Thèse Étude de la Persistance Virale du Sars-Cov-2 chez l'Hôte Approche par Imagerie In Vivo pour la Caractérisation du Covid Long et l'Exploration de Perspectives Thérapeutiques H/F

Doctorat.Gouv.Fr

Établissement : Université Paris-Saclay GS Santé et médicaments École doctorale : Innovation thérapeutique : du fondamental à l'appliqué Laboratoire de recherche : IDMIT - Immunological Diseases, Microbiology and Innovative Therapies Direction de la thèse : Thibaut NANINCK ORCID 0000000262616412 Début de la thèse : 2026-10-01 Date limite de candidature : 2026-04-30T23:59:59 Comprendre comment les agents pathogènes interagissent avec leurs hôtes est essentiel pour lutter contre les maladies infectieuses. Ces interactions - ainsi que la manière dont le système immunitaire y répond - déterminent si une infection est résolue, devient chronique ou plus sévère encore. Dans certaines infections, la présence persistante de molécules dérivées de l'agent pathogène peut entraîner une activation immunitaire continue, provoquant une inflammation chronique et des lésions des tissus. Cette hypothèse est l'une des principales pistes envisagées pour expliquer l'origine du Covid long.
Ce projet vise à ouvrir de nouvelles perspectives en déchiffrant les mécanismes à long terme des interactions virus-hôte après une infection par le SARS-CoV-2. En identifiant la nature, la cinétique et la biodistribution des composés viraux persistants, ce projet cherche mettre en évidence des éléments essentiels pour le diagnostic et le traitement du syndrome post-Covid.
Grâce à des stratégies d'imagerie in vivo de pointe, ce projet étudiera systématiquement la persistance du SARS-CoV-2 pendant 1 an et demi dans un modèle préclinique d'infection. Des primates non-humains infectés seront suivis dans le temps par imagerie TEP (tomographie par émission de positons) du corps entier, fournissant des données en temps réel sur la persistance virale. Ces évaluations in vivo seront complétées par une analyse virologique approfondie des tissus, du sang et des muqueuses, ainsi qu'un suivi fonctionnel de la respiration et de l'activité physique.
Ensemble, ces données multiparamétriques permettront de générer une cartographie 4D de la persistance virale post-Covid, offrant une vue sur la manière dont les interactions chroniques entre le virus et l'hôte peuvent contribuer au développement du Covid long. Infectious diseases are among the 4 leading causes of mortality worldwide according to WHO and epidemiological reports [1] (https://platform.who.int/mortality). They can be caused by various pathogen types including viruses, bacteria, parasites, fungi or even sometimes a combination of them. To fight against such diseases, it is therefore essential to understand how do pathogen enter, behave and interact in and with the body to cause the disease [2]. These interactions encompass molecular, cellular, and systemic processes that determine whether infection leads to clearance, latency, chronic disease, or death [3]. Actually, pathogen's virulence factors can modulate host signalling pathways, evading immune detection and undermining host defences [4]. Meanwhile, the host relies on both innate and adaptive immune responses, with pattern-recognition receptors, cytokine networks, and effector cells coordinating pathogen killing or isolation [5]. In some diseases, dysregulated interactions may result in immunopathology, where the immune response itself contributes to tissue damage. This is for instance clearly marked in sepsis where patients exhibit multi-organ dysfunction following massive immunological dysregulation [6]. On the contrary, some pathogens may persist for months or years in latent state with little to no immune responses from the host induced during that stage. It is particularly true in some Herpes Virus infections [7] and in many tuberculosis cases [8]. However, in some diseases, pathogen (or some of its compounds) may persist in the organism for long term but with ongoing activation of immune cells leading to exhaustion and immunological dysfunction. One main example of this feature is Human Immunodeficiency Virus (HIV) infection where persistent HIV exposure results in T-cell exhaustion [9]. In all these cases it is therefore essential to understand what are the mechanisms involved leading to the various pathological states. Insights from host-pathogen interactions and immune cell infiltrations over the body along the disease may then guide the rational design of vaccines, immunomodulatory therapies, and even antimicrobial agents [10].
Such investigations are however very challenging as these pathogen-host interactions obviously change with the microbial agent but also over the course of the disease with various patterns across the body. As biological samples collected from patients can provide valuable relevant data regarding pathogen-immune crosstalk in the clinical setting, they are by nature spatially and temporally restricted. To overcome this issue, relevant preclinical animal models that closely reproduce human pathology are of great interest (like Non-Human Primates for SARS-CoV-2 viral dissemination studies) together with implementation of non-invasive monitoring strategies. Among the promising technologies, molecular imaging is to me one of the main game-changers to date. Actually, techniques such as optical or nuclear imaging can allow to track over time, at various scales, specific targets of interest such as pathogens [11] or immune cells [12].
This project aims to integrate the full potential of molecular imaging in the context of infectious diseases and is therefore dedicated at developing a longitudinal whole-body imaging map of viral persistence, to decipher the leading pathologic cause for one disease of main interest across the world: Long Covid.
This project will therefore take advantage of recent in vivo imaging protocols we developed in our lab to visualise and characterize SARS-CoV-2 whole-body dissemination and long-term persistence following initial exposure in Non-Human Primates [13].
Aim 1: Establish a long-term mapping of SARS-CoV-2 antigen
The main objective of this project will be to implement a longitudinal in vivo imaging monitoring protocol based on SARS-CoV-2-specific Positron Emission Tomography coupled with X-rays Computed Tomography (PET/CT) imaging on cynomolgus macaques exposed to SARS-CoV-2 virus in an 18 months-long period. The candidate will then perform sequential (approx. every 3 months) acquisitions and in-depth image analysis to decipher a mapping of viral antigen persistence at the whole-body scale (with special focus on brain, lungs and gastrointestinal tract). This imaging mapping of SARS-CoV-2 antigen persistence will be associated with viral detection assays (RT-qPCR and ELISA-based assays) to characterize the presence of persisting virus, viral RNA or viral antigens (Spike & Nucleocapsid proteins) in the blood stream and in body fluids (swab samples, bronchoalveolar lavages).

