Cellular and Kaposi’s sarcoma-associated herpes virus microRNAs in sepsis and surgical trauma

Abstract

Once a patient is in septic shock, survival rates drop by 7.6% for every hour of delay in antibiotic therapy. Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and triage. Here, we study the potential roles of a panel of cellular and viral miRNAs as sepsis biomarkers. We performed genome-wide microRNA (miRNA) expression profiling in leukocytes from septic patients and nonseptic controls, combined with quantitative RT-PCR in plasmas from two cohorts of septic patients, two cohorts of nonseptic surgical patients and healthy volunteers. Enzyme-linked immunosorbent assay, miRNA transfection and chromatin immunoprecipitation were used to study the effects of Kaposi sarcoma herpes virus (KSHV) miRNAs on interleukin's secretion. Differences related to sepsis etiology were noted for plasma levels of 10 cellular and 2 KSHV miRNAs (miR-K-10b and miR-K-12-12*) between septic and nonseptic patients. All the sepsis groups had high KSHV miRNAs levels compared with controls; Afro-American patients had higher levels of KSHV-miR-K12-12* than non-Afro-American patients. Both KSHV miRNAs were increased on postoperative day 1, but returned to baseline on day 7; they acted as direct agonists of Toll-like receptor 8 (TLR8), which might explain the increased secretion of the IL-6 and IL-10. Cellular and KSHV miRNAs are differentially expressed in sepsis and early postsurgical patients and may be exploited for diagnostic and therapeutic purposes. Increased miR-K-10b and miR-K12-12* are functionally involved in sepsis as agonists of TLR8, forming a positive feedback that may lead to cytokine dysregulation.

Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding

“…Finally, to demonstrate that miR-29a binds directly to TLR8 we transfected human DCs with Flag-TLR8 plasmid. The transfected cells were incubated with miR-29a or miR-155 or U6 (negative controls) (39) and immunoprecipitation and RNA-IP was performed 72 hrs post-transfection. As shown in Fig.…”

Patients After Splenectomy: Old Risks and New Perspectives

“…Interestingly, Tudor et al observed that two KSHV miRNAs are up-regulated in the blood of septic and postoperative patients (52). It is well known that Kaposi Sarcoma (KS) is associated with immunosuppressive states, especially that of AIDS (59).…”

“…The most intriguing fact was that 2 of these miRNAs are viral miRNAs (miR-K-12-10b and miR-K-12-12*) belonging to the genome of Kaposi sarcoma-associated herpesvirus (KSHV). These two miRNAs are upregulated in sepsis (52). In a review article Benz et al presents all circulating miRNAs discovered and recommended as sepsis biomarkers (53).…”

“…The role of KSHV miRNAs is still debated. Tudor et al proposed that these miRNAs are agonist of TLR8 and are part of a positive feedback mechanism that induces an altered cytokine secretion (52).…”

The Inescapable Influence of Noncoding RNAs in Cancer

“…Next, Dr. George A. Calin (University of Texas MD Anderson Cancer Center, Houston, TX) presented his findings that cellular and Kaposi’s associated Herpesvirus (KSHV) miRNAs are differentially expressed in the plasma of sepsis and early postsurgical patients. In particular, virally encoded miR-K-10b and miR-K-12-12* expression was increased immediately following surgery, suggesting that the levels of the KSHV’s miRNAs in plasma can be used as biomarkers of sepsis(34). He also discussed how a novel lncRNA, CCTA2, transcribed from the 8q24, promoted metastasis and chromosomal instability in colon cancer(35).…”