TY - JOUR
AU - Pettersson, Sven
AB - It is becoming increasingly clear that there is a complex relationship between the intestinal immune system and pathogenic and commensal intestinal microbiota. Peyer's patches in normal individuals are highly reactive, with large germinal centres and increased T-cell activation compared with blood T cells. The gut mucosa in healthy individuals also contains very large numbers of IgA plasma cells and T cells. Studies in gnotobiotic animals have unequivocally demonstrated that the antigens that drive gut immune responses in healthy individuals are those of the normal bacterial flora. The absence of pathologic T cell responses to the normal flora in healthy individuals is not due to the inherent nonimmunogenicity of the flora but because responses are highly regulated, both by the host and by the bacteria. There clearly has been an evolutionary imperative to be able to mount rapid and effective antimicrobial immunity in the gut for survival, especially in the neonatal and early stages of life. From the teleological point of view, the extensive immune responses in healthy individuals to the normal flora can be seen as a direct consequence of the gut immune system's need to recognise pathogens in the lumen. Put simply, the immune system has to recognise indigenous Escherichia coli so that we can respond, when needed, to enteropathogenic E. coli. On the other hand, for the pathogenic microbe, there is also an imperative to be able to invade into the host, replicate, and survive, in the face of specific and nonspecific immunity. In the last few years there has been an explosion in our understanding of the strategies that microbes use to adhere to or invade the gut wall. Accompanying this however has also been an explosion in our understanding of the ways in which mammalian cells recognise microbial products and the counterpart to this, the way microbes can manipulate host immune responses to their advantage once within tissues. Mammalian Sensing Mechanisms for Bacteria Innate defense mechanisms in vertebrates, insects, and plants have revealed the existence of powerful host defense pathways with homologies in different species that diverged over a billion years ago. These mechanisms rest upon a conserved but limited set of recognition/signaling modules, typified by the Toll/IL [interleukin]-1-receptor homology domain and the Rel homology domain (RHD) (1,2). Myriad microbial components can trigger innate immune responses (3,4), and some of them may be harmful to the host, even at low concentration (5). In vertebrates, the skin and mucous membranes form a rigid closed biological barrier to prevent microbial components from being in contact with the innate immune system. At the same time, there is an urgent need for microbes and epithelial cells to adapt and establish an ecosystem that does not destroy either one due to protracted inflammation. Moreover, while lipopolysaccharides (LPS) can trigger host responses at concentrations of 2 ng/kg (6), we are at the same time exposed to 2 kg of microbes in the alimentary tract. Thus, there must exist a “regulatory sensing system” that prevents 2 kg of bacteria triggering inflammation. Innate immune recognition receptors have been shown to regulate a key player important for the interaction between microbes and mammalian cells, the transcription factor NF-kB. It follows that bacterial species must have developed ways to inhibit or attenuate effects elicited by NF-kB to block activation of an innate immune response, to help them colonize the host. Toll-Like Receptors Toll-like receptors (TLR) are transmembrane proteins that contain repeated leucine-rich motifs in their extracellular portions, similar to other pattern recognition proteins of the innate immune system. The proteins of TLRs contain a cytoplasmic domain, which is homologous to the signaling domain of the IL-1 receptor (7–13). While the ligands for TLRs have not yet been identified in mammals, it has been shown that bacteria can activate signal transduction pathways mediated by TLRs. While TLR-2 preferentially recognizes Gram-positive bacteria, Gram-negative bacteria are recognized by TLR-4 (3,4,14,15). These data support the possibility that different TLRs are capable of recognizing different types of microbes. NF-kB NF-kB (Rel-domain proteins) activates a cascade of genes important for the immune responses and can be induced in most cell types upon treatment with a whole panel of ligands, such as IL-1, TNF [tumor necrosis factor]-α, and microbes. These activators induce translocation of NF-kB from the cytoplasm to the nucleus and thus initiate transcription of target genes. The Relhomology domain