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N. Bram, M.B. B.CH., M.B.B.Ch., Ph.D.

Professor, Midwestern University Chicago College of Osteopathic Medicine

For the virulence studies, Caco-2 cells were grown to confluence, infected with Salmonella isolates and incubated for both one and 48 hours for the invasion and persistence assays, respectively. Additionally, Salmonella isolates were assessed for their ability to produce colicin toxins and inhibit other bacteria. All isolates infected Caco-2 cells after one hour incubation and persisted in the cells at 48 hrs. Persistent cell counts were observed to be significantly higher than invasion assay cell counts in 26% of the isolates. Over 78% (n=36) of Salmonella isolates were able to inhibit growth of at least one E. In this study, isolates carrying IncI1 plasmids were able to invade and often persist in elevated levels in the intestinal epithelial cell model and able to produce colicin toxins that may provide a selective colonization advantage. This study lays the foundation for additional studies to refine the contribution of the specific IncI1 plasmid-associated genes to virulence. Identification of genetic determinants relevant for increased virulence and toxin production would help to design screening tools for foodborne pathogens and enhance food safety. Improper utilization and disposal of pig faeces in pig farms have been a great concern due to their hazards and risks they constitute to the environment. This situation calls for conversion of animal waste to wealth through effective utilization of pig faeces for fish feed formulation. Growth, histology, and haematology of the fish samples were determined according to standard methods. Histological results confirmed the absence of lesions in the heart, gills and the intestine of fish samples. The functioning of the immune system is influenced by several factors including the diet. When food ingredients and functional foods are associated with immune modulation, there is not always a clear understanding as to whether these changes are indicative of an adverse, beneficial, or neutral effect. The purpose of the current work was to identify the immunomodulatory changes reported in these notifications and to distinguish which effects should be considered innocuous, versus those that could be indicative of safety concerns. Relevant toxicology data were systematically identified for each immunomodulatory factor to determine their significance in terms of safety in food. These findings, however, were not accompanied by significant changes in any other safety-related endpoints. Slight increases in cells with inflammatory potential are unlikely to be of immediate physiological significance without supporting evidence such as elevated levels of inflammatory cytokines. However, it appears that the safety issue relates to the potential long-term consequences of sustained immunostimulation, which is difficult to completely refute with short-term toxicology data. Food sources of L&Z include a variety of fruits and vegetables, with green leafy vegetables being the richest source. Observational studies indicate L&Z reduce risk for chronic diseases including cancer. L&Z possess important antioxidant properties, promote anti-carcinogenic effects, and have immune modulatory effects and apoptosis-inducing capabilities. Thus, our objective was to evaluate potential association between L&Z and all-cancer. The dataset served as baseline and was correlated with the National Death Index database for an 18-year (1988­2006) follow-up study. Not only do L&Z reduce carcinogenesis, they also enhance survival among cancer victims. These findings confirm dietary recommendations that promote intake of a variety of fruits and vegetables to protect health and prevent disease. Further studies are needed to explore the physiological mechanisms of this phenomena. As a practical exercise, intake modeling was conducted to determine the mean intake of oven-baked fries (=26 g/d), deep-fried fries (=37 g/d) and multigrain bread (=34 g/d).

