Genetic influence on bloodstream infections and sepsis

https://doi.org/10.1016/j.ijantimicag.2008.08.002Get rights and content

Abstract

Bloodstream infections (BSIs) are a major burden in health care today, associated with considerable morbidity, mortality and costs. They are either caused by direct influx of pathogens via devices into the blood (primary BSI) or by bacterial spillover from infected distant organs (secondary BSI). The recognition of invading microbes by sensing of conserved molecular patterns is pivotal for the host in staging an adequate immune response to eradicate the pathogen. Moreover, a balanced immune response is crucial to avoid over inflammation followed by additional damage to the host. This complex host response pattern is controlled by soluble proteins and cellular receptors, which have recently been found to contain substantial individual genetic variations. Single nucleotide polymorphisms have been shown to affect susceptibility to and the course of numerous diseases. A large number of genes and their products are involved in the host reaction to BSIs, and genetic variation in these molecules alters the frequency and course of these events. Here we summarise recent findings on genetic variations in molecules of the innate immune system and other systems as well as their connection with susceptibility to BSIs and sepsis and the way the host stages a beneficial response to infection.

Section snippets

Individual genetic variation and infection

Recent studies, particularly after elucidation of the human genome, have revealed that genetic variations of the individual have a major role in susceptibility to diseases, including those that are generally not viewed as inherited diseases. Many inherited diseases, such as cystic fibrosis or blood clotting disorders, are termed monogenetic diseases because one genetic variation causes a protein change that results in a lack of function and therefore creates a disorder state. In addition to

Bloodstream infections (BSIs) and host factors: general overview

BSIs are present when viable bacteria are diagnosed inside the vasculature and if they are proven by microbiological means. Pathogenicity and virulence are factors associated with the pathogen itself and are important in terms of the probability and severity of an infection [8]. Of course, prevention of bacteraemia by hygiene measures and early changing of indwelling catheters remains key to limiting BSIs and their consequences [9]. Moreover, early detection, identification and susceptibility

Host control of primary and secondary bloodstream infections

Systemic influx of bacteria or yeast through the lumen of a catheter (primary BSI) is potentially most dangerous as several levels of the normal defence system, such as the skin barrier and the innate immune system of the subcutaneous tissue, are bypassed by insertion of the catheter. Here the systemic reaction of the host to a given mass of bacteria or bacterial patterns, with cytokine release by blood leukocytes and responsive cells of the peripheral organs, will lead to systemic inflammation

Pathogen sensing and signal transduction

Pattern recognition receptors have recently been discovered and a concept has arisen focusing on microbial ‘patterns’ associated with pathogens. Numerous studies have been performed to link these receptors to disease phenotypes, although many of these were not specifically designed to identify risk factors for BSIs and it seems obvious that a risk factor for nosocomial infections itself should also be predictive of BSIs. TLRs are key cellular receptors for initiation of the inflammatory

Cytokine response

Cytokines play a major role both in innate immunity and in the organisation of an orchestrated response to local and generalised infections. In general there exists a distinction between pro- and anti-inflammatory cytokines. However, many have both properties, mainly depending on the time course of the events [14]. A number of variations in cytokine genes have been reported in gene association studies.

TNFα is a prototypical pro-inflammatory cytokine. Three promoter polymorphisms in the TNFα

Genetic variants in effectors related to the innate immune response

As pointed out earlier, the containment of localised infection is necessary to protect the host from generalised inflammation. Molecular systems in this context involve the coagulation system and vascular elements such as adhesion molecules and factors associated with the cellular response and therefore killing and eradication of pathogens. A close evolutionary relationship has been described for the coagulation system. This close relationship is frequently observed, since patients with severe

Conclusion

With the completion of the Human Genome Project and with large projects such as HapMap listing SNPs in public databases, one of the current tasks of biomedical research is to link this information of individual genetic variations with disease susceptibility. For BSIs, individual variations in the response pattern exist and currently several areas of genetic variations are being investigated, such as microbial recognition receptors, cytokines and coagulation. One of the goals of these studies is

Acknowledgments

RRS thanks the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)) for financial support.

Funding: No funding sources.

Competing interests: None declared.

Ethical approval: Not required.

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