controls nuclear-cytoplasmic shuttling, and provides NF-kB with its DNA binding domain and the docking site for the inhibitors of NF-kB, the I-kBs (17). For instance, IL-1 and TNF-α induce almost complete degradation of I-kBs within minutes. I-kBs are a small family of proteins, which is subject to ubiquitination and proteasome degradation, following phosphorylation by the I-kB kinase complexes, IKKs. These IKKs (IKKα, IKKβ, and IKK-NEMO) (16) are serine-specific and responsive to a number of potent NF-kB activators, most notably TNF-α and IL-1. The targeted disruption of NF-kB genes, which leads to impaired immune responses (17) and the use of NF-kB antisense oligonucleotides to block chronic inflammation in the alimentary tract (18), further emphasizes the importance of NF-kB in innate and adaptive immune responses. It follows that the host must have developed powerful mechanisms to rapidly terminate both IKK and NF-kB, as minor proinflammatory insults otherwise would lead to septic shock. Microbial Effector Mechanisms to Inhabit Intracellular Signalling The critical role of NF-kB in initiation of inflammatory responses suggests that microbes that colonize the alimentary tract are likely to harbor mechanisms that prevents the activation of innate immune responses. Possible mechanisms include regulation of TLR expression and/or modulation of their signal transduction pathways. The bacterial pathogen Yersinia pseudotuberculosis harbors a virulence plasmid that encodes a Type III secretion system, which allows Yersinia effector proteins (Yops) to be exported from the bacteria. Similar type III secretion systems are also present in many other Gramnegative bacteria. Upon cell contact, Yop proteins are translocated into eukaryotic cells (19,20) where they will interfere with cellular responses to ensure bacterial adherence without eliciting an immune response. Through the action of YopH, which targets focal adhesion structures, Yersinia can resist phagocytosis by macrophages (21,22). In addition, Yersinia abrogates signaling pathways that activate NF-kB, CREB, and AP-1 (via p38 MAPK-kinase), effects which are mediated by the YopJ protein (23–27). Interestingly, YopJ has recently been shown to have substrate specificity for several mitogen activated protein (MAP) kinase kinases (MKK) (28). MKKs are a conserved family of proteins that phosphorylate and activate specific downstream MAP kinases, which, in turn activate a variety of immediate early response genes critical for the production of cytokines and growth factors. In addition, by transfecting 293 cells with an YopJ-eukaryotic expression vector, IKKα-mediated activation of a NF-kB-linked reporter gene was blocked by protein-protein interaction between IKKα and YopJ (28). Thus, by blocking MKKs and IKKα, Yersinia possess a machinery to disrupt cytokine release, which ultimately decapitates the host's ability to efficiently mount an immune response and clear the infection (Fig. 1). It is interesting to note that YopJ-like sequences have also been found in other bacterial species, and the capacity to modulate inflammatory responses in animals or interfere with hypersensitivity responses in plants may therefore be evolutionary conserved (29,30). Fig. 1. View largeDownload slide The bacterial Yersinia outer protein, YopJ, inhibits NF-kB and AP-1 dependent gene expression in mammalian cells. Upon cell contact, Yop proteins are translocated into eukaryotic cells where they interfere with cellular responses to ensure bacterial adherence without eliciting an immune response. One of them is YopJ, which has been shown to physically interact with IKKβ and MKK proteins and as a result will abrogate the signaling pathway. Fig. 1. View largeDownload slide The bacterial Yersinia outer protein, YopJ, inhibits NF-kB and AP-1 dependent gene expression in mammalian cells. Upon cell contact, Yop proteins are translocated into eukaryotic cells where they interfere with cellular responses to ensure bacterial adherence without eliciting an immune response. One of them is YopJ, which has been shown to physically interact with IKKβ and MKK proteins and as a result will abrogate the signaling pathway. When Salmonella typhimurium invades host cells, they secrete an effector protein, SopE, which activates the GTP-binding proteins Rac-1 and Cdc42 to facilitate bacterial invasion (31). To counteract some of the proinflammatory effects triggered by the activation of Rac-1 and Cdc42, S. typhimurium also expresses its own secretory regulatory protein, StpP, to rapidly restore “normal membrane formation” of the invaded host cell. A similar mechanism may also account for the activity observed by the related toxin YopE