkötter C, Molle V, Dinh QT, Lammert F, Bals R, Herrmann M, Somerville GA, Tschernig T, Gaupp R (2017) CcpA affects Infectivity of staphylococcus aureus in a hyperglycemic environment. Front Cell Infect Microbiol.  https://doi.org/10.3389/fcimb.2017.00172 PubMedPubMedCentralGoogle Scholar
  5. 5.
    Dejani NN, Brandt SL, Piñeros A, Glosson-Byers NL, Wang S, Son YM, Medeiros AI, Serezani CH (2016) Topical prostaglandin E analog restores defective dendritic cell—mediated th17 host defense against methicillin-resistant staphylococcus aureus in the skin of diabetic mice. Diabetes 65(12):3718–3729.  https://doi.org/10.2337/db16-0565 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B (1997) Impaired leucocyte functions in diabetic patients. Diabet Med 14(1):29–34. https://doi.org/10.1002/(SICI)1096-9136(199701)14:1〈29::AID-DIA300〉3.0.CO;2-VCrossRefPubMedGoogle Scholar
  7. 7.
    Farnsworth CW, Schott EM, Jensen SE, Zukoski J, Benvie AM, Refaai MA, Kates SL, Schwarz EM, Zuscik MJ, Gill SR, Mooney RA (2017) Adaptive upregulation of clumping factor A (ClfA) by staphylococcus aureus in the obese, type 2 diabetic host mediates increased virulence. Infect Immun.  https://doi.org/10.1128/IAI.01005-16 PubMedPubMedCentralGoogle Scholar
  8. 8.
    Farnsworth CW, Shehatou CT, Maynard R, Nishitani K, Kates SL, Zuscik MJ, Schwarz EM, Daiss JL, Mooney RA (2015) A humoral immune defect distinguishes the response to Staphylococcus aureus infections in mice with obesity and type 2 diabetes from that in mice with type 1 diabetes. Infect Immun 83(6):2264–2274.  https://doi.org/10.1128/IAI.03074-14 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Foo N‑P, Chen K‑T, Lin H‑J, Guo H‑R (2010) Characteristics of pyogenic liver abscess patients with and without diabetes mellitus. Am J Gastroenterol 105(2):328–335.  https://doi.org/10.1038/ajg.2009.586 CrossRefPubMedGoogle Scholar
  10. 10.
    Jr Fowler VG, Proctor RA (2014) Where does a staphylococcus aureus vaccine stand? Clin Microbiol Infect 20(Suppl 5):66–75.  https://doi.org/10.1111/1469-0691.12570 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Garau J, Ostermann H, Medina J, Avila M, McBride K, Blasi F (2013) Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010–2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. Clin Microbiol Infect 19(9):E377–E385.  https://doi.org/10.1111/1469-0691.12235 CrossRefPubMedGoogle Scholar
  12. 12.
    Gottschalk F, Wilke T, Mueller S, Heinrich K, Maywald U, Fuchs A, Yu H (2017) Staphylococcus aureus infections in German patients with type 2 diabetes mellitus after orthopedic surgery: incidence, risk factors, and clinical and health-economic outcomes. Surg Infect 18(8):915–923.  https://doi.org/10.1089/sur.2017.063 CrossRefGoogle Scholar
  13. 13.
    Hansen M‑LU, Gotland N, Mejer N, Petersen A, Larsen AR, Benfield T (2017) Diabetes increases the risk of disease and death due to Staphylococcus aureus bacteremia. A matched case-control and cohort study. Infect Dis 49(9):689–697.  https://doi.org/10.1080/23744235.2017.1331463 CrossRefGoogle Scholar
  14. 14.
    Hanses F, Park S, Rich J, Lee JC (2011) Reduced neutrophil apoptosis in diabetic mice during staphylococcal infection leads to prolonged Tnfalpha production and reduced neutrophil clearance. PLoS ONE 6(8):e23633.  https://doi.org/10.1371/journal.pone.0023633 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hanses F, Roux C, Dunman PM, Salzberger B, Lee JC (2014) Staphylococcus aureus gene expression in a rat model of infective endocarditis. Genome Med 6(10):93.  https://doi.org/10.1186/s13073-014-0093-3 PubMedPubMedCentralGoogle Scholar
  16. 16.
