Review
Host–pathogen interactions in sepsis

https://doi.org/10.1016/S1473-3099(07)70265-7Get rights and content

Summary

Sepsis is a major health problem. The concept that sepsis mortality is the result of an uncontrolled hyperinflammatory host response has recently been challenged. It is now widely thought that the host response to sepsis involves many, concomitant, integrated, and often antagonistic processes that involve both exaggerated inflammation and immune suppression. Several novel mediators and pathways have been shown to play a part. Moreover, evidence is accumulating that microbial virulence and bacterial load contribute to the host response and the outcome of severe infections. A complex and dynamic interaction exists between pathogens and host immune-defence mechanisms during the course of invasive infection. Some pathogens have acquired the capacity to communicate with each other and sense the host's vulnerabilities. Bidirectional signals are detectable at the critical interface between the host and microbial invaders. The outcome of this interaction determines the fate of the host at the outset of the septic process. A formidable array of innate and acquired immune defences must be breached if a pathogen is to successfully disseminate and cause severe sepsis and septic shock. This Review summarises current knowledge of microbial pathogenesis and host–pathogen interactions during sepsis and the ensuing development of potential therapeutics.

Introduction

Sepsis is the second most common cause of death in non-coronary intensive care units and the tenth leading cause of death overall in high-income countries.1, 2 During the past two decades, the incidence of sepsis has increased annually by 9% to reach 240 per 100 000 population in the USA by 2000.3 Until very recently, the prevailing concept of the pathogenesis of sepsis was that mortality is the consequence of an uncontrolled hyperinflammatory, predominantly cytokine-mediated, response of the host. In part because of the failure of dozens of clinical trials that assessed anti-inflammatory agents in severe sepsis, and in part because of growing insights from preclinical models that more closely resemble clinical sepsis than originally used in this area of research, current knowledge of host–pathogen interactions and their consequences in sepsis have increased tremendously. Additionally, virulence and bacterial load are now thought to contribute to the host response and the outcome of severe infections. This Review summarises recent advances in the understanding of microbial pathogenesis and host–pathogen interactions during severe sepsis. The increased insights into the pathogenesis of sepsis have led to the design and development of novel therapies, some of which have reached the clinical phase of assessment.

Section snippets

Causative microorganisms

Whereas, until the early 1980s, Gram-negative bacteria were the predominant organisms that caused sepsis, the incidence of Gram-positive sepsis has steadily increased. In a large survey done in 2000 in the USA, Gram-positive bacteria accounted for 52·1% of sepsis cases, Gram-negative bacteria 37·6%, polymicrobial infections 4·7%, anaerobes 1·0%, and fungi 4·6%; the greatest relative changes were seen in the incidence of Gram-positive and fungal infections.3 The increasing frequency of fungal

Historical perspective

The assumption that sepsis is the consequence of an overwhelming inflammatory reaction of the patient to microorganisms was widely accepted for many years. This theory was based on studies in animals infused with large doses of bacteria or bacterial products. Such infusions result in a brisk systemic release of an array of inflammatory mediators, many of which have been found to be directly responsible for the death of the host, including the prototypic proinflammatory cytokines tumour necrosis

Conclusions

Sepsis remains a major challenge for clinicians. Microbial pathogens have proven to be more ingenious in avoiding and altering host defences than we originally anticipated. The capacity to subvert host defences, communicate with each other, and cooperate during the invasive phase of infection reveals a level of sophistication in microbial pathogenesis that is only beginning to be fully appreciated. Recent insights into the early interactions between pathogens and the host may pave the way for

Search strategy and selection criteria

Data for this Review were identified by searches of PubMed and references from relevant articles. Articles were also identified through searches of the extensive files of the authors. Search terms used were “bacterial virulence”, “quorum sensing”, “pathogenicity islands”, “pathogenesis of sepsis”, “bacterial toxins”, “endotoxin”, “superantigens”, “Toll-like receptors”, “sepsis AND coagulation”, “sepsis AND apoptosis”, and “sepsis AND complement”. Only English language articles were

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