Chikungunya virus (CHIKV) is an emerging arthropod-borne virus for which there are no vaccines or therapeutics. Infection with CHIKV can lead to severe and chronic arthralgia. CHIKV displays wide tropism targeting the epithelial, endothelial, and myeloid compartments. The innate immune system is the first line of defense. Viral nucleic acids are sensed, leading to the activation of classical type I interferons (IFN) which induces hundreds of interferon stimulate genes (ISGs). In response, viruses including CHIKV, encode antagonists of interferon signaling to attenuate these antiviral activities. In addition, there is a growing list of basally expressed, effector proteins known as intrinsic factors, which play roles in controlling infection. Altogether, it is clear that there are additional antiviral regulators that play important roles in controlling infection, and in particular, there is less known about antiviral responses in non-hematopoietic cells which are the major targets of CHIKV. Moreover, while much of our understanding of antiviral effectors has been focused on antiviral proteins, there is an emerging literature that suggests that noncoding (nc)RNAs can also play an important role in controlling infection. Long noncoding RNAs (lncRNAs) are an emerging and abundant subclass of ncRNAs that are known to dynamically regulate transcription and translation and can control innate immune responses. The contribution of lncRNAs to innate defense downstream of viral infection is poorly understood, and there is nothing known during CHIKV infection. We hypothesize that lncRNAs play a regulatory role in the control of innate antiviral immunity against CHIKV. Therefore, we will characterize the role of lncRNAs in the innate immune response to CHIKV infection. We are beginning our studies in endothelial cells, as these are a target during infection and little is known about antiviral defenses in this tissue. In addition, we are particularly interested in cytoplasmic lncRNAs as there is less known about their functions, and CHIKV replication occurs exclusively in the cytoplasm. To achieve these goals, our specific aims will (1) Characterize lncRNAs that control CHIKV infection and (2) define the mechanism of action of one antiviral lncRNA we have validated (chikvLNC)
Due to the dearth of antiviral strategies, there is an urgent need for the discovery of novel mechanisms by which we can overcome viral pathogens, in particular against emerging viruses. This project will uncover the functional roles of long noncoding RNAs that impact Chikungunya virus infection.
