Biology subjects

Mongelli, V.

Publications and source records attributed to Mongelli, V..

3 recordsLinked to original sources

bioRxiv2023

Viral infection disrupts intestinal homeostasis via Sting-dependent NF-kB signaling

Host-microbe interactions influence intestinal stem cell (ISC) activity to modulate epithelial turnover and composition. Here we investigated the functional impacts of viral infection on intestinal homeostasis and the mechanisms by which viral infection alters ISC activity. We report that Drosophila A virus (DAV) infection disrupts intestinal homeostasis in Drosophila by inducing sustained ISC proliferation, resulting in intestinal dysplasia, loss of gut barrier function, and reduced lifespan. We found that additional viruses common in laboratory-reared Drosophila also promote ISC proliferation. The mechanism of DAV-induced ISC proliferation involves progenitor-autonomous EGFR signaling, JNK activity in enterocytes, and requires Sting-dependent NF-kB (Relish) activity. We further demonstrate that activating Sting-Relish signaling is sufficient to induce ISC proliferation, promote intestinal dysplasia, and reduce lifespan in the absence of infection. Our results reveal that viral infection can significantly disrupt intestinal physiology, highlight a novel role for Sting-Relish signaling, and support a role for viral infection in aging. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/567400v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1925c83org.highwire.dtl.DTLVardef@1f7b9fcorg.highwire.dtl.DTLVardef@d36c18org.highwire.dtl.DTLVardef@5dd16c_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Hsc70-4 mediates internalization of environmental dsRNA at the surface of Drosophila S2 cells

The siRNA pathway is the primary antiviral defense mechanism in invertebrates and plants. The systemic nature of this defense mechanism is one of its more fascinating characteristics and the recognition and transport of double-stranded RNA (dsRNA) of viral origin is required for the systemic activity of the siRNA pathway. Indeed, cellular internalization of dsRNA from the environment is a widespread phenomenon among insects. Here we aimed to identify cell surface proteins that bind to extracellular dsRNA and mediate its internalization. To this end, we developed a novel co-immunoprecipitation protocol that we followed with proteomics analysis. Among the hits from our screens was Hsc70-4, a constitutively expressed member of the heat shock protein family that has been implicated in clathrin-mediated endocytosis. We found that silencing Hsc70-4 impaired dsRNA internalization. Surprisingly, despite lacking a predicted transmembrane domain, Hsc70-4 localizes to the cell membrane and this localization was preserved when Hsc70-4 was expressed in mammalian cells, suggesting a conserved role at the cell surface. Furthermore, Hsc70-4 shows a previously undescribed dsRNA-specific binding capacity. Our results show that Hsc70-4 is a key element of the dsRNA internalization process and its detailed study may facilitate the development of RNA interference (RNAi)-based technologies for pest and vector borne disease control. ImportanceTo protect plants from pathogens or pests, the technology of "Host-induced gene silencing" has emerged as a powerful alternative to chemical treatments. This is an RNAi-based technology where small RNAs made in the plant silence the genes of the pests or pathogens that attack the plant. The small RNAs are generally derived from dsRNA expressed in transgenic plants. Alternatively, dsRNA can be sprayed onto the plant surface, where it can be taken up into the plant or ingested by pests. We have identified a cell surface protein that mediates the early steps of extracellular dsRNA internalization in insect cells. This could facilitate the development of new strategies for pest management.

cell biology↗

bioRxiv2021

Innate immune pathways act synergistically to constrain RNA virus evolution in Drosophila melanogaster

Host-pathogen interactions impose recurrent selective pressures that lead to constant adaptation and counter-adaptation in both competing species. Here, we sought to study this evolutionary arms-race and assessed the impact of the innate immune system on viral population diversity and evolution, using D. melanogaster as model host and its natural pathogen Drosophila C virus (DCV). We first isogenized eight fly genotypes generating animals defective for RNAi, Imd and Toll innate immune pathways and also pathogen sensing and gut renewal pathways. Wild-type or mutant flies were then orally infected and DCV was serially passaged ten times. Viral population diversity was studied after each viral passage by high-throughput sequencing, and infection phenotypes were assessed at the beginning and at the end of the passaging scheme. We found that the absence of any of the various immune pathways studied increased viral genetic diversity and attenuated the viruses. Strikingly, these effects were observed in both host factors with antiviral properties and host factors with antibacterial properties. Together, our results indicate that the innate immunity system as a whole, and not specific antiviral defense pathways in isolation, generally constrains viral diversity and evolution.

evolutionary biology↗