The Modulation of Innate Immunity by Cellular and Viral Noncoding RNAs

Growing evidence demonstrates that endogenous and viral non-coding RNAs possess the ability to alter innate immunity and inflammatory responses. For example, endogenous non-coding RNAs can be recognized by pattern recognition receptors to trigger innate immune activation and inflammation. Many positive sense RNA viruses also produce non-coding RNAs. This includes Dengue virus 2 (DENV-2), which produces subgenomic flaviviral RNA (sfRNA), capable of inhibiting the innate immune system. We identified DENV-2 sfRNA in mosquito saliva using three different methods: northern blot, RT-qPCR and RNA sequencing. Salivary sfRNA is protected in detergent-sensitive compartments, which we hypothesize are extracellular vesicles. Infection with mosquito saliva containing higher sfRNA levels results in higher virus infectivity in human Huh7 cells and human primary dermal fibroblasts. Transfection of sfRNA prior to DENV 2 infection inhibited type I and III interferon induction and signalling and enhanced viral replication. Therefore, we posit that sfRNA present in salivary extracellular vesicles is delivered to cells at the biting site to inhibit innate immunity and enhance DENV-2 transmission. Many immunogenic endogenous RNAs are RNA polymerase III transcripts (RNAP III) which when dysregulated trigger the innate immune system. In the second part of this thesis, we show that the RNA binding protein YBX1 prevents the activation of inflammation in the absence of exogenous immune stimuli. Notably, YBX1 interacts with many RNAP III transcripts, including tRNAs and Y RNAS. YBX1 depleted cells display the transcriptional upregulation of ISGs including OAS-1, IFITM2, and pro-inflammatory cytokines like IL6 and LIF. Inhibition of RNAP III transcription via POL3RF and BRF1 knock down dampens the activation of innate immunity observed with YBX1 loss. Thus, we posit that YBX1 maintains cellular homeostasis by preventing endogenous RNAP III transcripts from aberrantly triggering the innate immune system.

Name thesis:degree_name

Biochemistry and Molecular Biology (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2025

Author dc:creator

• Strilets, Tania Irene 1998-

Advisor dc:contributor.advisor

• Garcia-Blanco, Mariano (rxh8rw@virginia.edu)

Committee members dc:contributor.committeemember

• Nir, Guy (niguy@utmb.edu)
• Leiman, Petr (pgleiman@utmb.edu)
• Wang, Tina (ti1wang@utmb.edu)
• Lambowitz, Alan (lambowitz@austin.utexas.edu)

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12884

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12884