Aneja, A. | Search bioRxiv

bioRxiv2025

Dual role of Human antigen R in Dengue virus infection: suppression of replication and promotion of cap-independent translation

Host RNA-binding proteins (RBPs) play a pivotal role in regulating dengue virus (DENV) translation and replication through interactions with untranslated regions (UTRs) of viral RNA. We investigated host proteins associated with detergent-resistant membranes (DRMs) of the DENV replication complex and identified Human antigen R (HuR) as a key RBP enriched in the DRM. HuR was found to negatively regulate DENV replication by binding the DENV-3'UTR and impeding the association of polypyrimidine tract-binding protein (PTB), a known RNA stabilizer. Additionally, infection-induced modulation of HuR stabilized host mRNAs involved in innate immunity. Interestingly, in vivo validation in AG129 mice model highlights an inverse correlation between HuR expression and viral load and implicates HuR in cytokine dysregulation. Notably, HuR promoted cap-independent translation of viral RNA during later stages of infection, when cap-dependent translation is suppressed. These findings reveal a dual role for HuR: restricting viral RNA replication while enhancing translation, highlighting its critical, phase-specific function in the DENV life cycle. Author summaryUnderstanding how Dengue virus interacts with human cells is key to finding better treatments. Our study looked at a human protein called HuR, which normally control the stability and the use of RNA inside our cells. We discovered that HuR has two important but opposite roles during dengue infection. Early on, it slows down the viruss ability to make copies of its genetic material, helping to reduce infection. But later, when the virus struggles to use the normal method of making proteins, HuR steps in to help the virus make its proteins in a different way. This double-edged role of HuR shows how the virus cleverly uses host cell machinery at different stages of infection. Overall, this study uncovers the novel role of a specific RNA-binding protein of the host in orchestrating dengue virus infection and pathogenesis, highlighting its potential as a target for antiviral therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/666571v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1a5a0fdorg.highwire.dtl.DTLVardef@ec7734org.highwire.dtl.DTLVardef@860cf0org.highwire.dtl.DTLVardef@bb65f5_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Sex-Specific Systemic Inflammatory Responses in Mice Infected with a SARS-CoV-2-like Virus and Femur Fracture

Patients with femur fractures who are concurrently infected with COVID-19 face a threefold increase in mortality, likely due to a compounded inflammatory response. Furthermore, sex-specific differences in immune responses to COVID-19 have been documented, implicating gender as a potential modulator of disease severity in these comorbid conditions. Understanding the inflammatory interplay underlying this association is critical for the development of effective, targeted therapies to mitigate mortality. In this study, we investigated the systemic, sex-specific inflammatory response in mice that sustain a fracture while infected with a murine coronavirus (MHV), which belongs to the same genus as SARS-CoV-2. Our findings reveal that the combined inflammatory incidents of MHV infection and fracture disrupt the systemic immune response in both female and male mice, leading to immune dysregulation characterized by altered cell recruitment and disruption of the normal inflammatory cascade. Notably, the study identifies sex-specific differences in immune response, with female subjects exhibiting significantly elevated levels of inflammatory cytokines, including IL-18 and TNF, while males exhibit a diminished response. These sexually dimorphic differences are also reflected in the systemic immune cell populations, suggesting that the quantity of immune factors released may contribute to the observed discrepancies. Notably, these differences were minimal or moderate in animals that either got an MHV infection or fracture alone. Our findings indicate that the overproduction of proinflammatory cytokines, such as IFN{gamma}, IL-18, and TNF--reminiscent of cytokine storm syndrome--drives immune dysregulation, exacerbating outcomes in patients with these comorbidities. The observed sex-specific responses may be influenced by factors such as sex hormones, including estrogen, highlighting the importance of considering gender in therapeutic approaches. These insights provide a foundation for the development of tailored interventions to improve outcomes for COVID-19 patients with musculoskeletal trauma, including fractures.

immunology↗