Obesity is associated with increased severity of infectious diseases. There is an urgent need to provide adapted lifestyle recommendation to reduce that risk which could be due to low grade inflammation and increased immune checkpoint (ICP) overexpression such as the PD-1/PDL1 pathway that leads to exhaustion of T-cells. Nutrim_Check is a new translational research collaborative network involving 4 groups of investigators that is organized into 6 complementary work-packages. Combining expertise in nutrition, metabolism, immunology and large-scale data analysis, our aim is to assess the interaction between NUTRition, IMmune CHECKpoints, and immune and metabolic health. Thanks to access to databases and biobanks with blood and adipose tissue samples from existing cohorts of subjects with metabolic deterioration, we will characterize obesity-related and cell and tissue-specific T cell dysfunction (ICP expression) and explore the interaction between dietary patterns, nutrients, gut microbiota (GM), metabolites and ICP modification (WP1). We will evaluate if T cell dysfunction can be rescued after dietary intervention known to improve metabolism and inflammation in a pilot study (WP2, i.e. called the pro immune diet). Mechanistic insights linking changes of T cell ICP expression will be addressed using ex vivo and in vitro models from human cells and detailed immune cell characterization will be undertaken (WP3). The infectious model of investigation will be the COVID-19, but this project extends broadly to viral infection vulnerability. Of note, an holistic and standardized mass cytometry approach will be used to obtain a detailed phenotyping of the immune populations. Patients from the pilot nutritional intervention will also be phenotyped in depth at the molecular level (metagenomics and metabolomics, WP4) and large-scale data analysis will be undertaken thanks to local expertise in biostatistic and machine learning (WP5). We will explore a novel not yet explored idea that chronic inflammatory tone due to increased expression of ICP contributes to adaptive immune evasion and sustained viral infection in dietary-related diseases. We propose this phenomenon may be fixable by nutritional amelioration in vulnerable populations such as people with obesity and metabolic diseases. Thanks to precise coordination (WP6), the project will provide information of academic and industrial interest with new information on food compounds known to broaden their spectrum of consumption, with emphasis on the immune response. The communication and dissemination Strategy will address the various target groups including the public, food, pharma and healthcare sectors and policy makers

Despite great progress in virome sequencing, a broad and holistic understanding of the phage’s role in human health is still lacking. Our goal is to unravel the functional properties of phage dark matter in the context of virome-immune mutualism and elucidate its relevance in the gut microbiome. We will combine clinical sampling with state-of-the-art approaches in viromics, immunology and bioinformatics to pursue the following objectives: 1) to establish a novel method to study direct virome-antibody binding, 2) to characterize phage communities interacting with Immunoglobulin (Ig) A and IgG in gut dysbiosis, and 3) to elucidate the impact of phage-Igs binding to the interconnected network of bacteria, phages and humoral immunity. With a novel objective proposed and little precedent work published in the field, we obtained preliminary data that suggests that gut virome should be further studied in conjunction with immune responses and interaction with members of the microbiome. The project will contribute to a paradigm shift in understanding how phages may affect mammalian hosts, such as in the context of microbe-immune interactions and it has possible implications for biotechnology and medicine.

