Once a patient is in septic shock, the survival rate drops by 8% for every hour of delay in appropriate therapy. Unfortunately, there is a lack of reliable early diagnostic and prognostic tools to guide clinical decisions in the care of septic patients. Therefore, there is a clear need to improve the early diagnosis and treatment for sepsis. A strategy to achieve these goals is to use new types of genes that have been identified to be involved in human diseases within the last decade, namely microRNAs (miRNAs). They are short RNA transcripts that are not translated into proteins; they directly regulate the expression of sets of proteins; and they are differentially expressed in all types of diseases analyzed to date. Our recent data identified cellular miRNAs and viral miRNAs coded by Kaposi Sarcoma Herpes Virus (KSHV) as being involved in an important signaling pathway in sepsis, by direct binding to Toll-Like Receptors (TLRs) and consequently inducing interleukin-6 and interleukin-10 secretion. Therefore, we hypothesize that viral-miRNAs (miRNA encoded by non-human genomes), along with cellular miRNAs, may be biomarkers for early detection, survival prediction, and therapeutic targets (when overexpressed) or drugs (when downregulated) to be used in early sepsis. Furthermore, we propose that viral miRNAs not only activate human TLR8 (mouse Tlr7) signaling to amplify inflammation in sepsis, but also contributes to the pathogenesis of septic shock by targeting a common set of immune genes that are normally regulated by cellular miRNAs, a phenomenon we named ?target mimicry?. To test these hypotheses, we have brought together a team of complementarily skilled scientists and clinicians with well-established expertise in miRNA function, sepsis mechanisms, patient care and mouse models. Our focus is on three aims: the first is to validate the cellular and viral miRNA signatures initially identified by us in sepsis using a prospective clinical study. Second, we will evaluate the functional effects of differentially expressed miRNAs in sepsis pathogenesis, including the KSHV-miRNAs as direct agonists of TLRs in human cells, and the targeting of sepsis-related coding genes and to prove the ?target mimicry? between viral miRs and cellular miRs. Then, we will test the functional roles of TLR7 and TLR8 in sepsis pathogenesis including the KSHV-miRNAs as direct agonists of these TLR?s using knock-out mouse models. Third, we will also examine candidate miRNAs (both viral and cellular) with clear pathogenic function as new therapeutic targets by infusing the antagonists (antago-miRs) or miR-mimics in mouse models of sepsis. This research will pioneer the measurements of a panel of plasma KSHV and cellular miRNAs as an early diagnostic and/or prognostic test for sepsis. A role of KSHV miRNAs in sepsis may contribute to the geographic and racial variations in sepsis mortality. After the withdrawal of drotrecogin alfa from the market, there is currently no FDA approved specific therapy for sepsis, and this research will identify new molecular targets for the development of new therapeutic strategy in sepsis to saved a large number of lives.