Contributions to microbiology最新文献

Therapy for severe sepsis and septic shock remains a major unmet medical need and novel treatments to regulate the disordered inflammatory response in sepsis are needed if improved outcomes in sepsis are to be realized in the future. Current therapy is primarily supportive and includes timely administration of antibiotics, source control of infection, aggressive fluid resuscitation, organ support and use of activated protein C where clinically indicated. Bacterial mediators including endotoxin and superantigens as well endogenous proinflammatory cytokines are critical to the pathogenesis of sepsis-induced organ failure and are being targeted with numerous molecules and removal devices. Additional therapeutic strategies are focused at restoring the natural anticoagulant levels, blocking deleterious effects of the complement cascade, preserving mitochondrial function, and inhibiting excessive lymphocyte apoptosis. Molecules with pluripotent activity such as inter-alpha inhibitor proteins, sirtuin activators and estrogen-receptor ligands are also being investigated. Efforts are underway to re-establish microbial clearance mechanisms and permit immune reconstitution following sepsis-induced immune suppression. A review of the most current agents being investigated and their current status are presented in this chapter. The organization of this chapter includes sections addressing therapies targeting microbial mediators, including endotoxin, as well as therapies targeting inflammation and coagulation. There is also a section on agents targeting novel mediators and pathways.

Sepsis is characterised by a hyper-inflammatory response due to microbial infection. We here review our current understanding of host mechanisms employed to mediate this hyper-inflammatory response, drawing together current knowledge pertaining to pathogen recognition and host pro-inflammatory response. Recognition of microbial derived ligands by pattern recognition receptors (PRRs) is a key step in initiating pro-inflammatory signalling pathways. Examples of PRRs linked to the aetiology of sepsis include Toll-like, C-type lectin, RIG-1-like and also Nod-like receptors, which are involved in the formation of the inflammasome, crucial for the maturation of some pro-inflammatory cytokines. Bacterial superantigens have evolved to exploit host MHC class II and T cell receptors (normally considered part of the adaptive immune response) as innate PRRs to propagate a so-called 'cytokine storm', while synergy between different microbial ligands and host-derived alarmins can augment the inflammatory response still further through as yet poorly understood interactions. The host pro-inflammatory response results in the characteristic features of inflammation: rubor, calor, dolor, and tumor. We will review herein the key mediators of inflammation in sepsis, identifying their overlapping and intersecting roles in vascular changes in tone, endothelial permeability, coagulation and contact activation, leukocyte mobilisation and activation.

In cancer, therapies are targeted at 6 important pathways. In sepsis, there is ongoing controversy regarding the number and relative roles of pathways that are activated or repressed and which are important in the progression from health to death. Adding to complexity, there is interaction of pathways, there are differences in temporal pattern of up and down-regulation of pathways and there are different responses of pathways to therapies of sepsis. In this review, we define four key pathways of sepsis: (1) inflammation and immunity, (2) coagulation and fibrinolysis, (3) apoptosis, and (4) endocrine. Each of these pathways can impair endothelial function, a unifying aspect of the pathophysiology of sepsis. There are few studies of interactions of pathways except for the interacttion of inflammation/immunity with coagulation/fibrinolysis. Successful treatment of cancer requires that cancer therapies interrupt several key pathways of cancer. Accordingly, we suggest that successful treatment of sepsis will require therapies that interrupt several key pathways of sepsis. Perhaps the paucity of approved therapies for sepsis is related in part to the underevaluation of novel pathways, to lack of understanding of interactions of pathways and to lack of interruption of key pathways of sepsis.

Sepsis is still a serious threat, especially to patients hospitalized in intensive care units (ICUs). Despite advances in modern technology that lead to an improved outcome in individuals suffering from sepsis, clinicians must be cautious when the septic condition is suspected. Changes in the epidemiology, etiology and foci of sepsis, together with a rise of antimicrobial resistance in the causative agents responsible for sepsis, create a qualitatively new situation. Because the septic patient must be treated without delay, the diagnosis of sepsis is usually based on the clinical findings, the knowledge of epidemiological history and predisposing conditions. Traditional methods used in the diagnosis of sepsis must be employed and used in combination with novel approaches of diagnosis, such as the detection of DNA from pathogenic microorganisms in the sterile body fluids and routine measurements of procalcitonin levels in the serum. Since many septic patients are hospitalized in ICUs, complications associated with the development of multiple organ dysfunction/failure are important. Respiratory, circulatory and renal failures are the most frequent types of organ dysfunction in the ICU. Furthermore, secondary nosocomial infections develop in about 20-50% of ICU patients. Thus, facing sepsis is a significant challenge, even for an experienced clinician.