in Yersinia, which also disrupts the actin cytoskeleton. Thus, Salmonella and Yersinia express secretory proteins to rapidly block or stall the stress responses triggered by the bacterium itself—some of which may converge on the p38 MAP kinase, which has been implicated in both the induction of innate and adaptive immune responses. Bacterial Proteins that Bind β1 Integrins Invasin Invasin is a 108kd outer membrane protein expressed on the surface of pathogenic Yersinia spp. It binds specifically to β1 integrins lacking I domains, such as α4β 1, α3β1, or α5β1 (32). The crystal structure of the C terminal 497 amino acids of invasin has recently been solved and reveals that the molecule has four IgSF domains with an N terminal C-type lectin domain (33). Invasin 497 coupled to inert beads are taken up by eukaryotic cells (34), showing that all the information for uptake of Yersinia is contained in this part of the molecule. Invasin binding to mammalian cells cross-links β1 integrins and activates focal adhesion kinase (FAK), which results in reorganization of the cytoskeleton, membrane ruffling, and internalisation of the bacteria (35). Since β1 integrins are expressed abundantly on cells of the immune system, there have been several studies on the immunoregulatory functions of invasin. Purified invasin strongly costimulates anti-CD3-stimulated human CD4+ T cells (36). Although human T cells express α3β1,α4β1,α5β1, and α6β1 integrins, the key functional invasin binding integrin appears to be α4β1. Invasin binding to resting T cells also induces increased motility and migration to extracellular matrix (37). Invasin on its own is insufficient to trigger T-cell division. Very recently it has been shown that invasin is needed for the binding of Yersinia pseudotuberculosis to lymphoblasts (38). Once this occurs, the bacteria use their type III secretion system to inject Yops into the cytoplasm of the cells where they can be processed through the ER and presented on class I major histocompatability complex (MHC) molecules. Invasin is also needed for the binding of Yersinia pseudotuberculosis to B cells and induces cell division (39). The potent immunostimulatory role for T and B cells does not seem to fit in well with Yersinia's strategy to avoid immune responses and survive in the extracellular spaces. However it may be the price the bacteria has to pay for strategies it uses where β1 integrins are exploited to the bacterium's advantage, as when Yersinia pseudotuberculosis or Yersinia enterocolitica adhere to M cells via β1 integrins to enter the Peyer's patches (40,41). This however is not the case with Yersinia pestis, which enters through a flea bite, which argues that there must be other roles for invasin-integrin interactions, such as attachment to the cell membrane for type III secretion. Intimin Intimin-α is a 94kd outer membrane protein present on enteropathogenic and enterohemorrhagic E. coli. Structurally, intimin has a similar domain structure to invasin (42) and also binds β1 integrins (43); however, there is only 20% sequence homology between the two molecules. Another similarity between intimin and invasin is that there are critical residues in the C-type lectin-like domain of invasin (aspartate at position 911) and intimin (cysteine at position 201 of the terminal 280 amino acid fragment), which are needed for integrin binding. Intimin however has a second well-defined receptor, tir (the transmissable intimin receptor). Tir is a bacterial protein which enteropathogenic E. coli inject into epithelial cells using the type III secretion system and which is then inserted into the apical aspect of the enterocyte in a reverse hairpin loop with the C and N terminal regions in the cytoplasm (44,45). Intimin binding to tir leads to tir phosphorylation and reorganisation of the host cytoskeleton to produce the pedestal characteristic of the attaching and effacing lesion of enteropathogenic Escherichia coli (EPEC) diarrhea (46). Like invasin, the terminal 280 amino acid fragment of intimin (int280) also binds to T cells, principally through α4β1 integrin (43). Recently, it has also been demonstrated that int280 costimulates T cells and elicits a Thltype cytokine response (47). It has to be stated that the ability of intimin to bind β1 integrins is somewhat controversial (48), and that the relative roles of tir and integrin binding on mammalian cells are still not clear. What is of more interest however is the potential of a noninvasive pathogen to produce a molecule that clearly has immunregulatory activity. Evidence that Intimin Interactions with T Cells have a Functional Role In Vivo EPEC do not infect rodents; however, there is a