Microbial mannan inhibits bacterial killing by macrophages: a possible pathogenic mechanism for Crohn's disease.
OBJECTIVE
Crohn's disease (CD) is mimicked by inherited phagocyte disorders and is associated with circulating antibodies against yeast mannan (anti-Saccharomyces cerevisiae antibody; ASCA). We speculated that mannans might impair phagocyte function.


METHODS
S cerevisiae mannan was assessed for its effects on human peripheral blood neutrophils, adherent monocytes, and monocyte-derived macrophages (MDM).


RESULTS
Mannan caused dose-related increased survival of CD Escherichia coli HM605 within adherent monocytes from 24% +/- 10.5% (control) to 114% +/- 22.7% with mannan 1 mg/mL at 2 hours (mean +/- SEM, n = 9; P = .0002). Electron microscopy showed E coli HM605 surviving and probably replicating within macrophage vesicles. Mannan (1 mg/mL) inhibited the respiratory burst in neutrophils and monocytes (both P = .002) and bacterial killing within MDM (P < .001). E coli survival was increased within macrophages from TLR4(-/-) (126% +/- 3.5% survival at 2 hours) and MyD88(-/-) (134.8% +/- 6.5%) mice compared with wild-type mice (both P < .0001). Mannan had no additional effect, showing that TLR4 and MyD88 are involved in bacterial killing by macrophages and its inhibition by mannan. Putative CD-associated micro-organisms were screened for the ASCA mannan epitope by Galanthus nivalis lectin (GNA) blotting. ASCA epitope was expressed by Candida albicans and Mycobacterium paratuberculosis but not by Mycobacterium tuberculosis or E coli. Supernatants from M paratuberculosis culture inhibited killing of E coli HM605 by adherent human monocytes and murine macrophages. The inhibitory activity was removed by GNA-affinity chromatography.


CONCLUSIONS
Suppression of mucosal phagocyte function by microbial mannans, possibly of Mycobacterial origin, may contribute to CD pathogenesis.
Mpofu
Chiedzo M
CM
Division of Gastroenterology, School of Clinical Science, University of Liverpool, Liverpool, United Kingdom.
Campbell
Barry J
BJ
Subramanian
Sreedhar
S
Marshall-Clarke
Stuart
S
Hart
C Anthony
CA
Cross
Andy
A
Roberts
Carol L
CL
McGoldrick
Adrian
A
Edwards
Steven W
SW
Rhodes
Jonathan M
JM
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002176:Candida albicans / Q000166:cytology / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003424:Crohn Disease / Q000382:microbiology* / Q000503:physiopathology; D004926:Escherichia coli / Q000166:cytology / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008351:Mannans / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D016927:Mycobacterium avium subsp. paratuberculosis / Q000166:cytology / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects* / Q000502:physiology; D016897:Respiratory Burst / Q000187:drug effects / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000276:immunology / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000166:cytology / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
D000276:Adjuvants, Immunologic; D008351:Mannans; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000119:Acetylmuramyl-Alanyl-Isoglutamine