Cellular metabolism is becoming an emerging field of investigation in immunology. For instance, it has been recently shown that a switch from oxidative phosphorylation to aerobic glycolysis in conventional T cells is a prerequisite for their proper activation. CD4+Foxp3+ regulatory T cells (Tregs) play a major role in the control of autoimmune and chronic inflammatory diseases. Current knowledge concerning the cellular metabolic characteristics of Tregs is limited and published studies are controversial. In this project, we will study the role of glucose and lipid metabolism in Treg homeostasis and function. First, we will compare the metabolic features of resting versus effector Tregs, and of Tregs from lymphoid versus non-lymphoid tissues. We will also analyze the effect of different types of chronic inflammation (such as high fat diet, cancer, autoimmunity or chronic infection) on Treg metabolism in specific tissues. Together, these data will allow us to obtain an integrative view of the metabolic features of Treg subsets according to their origin, activation state, tissue localization and inflammatory environment. We hypothesize that Tregs modify their metabolism depending on external cues and environment, providing an explanation for the existing controversies in the literature. Furthermore, we will use novel and unique models of conditional knock-out mice for genes that control critical hubs of glucose and lipid metabolism, to better understand how different aspects of glucose and lipid metabolism specifically in Tregs affect their biology in different tissues and thus their capacity to control inflammation. We will evaluate the influence of critical metabolic checkpoints for the development of spontaneous autoimmunity and other chronic inflammatory processes. Finally, in the last part of the project, we will make use of our conditional knock-out mice to narrow down the mechanism of action of metformin, a drug widely used in type 2 diabetic patients to regulate cellular metabolism. Because the drug has also an immuno-regulatory effect, we will assess whether part of its therapeutic action is due to a direct effect on Tregs. All in all, this project will increase our basic knowledge on the metabolism of Tregs, its impact on Treg homeostasis and function depending on environmental cues and last but not least, improve our understanding of the pathophysiology of major chronic immune-mediated diseases that are controlled by Tregs.

The repeated failures of previous clinical HIV-1 vaccine candidates and the moderate efficacy of the RV144 vaccine (31% at 42 months) have emphasized the need of new vectors inducing new immune functions and the setup of vaccine regimens combining several pre-existing immunogens/vaccine strategies. Measles virus (MV) vector priming combined with protein boosts could fulfill these conditions. In fact, in an initial study we demonstrated that vaccination with MV vectors expressing Gag, Env and Nef simian-human immunodeficiency virus immunogens (MV-SHIV) controlled the SHIVSF162p3 challenge virus in cynomolgus macaques. Indeed, the peak viral load median of the vaccinated monkeys was nearly 2 logs lower compared to the placebo group, and plasma virus load was strongly reduced within a week (p=0.0001, Wilcoxon test). Moreover in contrast to the control monkeys, the vaccinated monkeys maintained plasma CD4+ T-cell counts >1000 cells/µl following challenges. Consequently, the MV-SHIV vaccine markedly reduced the reservoir size in PBMCs, spleen, axillary and inguinal lymph nodes and rectum, as evidenced by 50% of the animals exhibiting = 10 proviral DNA copies per million of cells. Interestingly, the control of SHIV162p3 found in the vaccinated monkeys was correlated with the Gag-specific cellular immune responses. However MV-SHIV vaccine alone was not able to delay SHIV acquisition after repeated intrarectal challenges, which is crucial for a HIV-vaccine to prevent virus integration. This could be attributed to the lack of induction of plasma neutralizing IgG (against tier-2 SHIV162p3) and mucosal IgA (in rectal secretions), which are known to be associated in vivo with a sterilizing protection against SHIV and SIV challenges, or at least with a delay of acquisition. Thus, we propose in this study to combine the MV-SHIV vaccine with protein boosts of the external region of the HIV gp41 envelope subunit. That gp41 polypeptide will include 3 highly conserved functional domains: the immunosuppressive domain ISD (the target of IgA antibodies in “Exposed Uninfected” patients), the “3S-motif” (anti-3S antibodies inhibit NK activity and cytotoxicity) and the membrane-proximal external region MPER (recognized by neutralizing and anti-HIV transcytosis antibodies in macaques challenged by the SHIVSF162p3). Chemically synthesized gp41 polypeptide in the presence of PLGA-based nanoparticles and TLR4 and TLR7/8 agonists adjuvants, or recombinant gp41 expressed by measles virus vector will be first assessed in mice to define the protein-boost regimen yielding the highest levels of circulating and mucosal antibodies. Then, cynomolgus macaques will be primed with the previously assessed MV-SHIV vaccine and boosted with the best protein-boost regimen before intravaginal challenges with the SHIVSF162p3 strain. We aim to provide the proof of concept of the protective efficacy for this new vaccine regimen/combination in the perspective of a first-in-man Phase I clinical trial. The final objectives of this project are the evaluation in patients of this vaccine candidate as a prophylactic and therapeutic vaccine.