Gram-negative bacterial pathogens of humans have evolved a range of virulence factors to promote motility, attach to epithelial or endothelial cell surfaces, avoid host immune responses, activate or inactivate host cellular pathways and ultimately cause clinical disease. Gram-negative sepsis is a life-threatening complication of these events. This review discusses the virulence factors of common Gram-negative bacteria causing human sepsis with a focus on Neisseria meningitidis. Adherence, motility, colonization and cell entry involve bacterial pili, flagella and outer membrane proteins. Endotoxin (lipopoly-or lipo-oligosaccharide), other membrane components or exotoxins can be potent inducers of the host inflammatory cascade via innate receptor pathways. Capsular polysaccharides and outer membrane proteins can help the bacterium evade immune defenses. The role in pathogenesis of iron acquisition, bacterial secretion systems, quorum sensing, and biofilm formation is also reviewed. Through multiple genetic mechanisms leading to phase variation, Gram-negative bacteria can adapt to changing host and environmental conditions and selective pressures. Further, the antimicrobial resistance of Gram-negative bacteria driven by antibiotic use will continue to influence the clinical outcomes of Gram-negative sepsis in the coming years.

Sepsis is a very heterogeneous clinical syndrome broadly defined as the systemic host response to an infection. Until recently, the concept that mortality is the consequence of an uncontrolled hyperinflammatory response of the host was widely accepted. However, although some patients may die rapidly from septic shock accompanied by an overwhelming systemic inflammatory response syndrome triggered by a highly virulent pathogen, most patients survive the initial phase of sepsis, showing multiple organ failure days or weeks later. These patients often demonstrate signs of immune suppression rather than enhanced inflammation. As such, sepsis is now considered a misbalance between proinflammatory reactions (designed to kill invading pathogens but at the same time responsible for tissue damage) and anti-inflammatory responses (designed to limit excessive inflammation, but at the same time making the host more vulnerable for secondary infections). This chapter discusses key components of the pro- and anti-inflammatory response to sepsis and the regulation thereof.

Over the past two decades, it has become well accepted that sepsis exhibits two, oftentimes concomitant, inflammatory stages; a pro-inflammatory phase, referred to as the systemic inflammatory response syndrome (SIRS), and an anti-inflammatory phase, called the compensatory anti-inflammatory response syndrome (CARS). Considering that therapeutic interventions designed to attenuate the pro-inflammatory septic response have generally failed, much recent research has gone into understanding how and why septic patients display immunosuppressive characteristics, what the significance of septic immunosuppression may be and if there exists any therapeutic targets within the CARS. Herein, we describe the potential mechanisms of the immunosuppressive/CARS phase of sepsis by discussing what anti-inflammatory agents, receptors and cell populations are currently believed to contribute to CARS.

Severe sepsis and septic shock are frequent causes of ICU admission, commonly encountered complications during the course of hospitalization, and among the most common causes of death in the noncoronary ICU. Dr. Roger C. Bone was a pioneer in our struggles to improve the early recognition and management of severe sepsis and septic shock. Through his leadership and guidance, great strides were made to develop a uniform definition and to ensure the comparability of clinical research trials to evaluate new therapeutic strategies and antimediator agents. Dr. Bone also helped shape our understanding of the various stages or physiologic alterations that occur in the septic patient which also drove forward the development of new therapeutic strategies. This chapter briefly reviews the impact Roger Bone has had on our current understanding and approach to the septic patient.

Bacteria live almost exclusively in communities with other microorganisms, and often in association with multicellular hosts. These communities are capable of maintaining complex structural and functional stability over time, and exhibit fascinating properties of resiliency in response to environmental changes. This is a result of interactions between microbes and the environment and amongst members of the community. A multitude of chemical interactions occur in microbial communities where primary and secondary metabolites contribute to a wealth of interactions between organisms. The chemicals include a variety of nutrients, toxic or neutral metabolic byproducts, antibiotics, and cell-cell signaling molecules. These chemical and physical signals facilitate microbial relationship that can be competitive, cooperative or neutral, and thus are responsible for determining community structure. In turn, the surrounding community changes the microenvironment of individual cells who respond to chemical and environmental cues in a combinatorial manner. Current laboratory understanding of the genetics and mechanisms of interactions between microbes has the power to help us understand how complex microbial communities behave in the natural environment. In this chapter we review the current understanding of microbial communication, from the genetic and molecular aspects, to our current understanding of their ecological role.