Influenza, Immunity and Metabolism
INSERM U1019 – CNRS UMR9017 – Lille University – CHU Lille – Institut Pasteur de Lille
Presentation
Despite the availability of various vaccines and antimicrobial drugs, viral and bacterial respiratory infections still remain a leading cause of global morbidity and mortality. Aging and co-morbidities – including chronic diseases – worsen the outcomes of these infections. The research activities of the I2M team focus on major respiratory pathogens: influenza A virus (IAV), pneumococcus, and, since 2020, SARS-CoV-2, the aetiologic agent of COVID-19. Our general objectives are to (i) identify early antiviral and antibacterial defense mechanisms, (ii) define age- and comorbidity-associated factors that predispose to and/or exacerbate respiratory infections, and (iii) develop new strategies for reinforcing host’s defense against respiratory pathogens. Within that framework, our team has a strong interest for the gut microbiota and the adipose tissue, which are both known to be critical in human health and illness, including during respiratory infections. We expect that a better understanding of the gut/lung/adipose tissue axis will be instrumental in conceiving novel therapeutic options for patients, notably in high-risk populations such as the elderly.
Highlights
- Respiratory infections, gut microbiota and cellular senescence
The gut microbiota plays a critical role in health and disease. The group has recently patented several therapeutic applications in influenza and pneumococcal infections, including compounds produced by the gut microbiota such as short-chain fatty acids (ANR ACROBAT, ANR GUTSY). We have shown that these metabolites attenuate secondary disease outcomes during influenza – including bacterial superinfection (Cell Reports 2020). More recently, we have characterized IPA (3-indole propionic acid), a tryptophan microbial-derived metabolite, as an antiviral and anti-inflammatory component (Gut Microbes 2024). Pharmacological approaches, next-generation probiotics and postbiotics are being developed. These notably include bacterial strains selected for their strong anti-inflammatory potential and their ability to produce short-chain fatty acids or IPA in symbiosis with specific nutrients (Front Immunol 2024). We have reported the marked impact of SARS-CoV-2 on gut microbiota’s composition and function (Gut Microbes 2020, 2022a, 2022b). This might be important in the long-term effect of COVID19.
- Respiratory infections and the adipose tissue
Obesity and aging, which are both associated with changes in adipose tissue mass, distribution and function, are the strongest reported risk factors for severe respiratory infections (including IAV and SARS-CoV-2 infections), questioning the role of adipose tissue in the pathophysiology of these diseases. In the I2M team, Isabelle Wolowczuk reported that influenza infection induces persistent alterations in whole-body glucose metabolism, and alters adipose tissue’s inflammatory and metabolic functions, mostly characterized by the occurrence of brown-like adipocytes in the tissue (Commun Biol 2020). The mechanisms involved in white adipose tissue browning are currently under investigation in young adult and aged mice (CPER CTRL 19 FEDER DESTRESS-Flu). More recently, we reported that SARS-CoV-2 infection induces important adipose tissue damages that remarkably persist in the elderly (Cell Death & Disease 2023).
Transversal program
Impact of age-related dysfunction of the circadian cycle on innate immune defenses against respiratory infections (DREAM)
As part of our aim to characterize the impact of aging on respiratory infections, we initiated a collaborative program with Hélène Duez & Benoit Pourcet (INSERM U1011, Univ Lille, IPL). We have evidenced a link between dysregulated circadian oscillation and altered antibacterial pulmonary defenses in aged lung. We hypothesize that the uncontrolled expression of clock genes in aged lungs might impair innate immunity and thus result in defective antibacterial defences (CPER CTRL 19 FEDER and ANR DREAM). Several candidates that target the circadian oscillation circuit have been characterized.
Role of senescent cells during respiratory viral infections (INFLUENZAGING and SENOCOVID)
We have an interest in cellular senescence, a biological process that affects cell functions. In collaboration with Serge Adnot (INSERM U955-Univ Créteil) and David Bernard (CNRS 5286 Univ Lyon), we are investigating the role of age-associated naturally-occurring senescent cells as well as stress (virus)-induced senescent cells during experimental influenza and COVID-19 (ANR INFLUENZAGING and ANR SENOCOVID). Different approaches are being developed including pharmacological (senolytics) and genetic approaches. We have recently demonstrated that age-related cellular senescence favours the severity of COVID19 (Nature Aging 2023).
The gut-lung axis during respiratory viral infection
Aging and co-morbidities strongly influence the functionality of the gut microbiota. By developing relevant preclinical models (ageing, obesity), we are exploring the consequences of respiratory viral infections on the gut microbiota composition and functionality. We also aim to better understand the impact of gut dysbiosis on disease outcomes (FEDER-FSE-Région Hauts-de-France). Metagenomic and metabolomic approaches (coll with Marco Vinolo, Univ São Paulo) are developed to characterize potential bacteria and/or metabolite involved in disease severity and long-term disease outcomes. This allowed us to identify promising candidates. Probiotics will be designed in order to supplement the lacking factors and ameliorate the disease.
SARS-CoV-2 Infection of GnRH neurons, Neuroinflammation, Aging and Long-term consequences (SIGNAL)
In collaboration with Vincent Prévot (U1172-Univ Lille, PI of SIGNAL project), and other teams in Europe, we are investigating the consequences of SARS-CoV-2 infection on the brain. We mostly focus on hypothalamic inflammation and neurons producing gonadotropin-releasing hormone (GnRH). We are investigating whether and how the infection and loss of GnRH neurons both in adulthood and in fetal/neonatal life lead to long-term pathological alterations, and explore potential therapeutic options (ANRS SIGNAL).
Members
François TROTTEIN
DR1 CNRS, Head of the team I2M
ORCID number : 0000-0003-3373-1814
Technicienne, Institut Pasteur de Lille
Isabelle WOLOWCZUK
DR2 CNRS, Leader of the axis « comorbidity »
ORCID number : 0000-0001-6692-6904
Lucie DERUYTER
Technician, University of Lille
Thèse (Université de Lille)
Publications
Mammalian ganglioside species with specific ceramide backbones activate invariant Natural Killer T cells.
Plos Biology 17(3):e3000169.
Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production.
Cell Reports. 30:2934.
Ayari A, Rosa-Calatrava M, Lancel S, Barthelemy J, Pizzorno A, Mayeuf-Louchart A, Baron M, Hot D, Deruyter L, Soulard D, Faveeuw C, Sencio V, Le Goffic R, Trottein F and Wolowczuk I (2020).
Influenza A virus infection rewires energy metabolism and induces browning features in adipose cells and tissues.
Communications Biology 4;3:237
Delval L, Hantute-Ghesquier A* Sencio V, Flaman JM, Robil C, Silva Angulo F, Lipskaia L, Çobanoğlu O, Lacoste AS, Machelart A,, Danneels A, Corbin M, Deryuter L, Heumel S, Idziorek T, Seron K, Sauve F, Bongiovanni A, Prévot V, Wolowczuk I, Belouzard S, Saliou JM, Gosset P*, Bernard D*, Rouillé Y, Adnot S*, Duterque-Coquillaud M, Trottein F (2023).
Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters.
Nature Aging 3(7):829-845. Commented in PMID: 37414986.
Jan-Dec;16(1):2325067.
Keywords
Team contact
François Trottein
Head of the team « Influenza, Immunity, Metabolism »
françois.trottein@pasteur-lille.fr
03 20 87 78 85