Biology subjects

Trus, I.

Publications and source records attributed to Trus, I..

4 recordsLinked to original sources

bioRxiv2026

Persistent Japanese encephalitis virus infection in fetuses of an amplifying pig host affects virus genetic heterogeneity and drives transcriptional footprints in offspring

Japanese encephalitis virus (JEV) poses a global threat to public health. This study demonstrates that during fetal infection in natural amplifying hosts, pigs, the in utero environment is conducive to the emergence of new intra-host JEV variants. Transplacental and fetal infection in pigs with JEV resulted in the emergence of virus variants that at least partially resembled variants reported in field samples from JEV endemic regions. The JEV genetic heterogeneity acquired during fetal infection persisted in expelled fetal membranes and offspring. Like in fetuses, JEV mutations identified in afterbirth fetal membranes and offspring were previously reported in the field. Several selected fetal- and offspring-specific mutations that emerged during persistent in utero infection were stable during passage in cell culture. This comparative analysis with field-reported mutations, together with the stability of emerged mutations during serial passages, may suggest the potential for onward transmission of in utero-emerged JEV variants from infected fetal membranes or offspring. Exposure to JEV during fetal life also induced transcriptional footprints in blood cells and tonsils of live offspring, including alterations in pathways associated with epigenetic regulation and memory. Altogether, we generated new knowledge on JEV biology and pathogenesis in its natural amplifying hosts, pigs, during pregnancy. Our findings provide directions for future studies investigating pathways linking fetal infection to offspring and subsequent environmental dissemination, fetal infection as an additional source of JEV genetic diversification, and the mechanisms underlying molecular footprints and their long-term sequelae in JEV-affected offspring, including increased offspring susceptibility to zoonotic pathogens.

microbiology↗

bioRxiv2024

Endogenous ZAP is associated with altered global cellular gene expression during Zika virus infection

The zinc finger antiviral protein 1 (ZAP) has broad antiviral activity. ZAP is an interferon (IFN)-stimulated gene, which itself may enhance type I IFN antiviral response. In a previous study, Zika virus was identified as ZAP-resistant and not sensitive to ZAP antiviral activity. Here, we found that ZAP was associated with the inhibition of Zika virus in Vero cells, in the absence of a robust type I IFN system because Vero cells are deficient for IFN-alpha and -beta. Also, quantitative RNA-seq data indicated that endogenous ZAP is associated with altered global gene expression both in the steady state and during Zika virus infection. Further studies are warranted to elucidate this IFN-alpha and -beta independent anti-Zika virus activity and involvement of ZAP.

microbiology↗

bioRxiv2023

RNA 5' terminal nucleotide determines the strength of the RIG-I/IFN signaling pathway

The interferon (IFN) response is crucial for antiviral activity, but its overstimulation can lead to a wide range of autoimmune disorders. The cytoplasmic pattern recognition receptor RIG-I detects viral double-stranded RNAs (dsRNAs) and endogenous polymerase III transcripts carrying a 5'-triphosphate (5'-ppp) or 5'-diphosphate (5'-pp) moiety, triggering phosphorylation of IRF3 and IFN immune response. While many viral RNAs initiate with 5'-ppp-adenosine (5'-pppA) and most endogenous Pol III transcripts in higher eukaryotes start with 5'-ppp-guanosine (5'-pppG), no apparent reason for this bias has been identified so far. Here we demonstrate that dsRNAs initiating with 5'-pppA trigger stronger RIG-I/IFN response than those starting with 5'-pppG. We show that several GTP-binding proteins interact preferentially with 5'-pppG RNAs. Finally, supplementation with guanosine, but not adenosine, which rapidly increases intracellular concentrations of GTP and ATP, respectively, eliminates the difference in immunogenicity between 5'-pppG and 5'-pppA RNAs. Our findings suggest that 5'-pppG RNAs may enable certain RNA viruses and Pol III transcripts to limit detection by innate immune receptors. These results offer new insights into the sequence-dependent activation of the RIG-I/IFN pathway and have important implications for both antiviral immunity and the role of Pol III-derived RNAs in autoimmune diseases.

molecular biology↗

bioRxiv2021

TRIM25 inhibits Influenza A infection by destabilising its mRNA and is redundant for the RIG-I pathway.

The E3 ubiquitin ligase TRIM25 is a key factor in the innate immune response to RNA viruses. TRIM25 has been shown to play a role in the retinoic-acid-inducible gene-1 (RIG-I) pathway, which triggers expression of type 1 interferons upon viral infection. We and others have recently shown that TRIM25 is an RNA-binding protein, however not much is known about the RNA-binding roles of TRIM25 in the innate immune response to RNA viruses. Here, we demonstrate that influenza A virus (IAV A/PR/8/34_NS1(R38K41A)) infection is inhibited by TRIM25. Surprisingly, host RNA-binding deficient mutant TRIM25{Delta}RBD and TRIM25{Delta}RING, which lack E3 ubiquitin ligase activity rescued IAV inhibition in TRIM25 knock-out cells. Furthermore, we show that in human cultured cells activation of the RIG-I/interferon type 1 pathway mediated by an IAV-derived 5-triphosphate RNA does not require TRIM25 activity. Additionally, knocking out TRIM25 does not affect the activity of the IAV polymerase. We present new evidence that TRIM25 restricts IAV by directly binding to and destabilising its mRNAs. Finally, we show that direct tethering of TRIM25 to RNA is sufficient to downregulate the targeted RNA. In summary, our results uncover a novel mechanism that TRIM25 uses to inhibit IAV infection and regulate RNA metabolism.

molecular biology↗