Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA

Abstract

Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively de ned relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a novel cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the latent-lytic switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture, which impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 was su cient to trigger virus reactivation from latency thereby identifying it as a readily drugable master regulator of the herpesvirus latent-lytic switch.Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders like myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and Long-COVID.

Viral and Host Small RNA Response to SARS-CoV-2 Infection

“…It will be interesting to find out whether miR-210-3p and miR-30-5p miRNAs are also downregulated in COVID-19 patients because their downregulation could lead to reduced targeting of the SARS-CoV-2 genome, thus, diminishing their antiviral effect. In addition, a recent study showed that herpesviruses can downregulate multiple miR-30 family members to induce type I interferon response, which is necessary for the latency and reactivation of the virus [33]. Thus, the involvement of miR-30 family members in the host immune response to SARS-CoV-2 infection deserves further study in the future.…”

“…In addition, we found that both miR-30b-5p and miR-30c-5p were among the significantly downregulated miRNAs in the second plasma dataset of COVID-19 patients [14], and miR-30a/c/d/e-5p were present at high levels in the upper respiratory tract [19]. Therefore, miR-30-5p may be a host miRNA that can respond to SARS-CoV-2 infection and may have antiviral effects or be involved in the host immune response [33].…”

miRNAs from Plasma Extracellular Vesicles Are Signatory Noninvasive Prognostic Biomarkers against Atherosclerosis in LDLr-/-Mice

“…U6 is stable, abundant, highly conserved, and ubiquitous in eukaryotic cells. So, we choose U6 snRNA as an internal reference gene [ 27 , 28 ].…”

“…The miRNAs were obtained from extracellular vesicles in plasma using Express miRNA Extraction Kit (Tissue and cell). All-in-One First-Strand cDNA Synthesis kit (Haigene Biotech, Haerbin, China) was used for reverse transcription for total RNAs using U6 snRNA as an internal reference gene [27,28]. All samples were normalized to internal control, and fold changes were calculated through relative quantification.…”

Transcriptomics and RNA-Based Therapeutics as Potential Approaches to Manage SARS-CoV-2 Infection

“…In contrast to siRNAs, miRNAs are single-stranded RNAs with a length of 19–25 nucleotides [ 152 ] that can regulate not only one target, but may have different targets [ 153 , 154 ]; nevertheless, both noncoding RNAs share a similar mechanism of action through their association with RISC and Dicer for post-transcriptional inhibition of mRNA [ 155 , 156 ]. Such miRNAs have shown to play key roles during human diseases such as cancer [ 157 , 158 ] and in infectious diseases [ 159 , 160 ].…”