Mechanisms underlying the transition between homeostasis, inflammation and tolerance at the intestinal level are far from being fully understood. In particular, how the portal of entry of microbes and antigens influences the type, the magnitude and spatial-temporality of host responses are key unanswered questions. Listeria monocytogenes (Lm) is a well-established model microorganism for microbial pathogenesis and immunology and represents an ideal tool to address these questions. This proposal, based on the experimental models we have established, aims at investigating the fate of translocated Lm in the lamina propria, and understanding the intestinal immune responses to Lm. This project will critically improve the knowledge of Lm pathophysiology, contribute to a better understanding of the mechanisms leading to tolerance vs. immune responses, and the crosstalk between microbes, antigens and intestinal immune cells. It will also help develop more efficacious mucosal vaccines.

Coronavirus disease (COVID-19) is an infectious disease that primarily targets the human respiratory system and is caused by a novel virus denoted ‘Severe Acute Respiratory Syndrome coronavirus 2’ (SARS-CoV-2). The immune response to SARS-CoV-2 is the primary cause of the lung pathology and associated morbidities that lead to death in a substantial proportion of infected individuals. Nevertheless, immune responsiveness to this novel coronavirus appears quite variable in humans as indicated by reports of healthy viral ‘spreaders’ showing minimal disease. We have limited knowledge of the kinetics, intensity and diversity of cellular and humoral immune responses following SARS-CoV-2 infection in humans. Using an innovative technical pipeline based on the Milieu Intérieur cohort approach, we will characterize systemic as well as local nasal mucosal innate and adaptive immune responses during and after SARS-CoV-2 infection. We aim to identify immune signatures as well as potential environmental and/or host factors that can distinguish clinical outcomes in COVID-19 patients. Characterizing variability in the immune response to SARS-CoV-2 infection may help to identify patients who will clear the virus with few side effects versus those who will go on to have a catastrophic pathological response.

We recently reported a novel combined immunodeficiency in patients with loss of function mutations in the CTPS1 gene and characterized by high susceptibility to viral infection due to inability of T cell to proliferate and control infections. The project aims at acquiring fundamental knowledge on the biology of CTPS1, a key enzyme for the de-novo synthesis of CTP, including its role in embryonic development and in the immune system. Cellular and mouse models (including conditional KO and inducible KO) will be used to study the function and the regulation of CTPS1 under normal and pathological settings in the immune system. These studies will also help to determine whether CTPS1 could be a target for drugs to specifically dampen lymphocytes proliferation in autoimmune and inflammatory disorders. Chemical inhibitors of CTPS1 recently developed will be tested. The preliminary data already obtained by the team guarantee the workability of the project. This project relies on the complementary expertise of the four partners of the consortium.