related pathogen, Citrobacter rodentium, which colonises the mouse colon resulting in massive mucosal hyperplasia (49). C. rodentium produces attaching and effacing lesions on enterocytes in a similar fashion to EPEC; however, it uses a slightly different intimin, designated intimin β. Deletion of intimin β abolishes C. rodentium pathogenicity, and restoring intimin with intimin α of EPEC fully restores virulence (50). When investigating the types of immune reactions in the colon of C. rodentium infected mice, we were struck by the fact that the hyperplasia elicited by infection was similar to the hyperplasia seen in mouse models of IBD, and by the fact that in the mucosa of Citrobacter-infected mice there was a massive CD4+ T helper cell type 1 immune response (51). This local immune response may be induced by the large numbers of bacteria colonising the mucosa; however, we hypothesised that intimin itself may be playing a more direct role in this response. Intimin-negative Citrobacter do not colonise the gut; therefore, to assess the role of intimin, we formalin-killed C. rodentium and injected the bacteria into the colon of normal adult mice 15 minutes after an intracolonic injection of ethanol to break the mucosal barrier. Intiminnegative bacteria used in this protocol elicited no response in the mucosa; however, intimin-positive bacteria (either α or β) elicited a massive colonic hyperplasia (Fig. 2) and a CD4+ Thl response in the mucosa (47). This effect was not seen in interferon-γ receptor knockout mice and was also not seen in normal mice given Citrobacter-bearing intimin with the cys 201 mutation, which reduces integrin binding. Transfection of intimin into laboratory K12 E. coli also produced bacteria capable of eliciting mucosal hyperplasia. Fig. 2. View largeDownload slide Mucosal hyperplasia induced by the intracolonic administration of dead Citrobacter rodentium-expressing intimin. The top panel (A) shows the colonic mucosa of a mouse that received ethanol followed by formalin-killed intimin negative Citrobacter. The bottom panel (B) shows the colonic mucosa of a mouse treated identically, except they received intimin-positive Citrobacter. Sections were stained with antimouse MHC class II antibodies to highlight the massive epithelial expression of class II, which accompanies the Th1 response in the mucosa. Mice were killed 6 days posttreatment. Immunoperoxidase with antimouse MHC class II; original magnification, ×100. Fig. 2. View largeDownload slide Mucosal hyperplasia induced by the intracolonic administration of dead Citrobacter rodentium-expressing intimin. The top panel (A) shows the colonic mucosa of a mouse that received ethanol followed by formalin-killed intimin negative Citrobacter. The bottom panel (B) shows the colonic mucosa of a mouse treated identically, except they received intimin-positive Citrobacter. Sections were stained with antimouse MHC class II antibodies to highlight the massive epithelial expression of class II, which accompanies the Th1 response in the mucosa. Mice were killed 6 days posttreatment. Immunoperoxidase with antimouse MHC class II; original magnification, ×100. Taken together, these data indicate that intimin + bacteria, entering the colonic mucosa (either lymphoid follicles or lamina propria), drive CD4+ Thl responses and hyperplasia. Although this might seem counterintuitive, the mucosal hyperplasia, which invariably occurs during T-cell responses in the colon, can be seen to be advantageous to the bacterium. The limiting factor for bacterial colonisation is the surface area of the colon. By increasing crypt length the bacteria can colonise the top half of the glands, and provide an increased supply of fresh cells for daughter E. coli to colonise. Increased shedding of epithelial cells will increase transmission. There are many questions still to be answered in this system. The specificity of the T cells in the mucosa needs to be established. Are the bacteria boosting an anti-Citrobacter T-cell response or is it a bystander response to antigens of the flora? The site of T-cell activation needs to be established since normal mucosal T cells only express low levels of β1 integrins. It may be that the initial response occurs in Peyer's patches or lymphoid follicles in the colon. The implications of this work are important. EPEC infection in the small bowel of patients has been reported to also cause hyperplasia (52) and this also may be driven by intimin. However there is a strong possibility that intimin may also alter the responses to bystander antigens in the gut at the same time, leading to abrogation of oral tolerance. Clinically there is evidence that food hypersensitivity