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 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.

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.

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 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.

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.

In the emerging field of synthetic biology, a central goal is to reliably engineer bacteria to respond to environmental signals according to a pre-determined genetic program. The sensor systems and genetic circuitry inside bacteria are the 'eyes' and 'brain' of a new class of biotechnological applications in which bacteria are used as living, self-replicating computers that can beneficially interact with the physical world. These engineered gene networks are constructed by extracting natural sensor systems and other genetic parts from multiple organisms and recombining them into novel configurations. This chapter is a how-to guide. It describes several strategies for engineering new bacterial sensor systems and synthetic gene networks that are capable of sensing a desired stimulus and generating interesting dynamical or pattern-forming responses. We also provide specification sheets describing many two-component and quorum-sensing systems, focusing on the information that one needs to know in order to use them for engineering applications.

Magnetotactic bacteria orient and migrate along geomagnetic field lines. Magneto-aerotaxis increases the efficiency of respiring microaerophilic cells to efficiently find and maintain a position at a preferred microaerobic oxygen concentration. Magneto-aerotaxis could also facilitate access to regions of higher nutrient and electron acceptor concentration via periodic excursions above and below the preferred oxygen concentration level.

Recently, the list of ubiquitous bacterial secondary messengers which include cAMP and ppGpp has been extended by 3',5'-cyclic diguanylic acid (c-di-GMP). C-di-GMP metabolism is tuned by the tightly controlled activity of diguanylate cyclases and c-di-GMP-specific phosphodiesterases. As c-di-GMP-metabolizing enzymes are not only found frequently in bacterial genomes, but also are often numerous in individual genomes, the c-di-GMP metabolic network is highly complex whereby signaling specificity is adjusted on the level of expression, enzymatic activity, protein localization and, most likely, receptor affinity. The targets of c-di-GMP, which include protein and RNA receptors, are subsequently being unraveled. Besides the transition between sessility and motility, probably the most ancient regulatory control of bacterial behavior by c-di-GMP, many more phenotypes such as virulence are affected by c-di-GMP. However, the exact molecular mechanisms of c-di-GMP action remain to be discovered.

During the course of an infection, a pathogenic bacterium has to sense the environment and adjust its gene expression appropriately. One such environmental cue is the difference in temperature inside and outside the host. RNA thermosensors are structures that can respond to differences in temperature by altering their conformation and thereby allowing/preventing binding of the ribosome to the translational start site. This chapter discusses different types of RNA thermosensors in general and RNA thermosensors known to control virulence gene expression in particular.

Antimicrobial peptides (AMPs) form a crucial part of human innate host defense, especially in neutrophil phagosomes and on epithelial surfaces. Bacteria have a variety of efficient resistance mechanisms to human AMPs, such as efflux pumps, secreted proteases, and alterations of the bacterial cell surface that are aimed to minimize attraction of the typically cationic AMPs. In addition, bacteria have specific sensors that activate AMP resistance mechanisms when AMPs are present. The prototypical Gram-negative PhoP/PhoQ and the Gram-positive Aps AMP-sensing systems were first described and investigated in Salmonella typhimurium and Staphylococcus epidermidis, respectively. Both include a classical bacterial two-component sensor/regulator system, but show many structural, mechanistic, and functional differences. The PhoP/PhoQ regulon controls a variety of genes not necessarily limited to AMP resistance mechanisms, but apparently aimed to combat innate host defense on a broad scale. In contrast, the staphylococcal Aps system predominantly upregulates AMP resistance mechanisms, namely the D-alanylation of teichoic acids, inclusion of lysyl-phosphati-dylglycerol in the cytoplasmic membrane, and expression of the putative VraFG AMP efflux pump. Notably, both systems are crucial for virulence and represent possible targets for antimicrobial therapy.

The important human pathogen Staphylococcus aureus is able to satisfy its nutrient iron requirement by acquiring heme from host hemoglobin in the context of infection. However, heme acquisition exposes S. aureus to heme toxicity. In order to detect the presence of toxic levels of exogenous heme, S. aureus is able to sense heme through the heme sensing system (HssRS) two-component system. Upon sensing heme, HssRS directly regulates the expression of the heme-regulated ABC transporter HrtAB, which alleviates heme toxicity. Importantly, the inability to sense or respond to heme alters the virulence of S. aureus, highlighting the importance of heme sensing and detoxification to staphylococcal pathogenesis. Furthermore, potential orthologues of the Hss and Hrt systems are found in many species of Gram-positive bacteria, a possible indication that heme stress is a challenge faced by bacteria whose habitats include host tissues rich in heme.