Extracellular vesicles miRNA cargo induces inflammation during chlamydial infection

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ABSTRACT Chlamydia trachomatis is the most common sexually-transmitted bacterial infection in the world, and is especially prevalent among adolescents and young adults. A major consequence of infection is persistent inflammation and evolving damage to the reproductive organs, which in females can result in severe pelvic inflammatory disease and infertility. Several studies have shown the role for innate immune cells, CD8 T cells and inflammatory signaling pathways (IFN-β, IL-1β, and TNF-α,) in disease outcome. Our long-term goals are to identify how Chlamydia infection impacts host cellular processes to facilitate bacterial replication and how these interactions may result in disease. Previous reports indicated release of extracellular vesicles (EVs) during infections and have been shown to contain DNA, RNA, miRNA, protein, and microbial components. Determining EVs relevance in host-pathogen interactions is at an early stage of investigation and more work is needed to understand the biological relevance of EVs during infection. The bigger questions that have not been answered in the field of bacterial infections or in EV biology are: (1) Do the EVs impact immune cell function and inflammatory response, (2) Does the release of EVs help in bacterial invasion, (3) What is the role of EVs in the disease outcome, and (4) Does the composition of EVs vary with the type of pathogen?. Understanding these questions will determine EVs role in host defense and disease outcome. Our preliminary data clearly shows EVs release from Chlamydia-infected cells, and presence of miRNA cargo in EVs. To the best of our knowledge we are the first to show that EVs released during Chlamydia infection contain miRNAs. Our proposal is to determine the role of EV-miRNA cargo in inflammation and disease outcome and delineate their role in bacterial invasion. Based on our preliminary data we hypothesize that EV-miRNAs are involved in the induction of inflammation and pathology during Chlamydia infection. We test our hypothesis with two specific aims: (1) Determine the role of EV-associated miRNAs in inflammation and TLR7 activation during Chlamydia infection and (2) Identify the role of EVs in a mouse model of Chlamydia infection. Insight into the role of EV-associated miRNAs is impactful in terms of understanding the overall process of inflammatory response to infection. Furthermore, defining the in vivo function of EV-associated miRNAs is innovative and novel for studies related to Chlamydia infection. Completion of our high risk and high reward proposal will determine whether EVs induce inflammation via TLR7 during Chlamydia infection and will also enhance general understanding of EV biology. Insight into mechanisms involved in bacterial survival, inflammation and immune response would help in vaccine development and possibly therapeutic options.