HUMAN IMMUNE RESPONSE TO INJURY AND INFECTIONS

Inflammation is a common mechanism in human diseases. For nearly two decades, we study the human immune-inflammatory response to severe injury and infections, and our goal is to improve the systems level understanding of the key regulatory elements in inflammation, and their relative roles and importance that drive the host’s response to serious injury and infection. This project was initiated in 2001 by the Inflammation and the Host Response to Injury Glue Grant (http://www.gluegrant.org/),  a large-scale collaborative research program supported by the National Institute of General Medical Sciences, and later supported by several other grants from NIH and DARPA. 

PROJECT: HUMAN  IMMUNE RESPONSE TO INJURY AND INFECTIONS

A network-based analysis of systemic inflammation in human

Pathway analysis of representative genes involved in innate immunity. A prototypical inflammatory cell was constructed from 292 representative genes involved in inflammation and innate immunity. Genes for which the expression statistically increased from baseline are coloured red, those for which expression decreased are shown in blue. a, Composite changes in apparent expression over 24 h, identifying nodes and interactions. b, Temporal changes in apparent expression. The response to endotoxin administration in blood leukocytes can be viewed as an integrated cell-wide response, propagating and resolving over time.
We presented a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans

A genomic storm in critically injured humans

A genomic storm: Refining the immune, inflammatory paradigm in trauma. (A) The current paradigm explains complications of severe injury as a result of excessive proinflammatory responses (SIRS) followed temporally by compensatory anti-inflammatory responses (CARS) and suppression of adaptive immunity. A second-hit phenomenon results from sequential insults, which leads to more severe, recurrent SIRS and organ dysfunction. (B) The proposed new paradigm involves simultaneous and rapid induction of innate (both pro- and anti-inflammatory genes) and suppression of adaptive immunity genes. Complicated recoveries are delayed, resulting in a prolonged, dysregulated immune–inflammatory state.
Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected “genomic storm.” In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory anti-inflammatory responses, as well as in the  suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. The similarities in gene expression patterns between different injuries reveal an apparently fundamental human response to severe inflammatory stress, with genomic signatures that are surprisingly far more common than different. Based on these transcriptional data, we propose a new paradigm for the human immunological response to severe injury.
 
 
Dr. Wenzhong Xiao is in charge of this project.