Flagellin 'b' Mediated Innate Defense Against Urinary Tract Infections by Pseudomonas aeruginosa
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Pseudomonas aeruginosa is a complex gram-negative facultative anaerobe replete with a variety of arsenals to activate, modify, and destroy host defense mechanisms. The microbe is a common cause of nosocomial infections and an antibiotic-resistant priority pathogen. In the lung, P. aeruginosa disrupts upper and lower airway homeostasis by damaging the epithelium and evading innate and adaptive immune responses. The biology of these interactions is essential to understand P. aeruginosa pathogenesis. P. aeruginosa interacts directly with host cells via flagella, pili, lipoproteins, lipopolysaccharides, and the type III secretion system localized in the outer membrane. P. aeruginosa quorum-sensing molecules regulate the release of soluble factors that enhance the spread of infection. These characteristics of P. aeruginosa differentially affect lung epithelial, innate, and adaptive immune cells involved in the production of mediators and the recruitment of additional immune cell subsets. Pathogen interactions with individual host cells and in the context of host acute lung infection are discussed to reveal pathways that may be targeted therapeutically.
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Pseudomonas aeruginosa is a dangerous pathogen particularly because it harbors multiple virulence factors. It causes several types of infection, including dermatitis, endocarditis, and infections of the urinary tract, eye, ear, bone, joints and, of particular interest, the respiratory tract. Patients with cystic fibrosis, who are extremely susceptible to Pseudomonas infections, have a bad prognosis and high mortality. An important virulence factor of P. aeruginosa, shared with many other gram-negative bacteria, is the type III secretion system, a hollow molecular needle that transfers effector toxins directly from the bacterium into the host cell cytosol. This complex macromolecular machine works in a highly regulated manner and can manipulate the host cell in many different ways. Here we review the current knowledge of the structure of the P. aeruginosa T3SS, as well as its function and recognition by the immune system. Furthermore, we describe recent progress in the development and use of therapeutic agents targeting the T3SS. Keywords: Disease, immunity, immune evasion, infection, Pseudomonas aeruginosa, therapy, Type III secretion system, Pseudomonas aeruginosa, Inv-Mxi-Sp, SPI-1
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Macrophages form one of the first lines of defense on mucosal surfaces like urinary tract, providing protection against pathogens. These cells pour their secretory products, which include a cocktail of biomolecules, at the site of infection. In the present investigation, the effect of macrophage secretory products (MSPs) obtained after interaction of macrophages with Pseudomonas aeruginosa on the virulence of this organism in planktonic and biofilm cell mode was assessed employing a mouse model of ascending pyelonephritis. When urinary tract infection (UTI) was established with P. aeruginosa grown in the presence of 30% MSPs, the extent of pyelonephritis was enhanced. Of the two cell forms, biofilm cells had an edge over the planktonic cells with respect to in vivo virulence. The enhanced virulence of MSP-grown P. aeruginosa may be attributed to increased production of quorum-sensing systems as well as increased adherence to uroepithelial cells and evasion of phagocytosis. The results of the present study reveal that macrophages can play a key role during the course of UTI, not only through their phagocytic activity, but also through effects mediated by their secretory products. Utilization of MSPs by P. aeruginosa can have far-reaching consequences, including chronicity and recurrence of infections caused by this pathogen.
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Recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors triggers an innate immune response to colonizing or invading bacteria. Conversely, many bacteria have evolved mechanisms to dampen this response by downregulating the synthesis of such PAMPs. We have previously demonstrated that Pseudomonas aeruginosa growing in mucopurulent human respiratory mucus from cystic fibrosis patients represses the expression of its flagellin, a potent stimulant of the innate immune response. Here we demonstrate that this phenomenon occurs in response to the presence of neutrophil elastase in such mucus. Nonpurulent mucus from animals had no such repressive effect. Furthermore, lysed neutrophils from human blood reproduced the flagellin-repressive effect ex mucus and, significantly, had no effect on the viability of this organism. Neutrophil elastase, a component of the innate host defense system, has been described to be bactericidal for gram-negative bacteria and to degrade bacterial virulence factors. Thus, the resistance of P. aeruginosa to the bactericidal effect of neutrophil elastase, as well as this organism's ability to sense this enzyme's presence and downregulate the synthesis of a PAMP, may be the key factors in allowing P. aeruginosa to colonize the lungs. These findings demonstrate the dynamic nature of this bacterium's response to host defenses that ensures its success as a colonizer and also highlights the dual nature of defense molecules that confer advantages and disadvantages to both hosts and pathogens.
