Macrophages as therapeutic targets in HIV-1 and tuberculosis infection
PhD Committee
- Dr. Nathalie CHAZAL, Rapporteur, Institut de Recherche en Infectiologie de Montpellier (IRIM)
- Dr. Jean-Louis MEGE, Rapporteur, Faculté des Sciences Médicales et Paramédicales secteur Timone (Aix-Marseille Université)
- Dr. Paul LESBATS, Rapporteur, Laboratoire de Microbiologie Fondamentale et Pathogénicité (MFP)
- Dr. Cécile MALNOU, Examiner, INFINITy (Institut Toulousain des Maladies Infectieuses et Inflammatoires) INSERM
- Prof. Fabrice DUMAS, PhD supervisor, Université de Toulouse
- Dr. Christel VEROLLET, PhD co-supervisor, Institut de Pharmacologie et de Biologie Structurale (IPBS)
- Dr. Geanncarlo LUGO-VILLARINO, Co-supervisor, Institut de Pharmacologie et de Biologie Structurale (IPBS)
Summary
Macrophages play a fundamental role in tissue homeostasis and innate immunity. Within the lungs, alveolar macrophages (AM) maintain the balance between tolerance and the protection against pathogens. However, their ability to adapt and their specific environment also make them ideal targets for several pathogens, including Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus type 1 (HIV-1). These complex interactions contribute to infectious dissemination, the persistence of viral or bacterial reservoirs, and the modulation of local inflammation, highlighting the importance of considering macrophages as therapeutic targets.
During my thesis, I first established an in vitro model of human AMLs (AML for "AML-like") in the laboratory following a recently published protocol. This model more accurately reflects the biology of primary AM compared to the commonly used model of blood monocyte-derived macrophages. Using multiparametric spectral flow cytometry and unbiased analytical methods (UMAP and tSNE), I established the phenotypic signature of these cells, characterized by the presence of tissue and immunoregulatory markers, such as CD14, CD16, CD163, CD169, CD206, and PD-L1. I demonstrated that AML exhibit an antiinflammatory phenotypic profile, reproducible regardless of the donor, thus providing a physiologically more relevant and less variable alternative than primary AM isolated from patients. I also characterized them morphologically and infected them with Mtb in order to test the efficacy of anti-tuberculosis drugs in collaboration with two other teams at IPBS. Therefore, AMLs represent an optimized model for studying the dynamics of Mtb infection and for benchmarking pharmacological compounds targeting either the host or the pathogen's virulence mechanisms.
In parallel, I tested the antiviral effect of lipid derivatives on HIV-1 infection of monocyte-derived macrophages. This project is a continuation of previous research in the laboratory demonstrating that these lipid derivatives disrupt the structure of the plasma membrane. By using luminescent viruses, I evaluated the efficacy of fifteen lipid derivatives. Thus, I showed that three compounds significantly reduce macrophage infection differently depending on the viral strain used, without impacting the viral entry stage and certain functional characteristics of the macrophages. An analysis is still ongoing in order to elucidate the mode of action of these three lipids.
Therefore, this thesis highlights the key role of macrophages in the response to infections and proposes experimental models and innovative approaches to guide research toward therapies targeting not only the pathogen but also the host and its cellular environment.