Infections with the human pathogen (factors (e. unwanted bacteria and pathogens.
Infections with the human pathogen (factors (e. unwanted bacteria and pathogens. Forming this first effective barrier, epithelial cells show an apico-basolateral organization, which is primarily maintained by tight junctions, adherence junctions and a strictly regulated actin cytoskeleton [1,2]. Functional tight junctions are crucial for the maintenance of epithelial polarity and cell-to-cell adhesion, and form a paracellular barrier that precludes the free passage of molecules. Tight junctions are composed of several types of transmembrane proteins (e.g. occludin, claudins, junctional adhesion molecules [JAMs]) that bind to cytoplasmic peripheral proteins (e.g. zonula occludens [ZO] protein-1, -2 and ?3, cingulin or multi-PDZ protein-1 [MUPP1]) and link the transmembrane proteins to the actin cytoskeleton. Adherence junctions mediate intercellular adhesions between neighboring cells, control the actin cytoskeleton and, therefore, exhibit anti-tumor properties. They consist of the transmembrane protein E-cadherin that bridges adjacent epithelial cells GDC-0068 with the intracellular actin cytoskeleton. This involves a signaling complex composed of -catenin, p120-catenin, -catenin and epithelial protein lost in neoplasm (EPLIN), which is recruited to the intracellular domain of E-cadherin. These dynamic intercellular junctions are crucial for the integrity of the gastric epithelium and protect against intruding pathogens [1,2]. (has developed highly sophisticated mechanisms to establish life-long infections in the stomach if not therapeutically eradicated. This is why it is considered as one of Rabbit Polyclonal to Akt. the most successful bacterial pathogens. induces gastritis in all infected patients, but GDC-0068 only a minority of approximately 10-15% suffers from clinical symptoms. GDC-0068 The reason for the different responses to is not clearly understood, but many reports GDC-0068 point to individual genetic susceptibilities of the host to isolates harbor different patterns of genetic elements encoding for bacterial factors that are crucially involved in persistent colonization and pathogenesis. Some of these have already been defined as virulence factors , while others might serve as important niche and colonization determinants  or are still under investigation for GDC-0068 their pathological relevance. In the last three decades, remarkable progress has been made in the understanding of pathogenicity-related factors of and their functional interaction with gastric epithelial cell components. These virulence-related factors are either secreted, membrane-associated, or translocated into the cytosol of host cells, where they can directly interfere with host cell functions (Figure?1). As a consequence of their different locations during the infection process, is able to exploit a plurality of mechanisms to manipulate host cellular processes and to deregulate signaling cascades. The influence of on these signaling pathways results in adherence, induction of proinflammatory responses through cytokine/chemokine release, apoptosis, proliferation, and a pronounced motogenic response as characterized utilizes them to manipulate the gastric epithelium. Many of these factors act cooperatively, eventually leading to a complex scenario of pathogenesis-related signaling events. Figure 1 Cellular responses to expresses membrane-bound factors, secretes factors and exploits a type IV secretion system (T4SS) to inject effectors. These contribute to adhesion or induce signal … Membrane-associated factors: adhesins and beyond Despite gastric peristalsis and transportation of chyme, establishes a strong interaction with epithelial cells. In fact, adhesion of is considered to be the first important step in pathogenesis in the stomach. The large group of outer membrane proteins (OMPs) contains some adhesins (e.g. blood-group-antigen-binding adhesin [BabA], sialic acid binding adhesin [SabA], adherence-associated lipoprotein A and B [AlpA/B], and outer inflammatory protein A [OipA]) that mediate binding of to the host cell membrane, and other factors (e.g. lipopolysaccharide [LPS] and flagellin) that are able to trigger inflammatory responses in host tissues (Figure?2a). Figure 2 Model of establishes the first adherence. SabA, BabA, AlpA/B, OipA, HopZ, HorB, etc. are considered as important adhesins that bind to host cell … Although bacterial adherence is crucially important for pathogenesis, data showing direct effects of the above adherence factors on signaling pathways are scarce. This indicates that canonical adhesins may not directly activate signaling, but rather mediate a tight interaction.