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Pseudomonas exotoxin
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This article refers to:Pseudomonas aeruginosa proteolytically alters the interleukin 22-dependent lung mucosal defense
Mucosal Immunity
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The opportunistic pathogen Pseudomonas aeruginosa can cause severe infections in patients suffering from disruption or disorder of the skin barrier as in burns, chronic wounds, and after surgery. On healthy skin P. aeruginosa causes rarely infections. To gain insight into the interaction of the ubiquitous bacterium P. aeruginosa and healthy human skin, the induction of the antimicrobial protein psoriasin by P. aeruginosa grown on an ex vivo skin model was analyzed. We show that presence of the P. aeruginosa derived biosurfactant rhamnolipid was indispensable for flagellin-induced psoriasin expression in human skin, contrary to in vitro conditions. The importance of the bacterial virulence factor flagellin as the major inducing factor of psoriasin expression in skin was demonstrated by use of a flagellin-deficient mutant. Rhamnolipid mediated shuttle across the outer skin barrier was not restricted to flagellin since rhamnolipids enable psoriasin expression by the cytokines IL-17 and IL-22 after topical application on human skin. Rhamnolipid production was detected for several clinical strains and the formation of vesicles was observed under skin physiological conditions. In conclusion we demonstrate herein that rhamnolipids enable the induction of the antimicrobial protein psoriasin by flagellin in human skin without direct contact of bacteria and responding cells. Hereby, human skin might control the microflora to prevent colonization of unwanted microbes in the earliest steps before potential pathogens can develop strategies to subvert the immune response.
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Inflammation: A Double-Edged Sword in the Response to <b><i>Pseudomonas aeruginosa</i></b> Infection
The Gram-negative opportunistic pathogen <i>Pseudomonas aeruginosa</i> exploits failures of barrier defense and innate immunity to cause acute infections at a range of anatomic sites. We review the defense mechanisms that normally protect against <i>P. aeruginosa</i> pulmonary infection, as well as the bacterial products and activities that trigger their activation. Innate immune recognition of <i>P. aeruginosa</i> is critical for pathogen clearance; nonetheless, inflammation is also associated with pathogen persistence and poor host outcomes. We describe <i>P. aeruginosa</i> adaptations that improve this pathogen's fitness in the inflamed airway, and briefly discuss strategies to manipulate inflammation to benefit the host. Such adjunct therapies may become increasingly important in the treatment of acute and chronic infections caused by this multi-drug-resistant pathogen.
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We have shown previously that the PA-I lectin of Pseudomonas aeruginosa plays a key role in gut-derived sepsis during surgical stress. The aims of this study were to determine if the intestinal tract lumen of a stressed host contained soluble factors that could induce the expression of PA-I.Mice were subjected to either 30% surgical hepatectomy or sham-laparotomy, and P. aeruginosa was introduced into the cecum. Twenty-four hours later, feces were recovered, and PA-I and exotoxin A were determined by real-time polymerase chain reaction (PCR). In reiterative experiments, fecal filtrates from both hepatectomy and sham-operated mice were tested for their ability to induce PA-I expression in cultures of P. aeruginosa. Finally, the media from cultured human intestinal epithelial (Caco-2) cells stressed with excess glutamine was tested for its ability to induce the expression of PA-I in cultures of P. aeruginosa.Both PA-I and exotoxin A mRNA were increased in vivo in the intestinal tract of mice subjected to 30% hepatectomy. Soluble fecal filtrates from hepatectomy mice induced PA-I in vitro. Media from epithelial cells exposed to excess glutamine alone induced PA-I expression.The intestinal environment of a stressed host contains soluble factors capable of inducing lethal virulence traits in human opportunistic pathogen P. aeruginosa.
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