Hidradenitis Suppurativa (HS), also known as Verneuil’s disease, is an incurable skin disease manifesting as recurrent, painful abscesses leading to significant scarring. The estimated worldwide prevalence of HS is around 1%, with highest rates in Europe (1-4%) and a more than 2-fold higher incidence in women. In addition to causing intense pain, HS is commonly associated with disability, depression and anxiety. The aetiology of the disease remains unknown. The sustained production of pro-inflammatory cytokines in skin lesions suggests a defective regulation of inflammation. Moreover, a distinctive anaerobic microbiota was identified in HS skin lesions, the expansion of which correlates with lesion severity. While unable to systematically cure, immunomodulatory drugs and antibiotics correcting the uncontrolled inflammation and cutaneous dysbiosis that are associated with HS skin lesions are effective at reducing the disease’s symptoms, showing that immune and microbial components are both involved in lesion development. In order to better treat HS, it is essential to understand what triggers and connects its diverse clinical manifestations. To gain new insight into the causes of HS, we recently conducted an integrated metabolomic and transcriptomic analysis of patient skin. Our study revealed a dysregulation of tryptophan catabolism by host cells and local microbiota in HS skin lesions, correlating with defects in bacterial production of tryptophan-derived agonists of the immunoregulatory Aryl Hydrocarbon Receptor (AHR). We also identified a systemic tryptophan depletion in HS patients, likely accounting for the perturbed metabolism of this essential amino acid in HS skin lesions. In the present project, our consortium of immunologists and biophysicist with complementary expertise in bacterial skin infections, host-microbiota cross-talk and metabolomics proposes to establish causal relationships between systemic tryptophan depletion, defective AHR activation, uncontrolled inflammation and dysbiosis in the skin, as well as depressive symptoms. Specifically, our objectives will be to: - Determine whether and how systemic tryptophan depletion impacts the metabolism, microbiota composition and immune status of the skin - Delineate the potential role of AHR deficiency, alone or combined with tryptophan deprivation, in cutaneous dysbiosis and immune dysregulation - Test the impact of AHR deficiency, combined or not with tryptophan deprivation, on brain concentrations of tryptophan-derived neurotransmitters and induction of depression-like behaviour - Mine the skin microbiota for AHR ligand-producing species and evaluate the therapeutic potential of an AHR agonist-based topical treatment in HS Together, these inter-related mouse studies will test the new concept that dysregulation of the tryptophan metabolism/AHR signalling axis contributes to HS pathogenesis. In addition to improving our knowledge of HS pathophysiology, this research programme may lead to the identification of novel microbiota- or host-targeted therapies for HS, and provide pre-clinical proof of the therapeutic potential of AHR agonists in HS. More generally and beyond HS, it will generate a new understanding of skin immunity and biology of depression, based on the metabolism of tryptophan.

Rheumatoid arthritis (RA) and spondyloarthitis (SPA) are the two most common chronic inflammatory rheumatic diseases, with a prevalence of 0.5-1% for RA and about 0.35% for SPA. Many studies have described an increased risk of serious infectious diseases directly associated with increased morbidity and mortality among those patients. This increased risk (frequency and severity) results from the disease itself, especially if the rheumatism is not controlled with high disease activity, but also due to the immunosuppressive treatments used to treat these patients. The risk of infection is higher for patients on biotherapy than for patients on Disease Modifying Anti-Rheumatic Drugs (DMARDs - mainly Methotrexate) and the combination of corticosteroid therapy with the biotherapies further increases this risk of infection. Lung and upper respiratory tract infections are the most common infections observed under biotherapy. The risk of infection may be different depending on the biotherapy considered and moreover the vaccine response, as a corollary to this observation, is also highly variable depending on the biotherapy, treatments with Rituximab, methotrexate and abatacept being those that interfere the most with the quality vaccine response. Since December 2019, the first SARS-Cov-2 (Severe acute respiratory coronavirus 2 syndrome) infections have been described in Wuhan province in China. The first cases were declared in China then the virus spread throughout the world, the epidemic having been declared as a pandemic by the International Health Organization on March 11, 2020. In September 2020, 30835922 confirmed cases of SarS-Cov-2 infection across the world with 957.790 reported deaths. To date, we have no data concerning the seroconversion of infected subjects, the protective or non-protective nature of the specific antibodies generated, and the duration of protection among patients under immunosuppressive treatment. However, major questions are currently unanswered for patients on immunosuppressive treatments: Are they excreting the virus for longer periods of time? How long can this viral excretion be measured in the upper airways and in the stool? Do they develop a humoral and cellular immune response comparable to the general population? COVIRIC project aims to study the impact of immunosuppressive therapies used for patients with chronic inflammatory rheumatic diseases on the viral load and humoral and cellular responses during viral infection with SarSCoV2, compared to members of their infected family cluster. Accurate knowledge of the dynamics of the virus and the immune response induced will be essential for the development of strategies for antiviral treatment, vaccination protocols and for the epidemiological control of Covis-19 in this specific population of patients under immunosuppressive treatments.