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REVIEW PAPER: Modulation of Mononuclear Phagocyte Function by Mycobacterium avium subsp. paratuberculosis

Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN

Abstract

Pathogenic mycobacteria are highly adapted for survival within host mononuclear phagocytes. This is largely due to the organism's capacity to prevent macrophage activation, block phagosome acidification and maturation, and attenuate presentation of antigens to the immune system. Mycobacterium avium subsp. paratuberculosis (MAP) is one such organism that modulates the ruminant innate immune response. It is the causative agent in paratuberculosis, a chronic progressive granulomatous enteritis in ruminants. MAP initially interacts with cell membrane receptors on bovine mononuclear phagocytes and initiates cell signaling responses and phagocytosis. Mannosylated liparabinomannan (Man-LAM) is a major component of the MAP cell wall that interacts with the cell membrane of mononuclear phagocytes and may be a major virulence factor. Toll-like receptor 2 (TLR2) has been incriminated as major signaling receptor that binds to MAP and initiates signaling though the mitogen-activated protein kinase (MAPK)–p38 pathway. This pathway induces transcription of interleukin (IL)-10. Early production of IL-10 suppresses proinflammatory cytokines, chemokines, IL-12, and major histocompatability factor class-II expression. Both IL-10 dependent and IL-10 independent mechanisms appear to be involved in attenuation of phagosome acidification and phagolysosome fusion. Many of the suppressive effects of MAP on bovine mononuclear phagocytes can be reproduced by exposure of bovine monocytes to Man-LAM. Therefore, MAP Man-LAM-induced TLR2-MAPK-p38 signaling with resultant excessive IL-10 expression has emerged as one of the mechanisms by which MAP organisms suppress inflammatory, immune, and antimicrobial responses and promote their survival within host mononuclear phagocytes.

Key words: Bovine; cytokines; interleukin-10; macrophage; Mycobacterium avium subsp. paratuberculosis; paratuberculosis; phagosome acidification; phagosome-lysosome fusion; Toll-like receptors.

Request reprints from Douglas J Weiss, Department of Veterinary and Biomedical Sciences, University of Minnesota, 1971 Commonwealth Avenue, St. Paul, MN 55108 (USA). E-mail: weiss005{at}umn.edu.