Abstract
Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and treatment. A large panel of small non-coding microRNAs was reported to modulate the immune response in sepsis but have not been tested in clinical practice. Large-scale identification of microRNA networks in sepsis might reveal a new biological mechanism that can be also targeted by gene therapy. Therefore, the main objective of this study is to perform a comparison of the miRNA network between septic patients and healthy controls. We used the previously measured levels of expression of 16 different circulating human and viral microRNAs in plasma from 99 septic patients and 53 healthy controls. We used three different computational methods to find correlations between the expressions of microRNAs and to build microRNA networks for the two categories, septic patients and healthy controls. We found that the microRNA network of the septic patients is significantly less connected when compared to miRNA network of the healthy controls (21 edges vs 52 edges, P < 0.0001). We hypothesize that several microRNAs (miR-16, miR-29a, miR-146, miR-155, and miR-182) are being sponged in sepsis explaining the loss of connection in the septic patient miRNA network. This was specific for sepsis, as it did not occur in other conditions characterized by an increased inflammatory response such as in post-surgery patients. Using several target prediction instruments, we predicted potential common sponges for the miRNA network in sepsis from several signaling pathways. Understanding the dynamics of miRNA network in sepsis is useful to explain the molecular pathophysiology of sepsis and for designing therapeutic strategies that target essential components of the immune response pathways.
Highlights
Sepsis remains a major medical problem; each year 210,000 people die of sepsis in the United States, while diagnostic and therapeutic methods remain unreliable [1]
Clinical data and blood samples were obtained after the participants gave the written informed consent, according to protocols approved by the Fundeni Clinical Hospital (FCH) Ethics Committee and MD Anderson Cancer Center (MDACC) Institution Review Board
By comparing miRNA networks in healthy controls to miRNA networks in septic patients, we observed that the septic miRNA networks are less connected (Figs 1–3)
Summary
Sepsis remains a major medical problem; each year 210,000 people die of sepsis in the United States, while diagnostic and therapeutic methods remain unreliable [1]. Crucial steps were made in understanding the pathophysiology of sepsis and new biomolecular mechanisms were unveiled [2,3,4,5] This progress neither improves the diagnosis, nor the therapy, the outcome remains unchanged. MiRNAs are released outside the cells into plasma and remain in circulation in a stable form, being resistant to endogenous and exogenous RNAs activity, acute pH and extreme temperature conditions [10, 11]. This makes miRNA expression pattern to be detected in the peripheral blood of septic patients [7]
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