    Jaaskelainen IH, Hagberg L, Forsblom E, Jarvinen A (2017) Microbiological etiology and treatment of complicated skin and skin structure infections in diabetic and nondiabetic patients in a population-based study. Open Forum Infect Dis 4(2):ofx44.  https://doi.org/10.1093/ofid/ofx044 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Khatib R, Johnson LB, Fakih MG, Riederer K, Khosrovaneh A, Shamse Tabriz M, Sharma M, Saeed S (2006) Persistence in staphylococcus aureus bacteremia: incidence, characteristics of patients and outcome. Scand J Infect Dis 38(1):7–14.  https://doi.org/10.1080/00365540500372846 CrossRefPubMedGoogle Scholar
  18. 18.
    Korbel L, Spencer JD (2015) Diabetes mellitus and infection: an evaluation of hospital utilization and management costs in the United States. J Diabetes Complicat 29(2):192–195.  https://doi.org/10.1016/j.jdiacomp.2014.11.005 CrossRefPubMedGoogle Scholar
  19. 19.
    Liberatore RR Jr, Barbosa SFC, Alkimin MD, Bellinati-Pires R, Florido MP, Isaac L, Kirschfink M, Grumach AS (2005) Is immunity in diabetic patients influencing the susceptibility to infections? Immunoglobulins, complement and phagocytic function in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes 6(4):206–212.  https://doi.org/10.1111/j.1399-543X.2005.00136.x CrossRefPubMedGoogle Scholar
  20. 20.
    Lipsky BA, Itani KMF, Weigelt JA, Joseph W, Paap CM, Reisman A, Myers DE, Huang DB (2011) The role of diabetes mellitus in the treatment of skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus: results from three randomized controlled trials. Int J Infect Dis 15(2):e140–e146.  https://doi.org/10.1016/j.ijid.2010.10.003 CrossRefPubMedGoogle Scholar
  21. 21.
    Llorente L, La de Fuente H, Richaud-Patin Y, La Alvarado-De Barrera C, Diaz-Borjon A, Lopez-Ponce A, Lerman-Garber I, Jakez-Ocampo J (2000) Innate immune response mechanisms in non-insulin dependent diabetes mellitus patients assessed by flow cytoenzymology. Immunol Lett 74(3):239–244CrossRefPubMedGoogle Scholar
  22. 22.
    Loibl M, Stoyanov L, Doenitz C, Brawanski A, Wiggermann P, Krutsch W, Nerlich M, Oszwald M, Neumann C, Salzberger B, Hanses F (2014) Outcome-related co-factors in 105 cases of vertebral osteomyelitis in a tertiary care hospital. Infection 42(3):503–510.  https://doi.org/10.1007/s15010-013-0582-0 CrossRefPubMedGoogle Scholar
  23. 23.
    Marhoffer W, Stein M, Schleinkofer L, Federlin K (1993) Evidence of ex vivo and in vitro impaired neutrophil oxidative burst and phagocytic capacity in type 1 diabetes mellitus. Diabetes Res Clin Pract 19(3):183–188CrossRefPubMedGoogle Scholar
  24. 24.
    Martin ET, Kaye KS, Knott C, Nguyen H, Santarossa M, Evans R, Bertran E, Jaber L (2016) Diabetes and risk of surgical site infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 37(1):88–99.  https://doi.org/10.1017/ice.2015.249 CrossRefPubMedGoogle Scholar
  25. 25.
    Mauriello CT, Hair PS, Rohn RD, Rister NS, Krishna NK, Cunnion KM (2014) Hyperglycemia inhibits complement-mediated immunological control of S. aureus in a rat model of peritonitis. J Diabetes Res 2014:762051.  https://doi.org/10.1155/2014/762051 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mylona E, Samarkos M, Kakalou E, Fanourgiakis P, Skoutelis A (2009) Pyogenic vertebral osteomyelitis: a systematic review of clinical characteristics. Semin Arthritis Rheum 39(1):10–17.  https://doi.org/10.1016/j.semarthrit.2008.03.002 CrossRefPubMedGoogle Scholar
  27. 27.