However, they can prevent an infection being established, or failing that, contain it while an adaptive immune response develops. Only when a microorganism has successfully established a site of infection in the host does disease occur, and little damage will be caused unless the agent is able to spread from the original site of infection or can secrete toxins that can spread to other parts of the body. Extracellular pathogens spread by direct extension of the focus of infection through the lymphatics or the bloodstream. Usually, spread by the bloodstream occurs only after the lymphatic system has been overwhelmed by the burden of infectious agent. Obligate intracellular pathogens must spread from cell to cell; they do so either by direct transmission from one cell to the next or by release into the extracellular fluid and reinfection of both adjacent and distant cells. Many common food poisoning organisms cause pathology without spreading into the tissues. They establish a site of infection on the epithelial surface in the lumen of the gut and cause no direct pathology themselves, but they secrete toxins that cause damage either in situ or after crossing the epithelial barrier and entering the circulation. Most infectious agents show a significant degree of host specificity, causing disease only in one or a few related species. What determines host specificity for every agent is not known, but the requirement for attachment to a particular cell-surface molecule is one critical factor. As other interactions with host cells are also commonly needed to support replication, most pathogens have a limited host range. The molecular mechanisms of host specificity comprise an area of research known as molecular pathogenesis, which falls outside the scope of this book. While most microorganisms are repelled by innate host defenses, an initial infection, once established, generally leads to perceptible disease followed by an effective host adaptive immune response. This is initiated in the local lymphoid tissue, in response to antigens presented by dendritic cells activated during the course of the innate immune response. Antigen-specific effector T cells and antibody-secreting B cells are generated by clonal expansion and differentiation over the course of several days, during which time the induced responses of innate immunity continue to function. Eventually, antigen-specific T cells and then antibodies are released into the blood and recruited to the site of infection. A cure involves the clearance of extracellular infectious particles by antibodies and the clearance of intracellular residues of infection through the actions of effector T cells. After many types of infection there is little or no residual pathology following an effective primary response. In some cases, however, the infection or the response to it causes significant tissue damage. In other cases, such as infection with cytomegalovirus or Mycobacterium tuberculosis, the infection is contained but not eliminated and can persist in a latent form. We will focus on the strategies used by certain pathogens to evade or subvert adaptive immunity and thereby establish a persistent infection in the first part of Chapter 11. In addition to clearing the infectious agent, an effective adaptive immune response prevents reinfection. For some infectious agents, this protection is essentially absolute, while for others infection is reduced or attenuated upon reexposure. These are illustrated here for an infectious microorganism entering across an epithelium, the commonest route of entry. The infectious organism must first adhere to epithelial cells and then cross the epithelium. A local nonadaptive response helps contain the infection and delivers antigen to local lymph nodes, leading to adaptive immunity and clearance of the infection. Infectious diseases are caused by diverse living agents that replicate in their hosts. The agents that cause disease fall into five groups: viruses, bacteria, fungi, protozoa, and helminths (worms). Protozoa and worms are usually grouped together as parasites, and are the subject of the discipline of parasitology, whereas viruses, bacteria, and fungi are the subject of microbiology. The remarkable variety of these pathogens has caused the natural selection of two crucial features of adaptive immunity. First, the advantage of being able to recognize a wide range of different pathogens has driven the development of receptors on B and T cells of equal or greater diversity. Second, the distinct habitats and life cycles of pathogens have to be countered by a range of distinct effector mechanisms.

The key players regulating uterine receptivity are estradiol (E2) and progesterone (P4). Currently little is known about the roles of Gq/11-coupled receptors as regulators of uterine receptivity but based on preliminary findings we hypothesized that uterine Gq/11 signaling is essential for the acquisition of uterine receptivity. As a result, the luminal epithelium remained highly proliferative on D4 while the lumen failed to undergo closure, both processes are dependent on P4 signaling and are essential for embryo implantation. We therefore conclude uterine Gq/11 signaling mediates the progesterone dependent acquisition of uterine receptivity. We expect that these studies will be crucial to the future development of targeted therapies in the treatment of infertility and in understanding potential mechanisms underlying the action of toxicants. This work highlights the evolving intricacies of AhR biology and cross-talk with the epigenome. The AhR normally resides within a cytosolic protein complex that translocates to the nucleus upon AhR-agonist interaction. Metabolic homeostasis is regulated, in part, by a family of proteins called nuclear receptors through which lipophilic hormones and molecules regulate gene expression. Its activation is essential for white, brite (brownin-white), beige and brown adipogenesis, mature adipocyte maintenance, and insulin sensitivity. Accumulation of white adipocytes significantly increases the risk of metabolic syndrome. On the other hand, brown and brite adipocytes potentially counteract metabolic disease-related symptoms. Only Rosi and Rosco induced healthful energy expenditure, inducing mitochondrial biogenesis and enhancing mitochondrial respiration. Recently it has also been implicated in modulating energy metabolism and different aspects of multiple cancer pathways. Glycolysis was lowered by activation of the AhR as measured by decreases in glucose uptake and the production of pyruvate and lactate. At 5 days post fertilization, both AhR1a/AhR1b and AhR2 mutant larvae were normal, suggesting that adult phenotypes are due to defects in maturation or maintenance. AhR was shown to interact with estrogen receptor alpha, yet it is not known whether these interactions are constitutive or dependent on AhR1 genes. The aryl hydrocarbon receptor (AhR) is a crucial transcription factor involved in remediating xenobiotic chemicals from within the human body, yet the mechanisms by which AhR is able to elicit different responses to exogenous and endogenous AhR ligands remains unclear. The aryl hydrocarbon receptor (AhR) is a cytosolic receptor that mediates the effects of environmental contaminants on the body. During normal physiology this receptor plays a role in the differentiation of various pathways including hematopoiesis, B and T cells, and lymphoid systems. Toxic responses can occur when AhR is activated by exogenous ligands, like benzo-a-pyrene, and aberrant activation can occur. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that binds environmental toxins and regulates gene expression. AhR also regulates developmental processes, like craniofacial development and hematopoiesis, in the absence of environmental exposures. However, the degree to which AhR1a and AhR1b influence AhR2 signaling and contribute to fin and craniofacial development are not known. We generated zebrafish with mutations in each AhR gene and compared morphology of adult AhR2 mutants and AhR1a/AhR1b single and double mutant zebrafish. With the dietary intervention, perturbations in the gut microbiota associated with colitis were partially restored. Furthermore, increased levels of AhR ligands in the diet-modulated gut microbiome resulted in elevated AhR activation, which may contribute to the ameliorating effect on intestinal inflammatory status. Enriched bacterial genes and pathways in the biosynthesis of heme-related compounds that are known AhR ligands, in concert with strong correlations between specific bacterial species and these compounds suggested the involvement of gut bacterial activities in producing AhR ligands. Host metabolic profiling revealed restored metabolites that are relevant to inflammation and the gut microbiota. Thin layer chromatography was used to separate the coffee extracts into 3 bands, namely top, middle (containing caffeine) and bottom and subsequent bioanalysis of these fractions showed that the AhRactivity was concentrated in the top and bottom fractions and caffeine was inactive as an AhR ligand. Ongoing studies are focused on investigating other active constituents in coffee and their potential beneficial effects in the intestine and other target tissues. Depending on specific environmental stimuli, macrophages can be polarized either to pro-inflammatory. These data have translational implications, suggesting that environmental insults can influence the immune system and increase inflammation, creating an advantageous environment for cardiovascular disease progression.

