24 Chapter 2 alarmins), which can further stimulate PRRs. Immune suppression is characterized by massive apoptosis and thereby depletion of immune cells, reprogramming of monocytes and macrophages to a state of a decreased capacity to release pro-inflammatory cytokines and a disturbed balance in cellular metabolic processes. (C) Sepsis is by definition a disease with organ failure. The clinical manifestation can be heterogeneous. Clinicians use physical examination, laboratory testing and imaging techniques to determine the severity and origin of organ failure. Antimicrobial treatment is aimed to eliminate the causative pathogen, where supportive care is aimed to restore organ function. Abbreviations: ARDS: acute respiratory distress syndrome, AKI: acute kidney injury, DAMPs: danger-associated molecular patterns, DNA: deoxyribonucleic acid, HMGB1: high-mobility group box-1 protein, HSPs: heat shock proteins, LPS: lipopolysaccharide, LTA: lipoteichoic acid, PAMPs: pathogen-associated molecular patterns, PPRs: pattern recognition receptors, RNA: ribonucleic acid Pathogens and infection sites A successful pathogen must attach to and cross the mucosal barrier, escape the host defense system and multiply to ensure its own survival. All invading microorganisms with a sufficient load and virulence can cause sepsis. However, several pathogens are well known for their impressive arsenal to attack the host. In a point-prevalence study entailing 14,000 Intensive Care Units (ICUs) patients in 75 countries 62% of positive isolates were gram-negative bacteria, versus 47% gram-positive and 19% fungal [4]. The most common gram-negative isolates in sepsis patients are Escherichia coli, Klebsiella sp. and Pseudomonas aeruginosa; the most frequent gram-positive organisms Staphylococcus aureus and Streptococcus pneumoniae [5, 6]. The incidence of fungal infections as the cause of sepsis is rising, which is problematic due to the associated increased mortality. The most common site of infection is the respiratory tract with 63.5% of the culture-positive infections in the ICU, followed by abdominal infections (19.6%), bloodstream infections (15.1%), renal or urinary tract infections (14.3%), skin infections (6.6%), catheter-related infections (4.7%), infections of the central nervous system (2.9%) and others [4]. Host recognition of pathogens The host can recognize molecular components of invading pathogens, called pathogenassociated molecular patterns (PAMPs), with specific receptors. Examples of key bacterial PAMPs are lipopolysaccharide (LPS, also known as endotoxin, a cell wall component of gram-negative bacteria), peptidoglycan, lipopeptides (constituents of many pathogens), lipoteichoic acid (a cell wall component of gram-positive bacteria), flagellin (factor in the mobility of bacteria) and bacterial DNA [7]. In the early response to infection, pathogens or more specifically PAMPs, are recognized by a limited number of specialized host receptors, known as pattern recognition receptors (PRRs). PRRmediated pathogen recognition is an important defense mechanism of the host against invading pathogens and results in upregulation of inflammatory gene transcription and initiation of innate immunity [2, 7, 8]. However, if the innate immune system fails to eradicate the pathogen, overstimulation of PRRs by a growing bacterial load can result in dysregulation of the host response, which then no longer benefits the host but causes tissue injury, organ dysfunction and progression to sepsis. A contributing factor herein is that PRRs can also be stimulated by endogenous molecules released by injured cells, so-called danger-associated molecular patterns (DAMPs or alarmins)[9]. Examples of
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