Abstract
In sepsis, dysregulated immune responses to infections cause damage to the host. Previous studies have attempted to capture pathogen-induced leukocyte responses. However, the impact of mediators released after pathogen-leukocyte interaction on endothelial cells, and how endothelial cell responses vary depending on the pathogen-type is lacking. Here, we comprehensively characterized the transcriptomic responses of human leukocytes and endothelial cells to Gram negative-bacteria, Gram positive-bacteria, and fungi. We showed that whole pathogen lysates induced strong activation of leukocytes but not endothelial cells. Interestingly, the common response of leukocytes to various pathogens converges on endothelial activation. By exposing endothelial cells to leukocyte-released mediators, we observed a strong activation of endothelial cells at both transcription and protein levels. By adding IL-1RA and TNF-α antibody in leukocyte-released mediators before exposing to endothelial cells, we identified specific roles for IL-1 and TNF-α in driving the most, but not all, endothelial activation. We also showed for the first time, activation of interferon response by endothelial cells in response to leukocyte-released mediators, independently from IL-1 and TNF-α pathways. Our study therefore, not only provides pathogen-dependent transcriptional changes in leukocytes and endothelial cells during infections, but also reveals a role for IFN, together with IL1 and TNFα signaling, in mediating leukocyte-endothelial interaction in infections.
Highlights
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [1]
peripheral blood mononuclear cells (PBMCs) were isolated from eight healthy individuals and stimulated by five types of pathogens: Pseudomonas aeruginosa (P. aeruginosa), Streptococcus pneumoniae (S. pneumonia), Mycobacterium tuberculosis (M. tuberculosis), Candida albicans (C. albicans), and Aspergilus Fumigatus (A. fumigatus) for 4 and 24 h
We applied an integrative genomics approach to characterize the global transcriptional response of leukocytes and endothelial cells to many sepsis-causing pathogens, but to identify important molecular pathways induced during leukocyte-endothelium cross-talk in regulating overall immune response in sepsis
Summary
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. Despite advances in early recognition, sepsis affects around 30 million people worldwide every year and has a mortality rate of 20–40% [2]. Sepsis is known to be a heterogeneous syndrome with various outcomes that depend on pathogenic characteristics as well as on host susceptibility. It is known that an interaction between innate immune cells and endothelial cells is central for the pathogenesis of sepsis, with recognition of infectious pathogens as a first step toward full activation of inflammation. Failure in properly regulating these cellular responses and interactions often leads to multiple organ failure, and even mortality in sepsis patients
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