Autophagy in antiviral immunity – AutoVirim

Autophagy is a catabolic cellular process essential for quality control of proteins, adaptation to stress and regulation of inflammation. As a defense mechanism, autophagy participates in controlling infections but also connects with antigen (Ag) presentation and thus activation of T cell responses. Thereafter, autophagy contributes to the dialogue between innate and adaptive immunity. It is a promising therapeutic target to fight infections and to develop innovative vaccines. However, numerous viruses have developed means to escape or manipulate autophagy. Among them, we previously demonstrated that two viruses that represent major threats to human health and patient care, Human Cytomegalovirus (HCMV) and Measles virus (MeV), evolved opposite strategies to modulate autophagy. But, the consequences of virus-mediated autophagy alterations on the initiation of innate and adaptive immune responses are unknown.

Using human primary dendritic cells (DC), we will dissect the consequences of autophagy manipulation by MeV and HCMV on viral replication, innate sensing, and virus-specific T cell activation. Our project is divided in three complementary axes:
1- Autophagy an intrinsic/innate pathway blocking viral infections. Remarkably, we have shown that HCMV escapes autophagy to spread (partner 3), whereas MeV induces autophagy to enhance replication (partner 2). In DC, we will thus compare MeV and HCMV interactions with the autophagic machinery. Using viral mutants, we will highlight potential escape mechanisms developed by MeV and HCMV. Since autophagy is induced by innate sensors but also regulates inflammation, we will analyze the impact of autophagy induction and alterations on viral replication and antiviral cytokine secretion.
2- Autophagy and Ag presentation by MHC. We will dissect the impact of autophagy hijacking by viruses on viral Ag capture, routing, processing and presentation by MHC-I and -II molecules. To this end, we will diversify our existing library of virus-specific T cells (MeV- and HCMV-specific T cells) and monitor the amplitude and quality of T cell activation upon autophagy alterations. Manipulating autophagy, we will also develop innovative approaches to enhance the immunogenicity of vaccine Ag.
3- Defining the molecular links between autophagy and Ag presentation by MHC molecules. The molecular bridges between the autophagic machinery and the complex process of antigen presentation remain completely unknown. Using an in silico approach and validation with shRNA, we will identify molecular connections between autophagy and Ag presentation. We will ask whether MeV and HCMV target these newly identified effectors to escape autophagy-dependent Ag presentation and to facilitate replication.

We have established a consortium of three laboratories with very strong expertise in the study of HCMV, MeV and in T cell antiviral immunity. We developed tools and know-how to dissect the interactions of autophagy with viral replication and viral Ag presentation. We generated some promising data confirming the interplay between autophagy and Ag presentation in MeV and HCMV infections. They represent two complementary models to provide a comprehensive view of the role of autophagy in immunity against life-threatening viruses. This project provides a unique opportunity to reinforce a strong network of teams working on autophagy and antiviral immunity. The partners are active members of the French society on Autophagy (CFATG) and are currently implicated, with European colleagues, in launching of an EU COST action. Partner-1 and -3 collaborate in the frame of a project granted by Ile de France region.

Importantly, this project will bring new insights in the function of autophagy and the consequences of its alterations by viruses on antiviral immunity. It might help developing innovative strategies to fight viral infections.