First, they act on the leukocyte as it rolls along endothelial cells at sites of inflammation, converting this rolling into stable binding by triggering a change of conformation in the adhesion molecules known as leukocyte integrins. This allows the leukocyte to cross the blood vessel wall by squeezing between the endothelial cells, as we will see when we describe the process of extravasation. Second, the chemokines direct the migration of the leukocyte along a gradient of the chemokine that increases in concentration toward the site of infection. This is achieved by the binding of the small, soluble chemokines to proteoglycan molecules in the extracellular matrix and on endothelial cell surfaces, thus displaying the chemokines on a solid substrate along which the leukocytes can migrate. Chemokines can be produced by a wide variety of cell types in response to bacterial products, viruses, and agents that cause physical damage, such as silica or the urate crystals that occur in gout. Thus, infection or physical damage to tissues sets in motion the production of chemokine gradients that can direct phagocytes to sites where they are needed. In addition, peptides that act as chemoattractants for neutrophils are made by bacteria themselves. Thus, there is a common mechanism for attracting neutrophils, whether by complement, chemokines, or bacterial peptides. Neutrophils are the first to arrive in large numbers at a site of infection, with monocytes and immature dendritic cells being recruited later. We will now turn to the molecules that mediate leukocyte endothelium adhesion, and then describe the process of leukocyte extravasation step by step, as it is known to occur for neutrophils and monocytes. Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response. The recruitment of activated phagocytes to sites of infection is one of the most important functions of innate immunity. Recruitment occurs as part of the inflammatory response and is mediated by cell-adhesion molecules that are induced on the surface of the local blood vessel endothelium. Before we consider the process of inflammatory cell recruitment we will first describe some of the cell-adhesion molecules involved. A significant barrier to understanding cell-adhesion molecules is their nomenclature. Most cell-adhesion molecules, especially those on leukocytes, which are relatively easy to analyze functionally, were named after the effects of specific monoclonal antibodies against them, and were only later characterized by gene cloning. The selectins are membrane glycoproteins with a distal lectinlike domain that binds specific carbohydrate groups. Members of this family are induced on activated endothelium and initiate endothelial leukocyte interactions by binding to fucosylated oligosaccharide ligands on passing leukocytes (see. People with this disease suffer from recurrent bacterial infections and impaired healing of wounds. The family members shown here are limited to those that participate in inflammation and other innate immune mechanisms. The same molecules and others participate in adaptive immunity and will be considered in Chapters 8 and 10. Sulfation can occur at either the sixth carbon atom of the galactose or the N-acetyl-glucosamine, but not both. Both these proteins interact with sulfatedsialyl-Lewisx, which is present on the surface of neutrophils. This may be used by circulating monocytes to navigate out of the vessels and into their tissue sites, which happens continuously and essentially ubiquitously. The first step (top panel) involves the reversible binding of leukocytes to vascular endothelium through interactions between selectins induced on the endothelium and their carbohydrate ligands on the leukocyte, shown here for E-selectin and its ligand the sialyl-Lewisx moiety (s-Lex). This interaction cannot anchor the cells against the shearing force of the flow of blood, and instead they roll along the endothelium, continually making and breaking contact. Spragg Cell-adhesion molecules have many other roles in the body, directing many aspects of tissue and organ development. In this brief description, we have considered only those that participate in the recruitment of inflammatory cells in the hours to days after the establishment of infection. Neutrophils make up the first wave of cells that cross the blood vessel wall to enter inflammatory sites. The physical changes that accompany the initiation of the inflammatory response have been described in Section 2-4; here we give a step-by-step account of how the required effector cells are recruited into sites of infection. Under normal conditions, leukocytes are restricted to the center of small blood vessels, where the flow is fastest.