Mycobacterium aviumsubsp.paratuberculosisFibronectin Attachment Protein Facilitates M-Cell Targeting and Invasion through a Fibronectin Bridge with Host Integrins

Abstract

Paratuberculosis is a chronic granulomatous enteritis of domestic and wild ruminants that is caused by Mycobacterium avium subsp. paratuberculosis, a slow-growing intracellular acid-fast bacillus. Animals are usually infected within the first few months of life; however, the chronic wasting and profuse diarrhea that characterize clinical paratuberculosis are usually not observed until 3 or more years after infection (4, 7).M. avium subsp. paratuberculosis enters intestinal tissue through M cells present in the dome epithelium covering the continuous Peyer's patches in the distal ileum of calves and goats (22,32). The discrete Peyer's patches in the intestinal tracts of other mammals and the jejunum of ruminants are secondary lymphoid organs, in which an adaptive immune response can be initiated following exposure to foreign antigens. In contrast, the continuous Peyer's patch in the ruminant ileum is a primary lymphoid organ, wherein B-cell development occurs (36).Fibronectin attachment proteins (FAPs) are a family of fibronectin (FN)-binding proteins present in several species of mycobacteria (25,(28)(29)(30)42). Attachment and internalization of Mycobacterium bovis BCG, M. leprae, and M. avium subsp. paratuberculosis by epithelial cells in vitro have been shown to be dependent on the interaction between FAP and FN (18,29,31). ␤1 integrins have been identified as the host cell receptor for FN-opsonized mycobacteria in vitro (3, 18). M cells are unique among cells of the intestinal epithelium in that they display ␤1 integrins on their luminal faces at high density (6). Thus, the interaction between cell surface integrins and FN bound by organisms may explain why M cells are the portals of entry for M. avium subsp. paratuberculosis. However, adherence and internalization assays with macrophages, monocytes, and epithelial cell lines give only a general picture of the adhesive and invasive potential of mycobacteria. The nature and density of potential host cell receptors vary for each culture system to such an extent that the significance of hostpathogen interactions observed in vitro must be interpreted with caution. Moreover, the distribution of receptors on cells in culture is often markedly different from that on cells in intact tissue, particularly for intestinal epithelial cells (8,15,37). Thus, it is imperative that putative adhesins and invasins be evaluated in in vivo model systems before any degree of significance can accurately be attributed to their expression.The expression of FAP was found to be important for attachment of M. avium subsp. avium to respiratory explants and attachment of M. bovis BCG to murine bladder mucosa in vivo (20,41). However, demonstration of FAP-mediated mycobacterial attachment required exposure of the extracellular matrix. This mechanism is insufficient to explain M-cell targeting by M. avium subsp. paratuberculosis. Thus, the contribution of the FAP of M. avium subsp. paratuberculosis (FAP-P) to the invasive potential of M. avium subsp. paratuberculosis for intestinal

Peyer's Patch-Deficient Mice Demonstrate ThatMycobacterium aviumsubsp.paratuberculosisTranslocates across the Mucosal Barrier via both M Cells and Enterocytes but Has Inefficient Dissemination

“…Whether the mechanisms of interaction are the same is currently unknown. Bacterial genes required for the invasion of bovine epithelial cells have been identified (1), but all the evidence so far supports the hypothesis that uptake by M cells follows binding to the ␤ 1 integrin receptor (15,23,24). Our study confirmed that in vitro, invasion of MDBK cells by M. avium subsp.…”

A Processed Multidomain Mycoplasma hyopneumoniae Adhesin Binds Fibronectin, Plasminogen, and Swine Respiratory Cilia

“…In this study we report M. hyopneumoniae as a bacterial pathogen capable of binding fibronectin. The ability of bacteria to bind fibronectin can provide a mechanism for host cell adhesion or cytoskeletal rearrangements, which may facilitate bacterial internalization (41)(42)(43)(44)(45). SPR analysis demonstrated that F4 P116 -bound fibronectin in a dose-dependent manner with a physiologically relevant K D value.…”

Infection with Mycobacterium avium subsp. paratuberculosis Results in Rapid Interleukin-1β Release and Macrophage Transepithelial Migration

“…Like other intracellular pathogens, such as Yersinia spp., Salmonella enterica serovar Typhimurium, and Shigella spp., M. avium subsp. paratuberculosis infects M cells due to their lack of hydrolytic enzymes and inability to form mature phagosomes (6,27,28,41,42,44). However, further investigations have revealed that M. avium subsp.…”