Uncovering antiviral mechanisms in the insect gut during oral virus infection

Informations projet

DmGAR

N° de convention de subvention: 101024099

DOI

10.3030/101024099

Projet clôturé

Date de signature de la CE 27 Avril 2021

Date de début 1 Janvier 2022

Date de fin 31 Decembre 2023

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 196 707,84

Contribution de l’UE

€ 196 707,84

Coordonné par

INSTITUT PASTEUR
France

Periodic Reporting for period 1 - DmGAR (Uncovering antiviral mechanisms in the insect gut during oral virus infection)

Période du rapport: 2022-01-01 au 2023-12-31

Résumé du contexte et des objectifs généraux du projet

As the first tissue barrier encountered by orally acquired pathogens, the intestinal epithelium plays a crucial role in responding to and controlling viral infections. Gaining a greater understating of viral infections in the intestine is an important goal for several reasons. Enteric viral infections are a major cause of morbidity and mortality in humans as they are associated with numerous inflammatory conditions including inflammatory bowel disease and colorectal cancer. Moreover, mosquito-transmitted viruses such as dengue virus, chikungunya virus, and zika virus must first successfully infect the mosquito intestine to initiate their transmission cycles. Similarly, enteric viral infections in insect vectors of pathogenic plant-infecting viruses have a major impact on agricultural productivity.

The goal of DmGAR was to provide a comprehensive understanding of host-virus interactions during enteric viral infection in the Drosophila melanogaster model. We sought to answer the following questions: What are the dynamics and outcomes of viral infection in the intestine? What are the genetic responses to enteric viral infection? How does viral infection impact intestinal homeostasis? By addressing these questions our goal was to uncover crucial roles of the gut epithelium in responding to viral infection and to understand how the gut response to infection influences organismal health.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We found that persistent infection was a common outcome of viral infection in the D. melanogaster intestine. Importantly, we found that persistent viral infection causes an inflammatory state characterized by chronic activation of inflammatory immune signaling pathways and sustained dysregulation of cellular turnover in the intestinal epithelium. These alterations to cellular turnover disrupt intestinal homeostasis, reduce the lifespan of infected individuals, and may accelerate aging processes. We found that genetic interventions blocking virus-induced inflammatory signaling ameliorated the impact of viral infection on lifespan by preventing disruptions to intestinal cell turnover and homeostasis.

The results of the project were disseminated through international conference presentations, open access preprints, and social media posts targets to a general audience. Specifically, the results of DmGAR were presented during the “Flying Through the Gut” public seminar series (Zoom, April 2022), the European Society for Human Genetics conference (Vienna, Austria, June 2022), the American Society for Virology annual meeting (Madison, WI, USA, July 2022), the EMBO | EMBL Symposia “Innate immunity in Host Pathogen Interactions” (Heidelberg, Germany, July 2022), and the Jacques Monod conference “Insect Models for Infection Biology” (Roscoff, France, June 2023). The main results of the project were posted as a BioRxiv preprint that is currently undergoing peer review (https://doi.org/10.1101/2023.11.16.567400) and were summarized for a general audience in a public post on social media (https://twitter.com/SalehLabParis/status/1725530496137052253).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The results of DmGAR went beyond the state of the art in several important ways. First, our use of the genetically tractable D. melanogaster model allowed us to reveal the impact of viral infection on cellular turnover in the intestine and the influence of intestinal biology on organismal health with unprecedented mechanistic detail. Second, our study uncovered previously unappreciated impacts of viral infection on many important phenotypes in D. melanogaster (aging, intestinal homeostasis, inflammatory signaling). Persistent viral infections are extremely common in laboratory reared Drosophila. These infections are often undetected and have historically been considered to have minimal impacts on host biology. In contrast, our study reveals that viral infections have dramatic impacts on numerous phenotypes, indicating that the presence of viral infection should be an important consideration for all studies involving the D. melanogaster model. Finally, our study uncovered a novel role for STING-dependent NF-kB signaling in regulating intestinal homeostasis. Together our findings reveal important insights that may inform strategies to treat the deleterious impacts of enteric viral infection in humans and/or disrupt the transmission of viruses by insect vectors.

Graphical summary of main data from the project