Although mast cells have been implicated in a variety of inflammatory conditions including immediate hypersensitivity and interstitial cystitis, their physiological role in the body is unknown. We investigated the role of mast cells in host defence against bacterial infections using a well characterized mast-cell-deficiency mouse model. We report here that mast cells, which are selectively located at portals of bacterial entry, are important to host defence. Mast-cell-deficient WBB6F1-W/Wv mice (W/Wv) were up to 20-fold less efficient in clearing enterobacteria than control WBB6F1 +/+ (+/+) mice or mast-cell-reconstituted W/Wv (W/Wv+MC) mice. With higher bacteria inocula, only W/Wv mice died (80%). The limited bacterial clearance in W/Wv mice directly correlated with impaired neutrophil influx. The mast-cell chemoattractant TNF-alpha was implicated in the neutrophil response because TNF-alpha was locally released only in +/+ and W/Wv+MC mice, TNF-alpha-specific antibodies blocked over 70% of the neutrophil influx, and purified mast cells released TNF-alpha upon incubation with bacteria. Additionally, the type-1 fimbrial subunit, FimH, was the necessary enterobacterial component for mast-cell activation and neutrophil influx because an isogenic FimH- mutant evoked a limited neutrophil response in +/+ mice compared to wild-type bacteria.

Mast cells are well known for their harmful role in IgE-mediated hypersensitivity reactions, but their physiological role remains a mystery. Several recent studies have reported that mast cells play a critical role in innate immunity in mice by releasing tumor necrosis factor ␣ (TNF-␣) to recruit neutrophils to sites of enterobacterial infection. In some cases, the mast cell TNF-␣ response was triggered when these cells directly bound FimH on the surface of Escherichia coli. We have identified CD48, a glycosylphosphatidylinositol-anchored molecule, to be the complementary FimH-binding moiety in rodent mast cell membrane fractions. We showed that (i) pretreatment of mast cell membranes with antibodies to CD48 or phospholipase C inhibited binding of FimH ؉ E. coli, (ii) FimH ؉ E. coli but not a FimH ؊ derivative bound isolated CD48 in a mannose-inhibitable manner, (iii) binding of FimH ؉ bacteria to Chinese hamster ovary (CHO) cells was markedly increased when these cells were transfected with CD48 cDNA, and (iv) antibodies to CD48 specifically blocked the mast cell TNF-␣ response to FimH ؉ E. coli. Thus, CD48 is a functionally relevant microbial receptor on mast cells that plays a role in triggering inf lammation.

Strains of Escherichia coli persist within the human gut as normal commensals, but are frequent pathogens and can cause recurrent infection. Here we show that, in contrast to E. coli subjected to opsonic interactions stimulated by the host's immune response, E. coli that bind to the macrophage surface exclusively through the bacterial lectin FimH can survive inside the cell following phagocytosis. This viability is largely due to the attenuation of intracellular free-radical release and of phagosome acidification during FimH-mediated internalization, both of which are triggered by antibody-mediated internalization. This different processing of non-opsonized bacteria is supported by morphological evidence of tight-fitting phagosomes compared with looser, antibody-mediated phagosomes. We propose that non-opsonized FimH-expressing E. coli co-opt internalization of lipid-rich microdomains following binding to the FimH receptor, the glycosylphosphatidylinositol-linked protein CD48, because (1) the sterol-binding agents filipin, nystatin and methyl beta-cyclodextrin specifically block FimH-mediated internalization; (2) CD48 and the protein caveolin both accumulate on macrophage membranes surrounding bacteria; and (3) antibodies against CD48 inhibit FimH-mediated internalization. Our findings bring the traditionally extracellular E. coli into the realm of opportunistic intracellular parasitism and suggest how opportunistic infections with FimH-expressing enterobacteria could occur in a setting deprived of opsonizing antibodies.

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Mast cells are key elements of the immune system. These cells release a wide variety of pro-inflammatory mediators which are responsible for the pathophysiology of many allergic diseases. Recent studies, however, have shown that mast cells have the capacity to modulate the host's innate immune response to gram negative bacteria by their ability to phagocytose bacteria, process and present bacterial antigens to T cells and recruit phagocytic help through the release of physiological amounts of pro-inflammatory mediators. Here, current knowledge of mast cell responses to gram negative bacteria and molecular mechanisms associated with mast cell bacteria interaction is reviewed.

The strategic location of mast cells at the host-environment interface and their ability to release potent mediators of inflammation have suggested that these cells may play a pivotal role in host defense against bacterial infection. The ability of the opportunistic pathogen, Escherichia coli, to induce degranulation of mast cells obtained from the mouse peritoneum was investigated. We determined that unlike a mutant derivative deficient in the FimH subunit of the fimbriae or nonfimbriated E. coli, type 1 fimbriated E. coli induced mast cell degranulation in vitro. The magnitude of mast cell degranulation was directly proportional to the number of adherent bacteria on the cell surface in the initial period of the interaction. Using a mouse model of bacterial peritonitis, we demonstrated mast cell degranulation and histamine release by type 1 fimbriated bacteria in vivo. Furthermore, beads coated with FimH but not with FimA, the major subunit of type 1 fimbriae, evoked mast cell release of histamine in vivo in amounts comparable to that elicited by type 1 fimbriated E. coli. These studies reveal that mast cells can be degranulated by interaction with type 1 fimbriated E. coli and that FimH, the mannose-binding component of the fimbriae, is a potent mast cell stimulant. (J. Clin. Invest. 1994.

Mast cells remain one of the most enigmatic cells in the body. These cells secrete significant amounts of numerous proinflammatory mediators which contribute to a number of chronic inflammatory conditions, including stress-induced intestinal ulceration, rheumatoid arthritis, interstitial cystitis, scleroderma, and Crohn's disease (6, 14, 24, 76). Mast cells are also prominent in the development of anaphylaxis (14, 24, 76). Yet despite the negative effects of their secretions, mast cells or mast cell-like cells have been described even among the lowest order of animals (31). The phylogenic persistence of these cells through evolution strongly suggests that they are beneficial in some fashion to the host. Mast cells are selectively found in relatively large numbers adjacent to blood or lymphatic vessels but are most prominent immediately beneath the epithelial surfaces of the skin and the mucosae of the genitourinary, gastrointestinal, and respiratory tracts. Estimated concentrations of mast cells range from 500 to 4,000 per mm 3 in the lungs, 7,000 to 12,000 per mm 3 in skin, and 20,000 per mm 3 in the gastrointestinal tract (76). Because many of these sites also happen to be portals of infection, mast cells may represent one of the first inflammatory cells encountered by an invading pathogen. There is considerable evidence that mast cells recognize and react to a wide range of microorganisms or their products (Table 1). Such interactions lend further credence to the notion that mast cells have the potential to markedly influence the course of microbial infections. In this paper, we review data that support the possibility that the raison d'être for the mast cell is initiating and coordinating the host's inflammatory and immune responses against microbial pathogens. SPECIFIC MAST CELL RECOGNITION OF MICROBIAL PATHOGENS

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