follows gastroenteritis. In the past it was considered that this might be due to increased permeability due to epithelial barrier damage; however, in this new scenario bacterial proteins may be altering T-cell responses in the gut. There is also emerging evidence that EPEC, like Yersinia spp., may have further immunoregulatory activity. Uptake of EPEC into mouse macrophage cell lines inhibits further EPEC phagocytosis (53). This phenomenon depends completely on an intact type III secretion system and is partially dependent on intimin and tir. Further studies are needed to determine the detailed mechanisms involved in this antiphagocytic response. EPEC has also been reported to cause apoptosis of fibroblasts and epithelial cells, although unlike Shigellae, Yersiniae, and Salmonellae, they have not been demonstrated to induce death of phagocytes (54). Although these results are preliminary, they serve to further reinforce the notion that EPEC, ostensibly noninvasive pathogens, are capable of interacting with host immune cells to their own advantage. Pathogenic Bacteria Secrete Proteins that Induce Cell Death When invasive gut pathogens cross the epithelial barrier and enter the dome area of the follicles, they immediately encounter resident phagocytes. Since the numbers of bacteria that actually manage to cross into the follicle are very small, it is of crucial importance that these few bacteria are not immediately killed by nonspecific cellular immunity. Different bacteria have evolved different strategies to overcome this problem. Yersiniae have antiphagocytic proteins, YopE and YopH, which function to disrupt FAK thereby preventing the cytoskeletal reorganisation necessary for the formation of the phagocytic vacuole (22). Salmonellae are facultative intracellular pathogens and can survive within the phagocytic vacuole. Shigellae rapidly leave the phagocytic vacuole, enter the cytoplasm, and trigger apoptosis. It was first demonstrated that murine macrophages infected with Shigella flexneri rapidly undergo apoptosis (55). In vivo experiments confirmed that there is also extensive apoptosis when Shigellae invade the dome region of Peyer's patches (56). The molecular basis for this response was elucidated when it was discovered that IpaB, a polypeptide encoded by the 220kb virulence plasmid, binds to and activates caspase 1, the interleukin-1 converting enzyme, which is also involved in the caspase pathway of programmed cell death (57). Similar results were found when Shigella flexneri infected human monocyte-derived macrophages (58). However, another study reporting that Shigella causes human macrophage cell death suggests that it is not due to apoptosis but by a nonspecific response called oncosis (59). Invasive Salmonella typhimurium are also able to induce cell death in macrophages by apoptosis (60) and, as with Shigellae, this is due to activation of caspase 1 by SipB, the Salmonella homologue of IpaB (61). Summary If we are to understand pathological processes within the alimentary tract, it is apparent that the fundamental aspects of microbe-host interactions need to be examined in greater detail. Pathogenic bacteria have evolved strategies to alter and subvert the function of T cells and phagocytes in the gut wall, and exploiting these molecules may lead to new treatments for chronic inflammatory bowel diseases. The adaptation of microbes to their host must involve microbe-mediated interference of the host innate immune response. The recent demonstration that nonpathogenic E. coli have a beneficial effect in ulcerative colitis (62) further supports the notion that normal flora may alter the expression of the innate immune receptors or recognize alternative receptors compared with pathogenic variants. Such differences may conceivably lead to beneficial and protective alterations to the host through cytokine and antimicrobial peptide expression. Perhaps the contact point between microbes and host cells lies with the pattern-recognition receptors such as the TLRs. However, although much light has been shed on the downstream consequences of TLR activation, many more questions remain unsolved. For example, little is known about the expression profiles of the different TLRs throughout the gastrointestinal tract. Additionally, ambiguities remain over the natural ligands for TLRs. 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TI - Bacterial Regulation of Intestinal Immune Responses
JF - Inflammatory Bowel Diseases
DO - 10.1097/00054725-200005000-00008
DA - 2000-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/bacterial-regulation-of-intestinal-immune-responses-n6044N7J3K
SP - 116
EP - 122
VL - 6
IS - 2
DP - DeepDyve
ER -