    Park S, Rich J, Hanses F, Lee JC (2009) Defects in innate immunity predispose C57BL/6J-Leprdb/Leprdb mice to infection by staphylococcus aureus. Infect Immun 77(3):1008–1014.  https://doi.org/10.1128/IAI.00976-08 CrossRefPubMedGoogle Scholar
  28. 28.
    Patel AR, Alton TB, Bransford RJ, Lee MJ, Bellabarba CB, Chapman JR (2014) Spinal epidural abscesses: risk factors, medical versus surgical management, a retrospective review of 128 cases. Spine J 14(2):326–330.  https://doi.org/10.1016/j.spinee.2013.10.046 CrossRefPubMedGoogle Scholar
  29. 29.
    Perumal Samy R, Stiles BG, Sethi G, Lim LHK (2017) Melioidosis: Clinical impact and public health threat in the tropics. PLoS Negl Trop Dis.  https://doi.org/10.1371/journal.pntd.0004738 PubMedPubMedCentralGoogle Scholar
  30. 30.
    Scully IL, McNeil LK, Pathirana S, Singer CL, Liu Y, Mullen S, Girgenti D, Gurtman A, Pride MW, Jansen KU, Huang PL, Anderson AS (2017) Neutrophil killing of Staphylococcus aureus in diabetes, obesity and metabolic syndrome: a prospective cellular surveillance study. Diabetol Metab Syndr 9:76.  https://doi.org/10.1186/s13098-017-0276-3 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Seidl K, Goerke C, Wolz C, Mack D, Berger-Bachi B, Bischoff M (2008) Staphylococcus aureus CcpA affects biofilm formation. Infect Immun 76(5):2044–2050.  https://doi.org/10.1128/IAI.00035-08 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Shah BR, Hux JE (2003) Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 26(2):510–513CrossRefPubMedGoogle Scholar
  33. 33.
    Thomsen RW, Jepsen P, Sorensen HT (2007) Diabetes mellitus and pyogenic liver abscess: risk and prognosis. Clin Infect Dis 44(9):1194–1201.  https://doi.org/10.1086/513201 CrossRefPubMedGoogle Scholar
  34. 34.
    de Toni S, Piva E, Lapolla A, Fontana G, Fedele D, Plebani M (1997) Respiratory burst of neutrophils in diabetic patients with periodontal disease. Ann N Y Acad Sci 832:363–367CrossRefPubMedGoogle Scholar
  35. 35.
    Walrand S, Guillet C, Boirie Y, Vasson M‑P (2004) In vivo evidences that insulin regulates human polymorphonuclear neutrophil functions. J Leukoc Biol 76(6):1104–1110.  https://doi.org/10.1189/jlb.0104050 CrossRefPubMedGoogle Scholar
  36. 36.
    Wertheim HFL, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, Nouwen JL (2005) The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis 5(12):751–762.  https://doi.org/10.1016/S1473-3099(05)70295-4 CrossRefPubMedGoogle Scholar
  37. 37.
    Wetzler C, Kampfer H, Stallmeyer B, Pfeilschifter J, Frank S (2000) Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol 115(2):245–253.  https://doi.org/10.1046/j.1523-1747.2000.00029.x CrossRefPubMedGoogle Scholar
  38. 38.
    Yano H, Kinoshita M, Fujino K, Nakashima M, Yamamoto Y, Miyazaki H, Hamada K, Ono S, Iwaya K, Saitoh D, Seki S, Tanaka Y (2012) Insulin treatment directly restores neutrophil phagocytosis and bactericidal activity in diabetic mice and thereby improves surgical site Staphylococcus aureus infection. Infect Immun 80(12):4409–4416.  https://doi.org/10.1128/IAI.00787-12 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Interdiziplinäre Notaufnahme und Stabsstelle InfektiologieUniversitätsklinikum RegensburgRegensburgDeutschland

Personalised recommendations