Aim 2: Assess respiratory function of animals in the long term
In order to assess respiratory manifestations occurring following SARS-CoV-2 exposure, the second aim of this PhD project will be to set up a longitudinal monitoring of respiratory function of animals. This will be performed though plethysmography and mechanical ventilation assays on anesthetized animals prior imaging sessions. These functional assays will be then coupled with morphological monitoring of airways that will be performed thanks to chest CT scans from Aim 1 acquisitions for a comprehensive assessment of airways parameters.

Aim 3: Characterize viral persistence in tissues
In addition to in vivo imaging mapping of SARS-CoV-2 antigen persistence, this PhD project also aims at characterizing the nature of viral persistence occurring in tissues. Thanks to in vivo imaging data, key regions and tissues of interest will be sampled in order to deeper characterize and quantify viral features (replicative virus, viral genome as well as viral proteins) presence as already described in the first aim for body fluid analysis. These data will be then correlated with the quantitative imaging analysis in order to strengthen this non-invasive detection protocol.

Aim 4: Assess dosimetry radiation burden of preclinical SARS-CoV-2 in vivo imaging PET/CT protocol for clinical translation
The final goal of this project would be to transpose our PET/CT imaging protocol to patients suffering from Long Covid syndrome to assess if persisting virus or associated compounds may be at the origin of their pathology. To do so, several regulatory and safety aspects must be tackled. First of all, the total radiation burden (or dosimetry) of such imaging protocol must be assessed. We therefore aim at evaluating this dosimetry first in our NHP experiments using tracer uptake data from the first aim in various regions of interest. This dosimetry quantification will be performed using dedicated software and will be then compared to reference regulatory values for clinical use. We will then potentially refine our imaging protocol to reduce this radiation burden for future clinical use.