Just as the human host has evolved multiple mechanisms to prevent infection by pathogenic microorganisms, the microorganisms themselves have evolved diverse and effective mechanisms that thwart their host's defense mechanisms to enable successful infection. As previously mentioned, for example, many bacteria have evolved stress response systems that enable them to survive highly acidic conditions such as those encountered during passage through the human stomach. After reaching the intestine, an essential step in any successful foodborne infection is pathogen adhesion. Adherence prevents the pathogen from being flushed away and allows it to begin the infectious process that will enable its reproduction and propagation. Foodborne bacteria have evolved multiple mechanisms of adherence. One adherence mechanism that bacteria use is to attach using long filamentous structures known as pili or fimbrae. Pili often bind to glycolipid and glycoprotein receptors on host epithelial cells (Salyers and Whitt, 1994; Taylor, 1991).
Some foodborne pathogenic bacteria have specific cell surface proteins that bind to specific host cell receptors. The bacterial surface protein internalin (InlA) of L. monocytogenes, for example, uses the intestinal epithelial cell surface protein E-cadherin as its receptor (Mengaud et al., 1996). Pace et al. (1993) reported the activation of epidermal growth factor (EGF) receptor upon Salmonella enterica Typhimurium invasion of cultured epithelial cells, suggesting that Salmonella may use the EGF receptor for adherence. Others, however, have found that Salmonella Typhimurium can invade cultured cells that lack the EGF receptor and can invade the gastrointestinal tracts of mice expressing an EGF receptor with reduced activity, thus suggesting that the EGF receptor has a limited role, if any, as a Salmonella receptor (Jones et al., 1993; McNeil et al., 1995). Much remains unknown about the specific ligand-receptor interactions between bacteria and their host cells, and about other mechanisms of and structures involved in adhesion.
Another bacterial adherence mechanism that has only relatively recently been recognized as playing an important role in the pathogenesis of some foodborne infections is adhesion through the formation of biofilms. A biofilm is a layer of bacterial cells attached to a solid surface and surrounded by a thick polysaccharide matrix (Donlan and Costerton, 2002). The cells in the most basal layer of the biofilm are attached to the host structure, while cells in the outer layers of the biofilm attach themselves to the polysaccharide matrix or to the bacterial cells beneath them. Adherence via a biofilm is a very effective mechanism used by bacteria to avoid several of the host defenses aimed at preventing enteric infection. For example, the majority of bacteria in a biofilm are protected under several layers of extracellular polysaccharide matrix and, therefore, are not easily flushed away or easily accessed by secretory antibodies, bacteriocidal enzymes, phagocytic immune system cells or antibiotics (Donlan and Costerton, 2002). Adherence via biofilms can contribute to persistence of an infection. Prouty et al. (2002) for example, demonstrated that Salmonella enterica can form biofilms on gall stones and thus cause chronic infection and be continually shed. Finally, the changes in gene expression that occur as a result of living in a biofilm often enhance stress resistance and may facilitate virulence. For example, biofilm-producing strains of Enterococcus faecalis were able to survive inside peritoneal macrophages 24 h longer than strains that were unable to produce biofilms (Baldassarri et al., 2001), while Salmonella Typhimurium grown as a biofilm were recovered from the spleens of intraperitoneal infected mice up to 5 days post-infection in greater numbers than cells grown planktonically (Turnock et al., 2002).
Because adhesion is a requisite step for any foodborne infection, it stands to reason that preventing bacterial adhesion is a principal way to prevent foodborne infections. A key contributing factor to the prevention of adhesion by foodborne pathogens is the resident competitive microflora in our large intestine. These resident microorganisms are very diverse and most cannot be cultured ex vivo (Hooper and Gordon, 2001). Using traditional culture techniques if possible and, more recently, molecular approaches such as 16S ribosomal RNA gene sequencing, members of the Bacteroides, eubacteria, bifidobacteria, anaerobic Gram-positive cocci, clostridia, lactobacilli, Escherichia, methanogens, fusobacteria, entero-bacteria, Veillonella, staphylococci, Proteus and Pseudomonas, among others, have been identified in the intestine (Bourlioux et al., 2003). The intestinal microflora prevents adhesion by pathogenic organisms by competing with them for limited space and nutrients, as well as by producing antimicrobial molecules (Bourlioux et al., 2003). The importance of the resident intestinal microflora can be seen clearly in the symptoms manifested when the balance of microflora is acutely disturbed; for example, diarrhea is a common side effect of antibiotic therapy. Similarly, infants less than 1 year old are susceptible to gastrointestinal botulism if they are fed foods such as honey that contain Clostridium botulinum spores (Tanzi and Gabay, 2002). While healthy adults are not affected by ingesting Cl. botulinum spores, infants are susceptible because the competitive microflora in their gut is not well enough developed to successfully out-compete the botulinum spores.
The next requisite step for many, but not all, foodborne bacterial pathogens is invasion of the target host tissue. Some foodborne pathogens such as V. cholerae, C. jejuni, and some strains of E. coli adhere to host intestinal tissue and cause disease extracellularly via toxin production. In the case of cholerae infection, for example, the cholera toxin induces water release into the intestinal lumen, causing watery diarrhea and facilitating dissemination of the bacteria (Sack et al., 2004). Similarly, in E. coli O157:H7 infections, production of shiga-like toxins causes tissue fluid loss and severe damage to blood vessels (LeBlanc, 2003). Other foodborne bacterial pathogens, however, have evolved to invade the intestinal tissues in order to access the protected intracellular environment and escape destruction by the host's humoral immune system, to access nutrient-rich areas of the host's body, and to facilitate their spread within the mammalian host. Examples of foodborne bacteria capable of invading human host cells include Salmonella enterica, Sh. flexneri and L. monocytogenes.
Facultatively intracellular foodborne pathogens have evolved numerous mechanisms to exploit eukaryotic host cell function in ways that will promote their own uptake into host cells or their cell-to-cell spread. Some pathogens, for example, such as Salmonella enterica, Shigella species and Yersinia entercolitica, are able to exploit the natural phagocytic ability of M cells in order to reach the underlying cells, blood and lymph (Neutra et al., 2003). Other bacteria interact with epithelial host cell receptors in ways that interfere with normal host cell signaling processes and result in underlying cytoskeletal actin rearrangements. The effect of such actin rearrangement resulting from the interaction of Salmonella Typhimurium with its host cell receptors, for example, is host cell membrane ruffling that facilitates bacterial uptake (Francis et al., 1993). Actin rearrangements can be initiated by bacteria in the host cell cytosol as well. The facultative intracellular pathogens L. monocytogenes and Sh. flexneri, upon entry into the cytosol, express the protein analogs ActA and IcsA, respectively, that initiate a cascade of cellular protein interactions culminating in the formation of actin comet-like tails at the bacterial pole that propels the bacteria into neighboring cells (Cossart, 2000; Gouin et al., 1999). Another well-known example of a pathogenic bacterium that modifies host cell signaling processes is enteropathogenic E. coli (EPEC). An EPEC cell attaches to a host intestinal epithelial cell using bundle-forming pili and then uses a Type III secretion apparatus to inject its own receptor, TIR (translocated intimin receptor), into the epithelial cell. Injection of TIR causes actin rearrangements in the host cell that result in the formation of a membrane pedestal-like structure known as an attaching and effacing (A/E) lession. Binding between the E. coli surface protein intimin and its injected receptor TIR creates an intimate attachment (Clarke et al., 2003; Frankel et al., 1998).
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