Mechanisms and regulation of the gene-expression response to sepsis

Abstract

Sepsis is defined as the systemic inflammatory response of the human host that is triggered by an invading pathogen. Despite tremendous advances in both our knowledge of and treatment strategies for this syndrome, sepsis remains among the major causes of morbidity and mortality in children worldwide. Thus, we hypothesize that an improved mechanistic understanding obtained via basic and translational science will continue to identify novel therapeutic targets and approaches. As a result, given the central importance of the alterations in gene expression in regulating the human host's physiologic response to a pathogen, we review the complex factors-genetics, transcriptional expression, and epigenetics-that regulate unique gene-expression patterns in pediatric sepsis and septic shock. We anticipate that emerging data from genetic, genomic, and other translation studies in pediatric sepsis will advance our biological understanding of this response and undoubtedly identify targets for newer therapies.

Figure 1

Following exposure to an acute infectious insult, the pediatric patient mounts an immune response to defend against microbial invasion. Pathogen recognition receptors on local and peripheral leukocytes are activated by the presence of microbial products. Leukocyte activation results in transcription of genomic DNA to messenger RNA that leads to protein production (e.g. interleukins, acute phase reactants). Isolation of nucleic acids permits high throughput sequencing of DNA and expression profiling of mRNA via array-based analyses. The presence of altered DNA sequences (e.g. polymorphisms) and patterns of mRNA production can then be correlated with a clinical outcome such as mortality to gain insight into genetic influences on and involved pathways in this complex pathobiology.

Figure 2

Cartoon depiction of the relationship between DNA (chromatin) and interacting nucleosomes containing histone proteins. Histones can undergo post-translational modifications (e.g. methylation patterns) that alter the ability of transcriptional activation factors to access promoter regions. Depending on the pattern, these “methylation signatures” can result in either increased (e.g. me²H3K27) or repressed (e.g. me³H3K4) gene expression.