Our general objectives are to:
(I) identify early antiviral and antibacterial defence mechanisms,
(II) define age- and comorbidity-associated factors that predispose to respiratory infections,
(III) develop new strategies for reinforcing the host’s defence against respiratory pathogens.
The group’s results have given it internationally acknowledged stature in this field. 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 (SCFAs; grant: ANR ACROBAT). We have shown that these metabolites attenuate secondary disease outcomes during influenza - including bacterial superinfection (Cell Reports 2020). Pharmacological approaches, prebiotics, and next-generation probiotics are being developed. These notably include bacterial strains selected for their strong anti-inflammatory potential and their ability to produce SCFAs in symbiosis with specific fibres.
Obesity, which corresponds to excessive white adipose tissue expansion, is one of the strongest reported risk factor for severe respiratory infections. We recently reported that influenza infection induces persistent alterations in whole-body glucose metabolism, and alters white 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, in young adult and aged mice, are currently under investigation (CPER CTRL 19 FEDER DESTRESS-Flu).
We are characterizing the impact of ageing on respiratory infections. We have a particular interest in the link between cellular senescence and respiratory infection (grants: ANR INFLUENZAGING and SENOCOVID). In collaboration with INSERM unit U1011, our data in elderly mice indicated links between the circadian oscillator, lung dysfunction, and altered antibacterial defences in the 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).
Theme 1: Innate immune responses to respiratory infections
Innate immunity plays a critical role in host defense against pathogens and regulates the balance between inflammation and tissue repair. The laboratory has a major focus on pulmonary innate immune cells including dendritic cells, macrophages, non-conventional T lymphocytes and respiratory epithelial cells. Natural Killer T (NKT) lymphocytes are non-conventional T lymphocytes that recognize self-lipid antigens, including gangliosides (PLoS Biology 2019). Our data show a major role for NKT cells in the early steps of influenza and S. pneumoniae infections (PLoS Pathog 2014, Front Immunol 2018, 2019). During influenza, NKT cells produce interleukin-22 that protects against epithelial damage instigated by the virus (Infect. Immun 2018). During S. pneumoniae infection, NKT cells participate in bacterial clearance by promoting the effector functions of neutrophils and alveolar macrophages (MBio 2016). More recently, we have identified early mechanisms leading to the activation of protective IL-17-producing gamma delta T cells in response S. pneumoniae infection (Mucosal Immunol 2017 and 2020). Our studies now seek to understand the functions of these innate immune cells and the contribution of Th17-type cytokines in host defense and tissue repair processes during influenza and S. pneumoniae infections. In this setting, the influence of ageing is studied.
Theme 2: Susceptibility factors for respiratory infections
Acute or chronic lung inflammation, either induced by infections or associated with metabolic disorders, can predispose to respiratory infections. Influenza infection is often complicated by bacterial superinfections. In this context, dysfunction of innate immune defenses against bacteria and alteration of epithelial barrier functions are crucial factors. We showed that influenza instigates inhibitory mechanisms (via IL-10) that hamper the innate protective role of NKT cells against S. pneumoniae (MBio 2016, Mucosal Immunol 2017). This mechanism favors secondary pneumococcal infections. In contrast, IL-22 produced during influenza reinforces the epithelial barrier function, thus limiting bacterial translocation and systemic infection (J Virol 2013, IAI 2018). Influenza infection is also associated with impairment of DC poeisis in the bone marrow and renewal of conventional DCs in the lungs, a phenomenon that contributes to secondary bacterial infection (PLoS Pathogens 2018). The gut microbiota is well known to maintain immune cell homeostasis and functions in the lungs. Our recent data underlines the critical role of gut dysbiosis during influenza on secondary bacterial infection. In this setting, the altered production of short-chain fatty acids (SCFAs) - major metabolites of the gut microbiota - is critical in shaping effector functions of alveolar macrophages. These findings provide a novel mechanistic scenario for post-influenza bacterial superinfection and might have therapeutic applications in diseases associated with dysbiosis and secondary infections (Cell Reports 2020).
Obesity is characterized by low grade chronic inflammation and predisposes to respiratory infections. We have recently developed experimental models to elucidate the association between obesity, lung inflammation, and viral and bacterial infections. Due to its pro-inflammatory potential, the adipose tissue lies at the crossroads between nutrition (energy sources), metabolism (obesity, insulin resistance) and immunity. Despite the reported association between obesity and severe influenza, the impact of influenza on the adipose tissue per se and its potential role on disease outcomes is elusive. We recently showed that influenza strongly alters adipose tissue metabolic, immune and inflammatory functions, coincident with viral genome detection in the tissue (Commun Biol 2020). The mechanisms and consequences of these unexpected observations are being studied.
Theme 3: Therapeutic strategies-Development of mucosal immunostimulators
Immune-intervention represents a promising way to prevent or treat infectious diseases. Whenever possible, we try to exploit the therapeutic potential of compounds derived from our unbiased investigations (see themas 1 and 2) (e.g. IL-22, Flt3L in the case of superinfection). We also have a strong focus on the immuno-stimulatory molecule a-Galactosylceramide (-GalCer, a potent iNKT cell agonist). We have shown that a-GalCer exerts prophylactic/therapeutic activities against S. pneumoniae infection (Ivanov JID 2012), including in the context of prior influenza (Barthelemy, mBio 2016 and PCT/EP2013/070441). Through its capacity to induce appropriate adaptive immune responses, a-GalCer is also viewed as a potent adjuvant for vaccination, particularly at mucosal sites. We have developed a novel strategy to optimize the development of protective CD8+ T cell response by codelivering antigen and adjuvant (a-GalCer) directly to cross-priming dendritic cells (J. Immunol 2014; OncoImmunol 2017; Front Immunol 2017). These data might have important implications in vaccine development (Cancer Res 2014; Front Immunol 2017). Lastly, components derived from the gut microbiota (i.e. SCFAs) are currently being used to reinforce pulmonary defences against respiratory infections. Pharmacological as well as prebiotics and probiotics approaches are developed. As such, probiotics, mainly lactobacilli and bifidobacteria, have been selected for their anti-inflammatory capacities and their abilities to (i) strengthen the gut barrier (Benef Microbe 2017, Sci Rep 2017, Cell Physiol Biochem 2019), (ii) to stimulate antimicrobial responses and adaptative immunity (Sci Rep, in revision), but also (iii) to counteract obesity development (Environ Microbiol 2016). We are also developing next-generation probiotics derived from human gut microbiota, better adapted to the gastro-intestinal tract.
Sencio V, Barthelemy A,Tavares LP, Gomes Machado M, Soulard D, Cuinat C, Noordine ML, Salomé Desnoulez S, Deryuter L, Foligné B, Wahl C, Thomaz Viera A, Paget C, Milligan G, Ulven T, Wolowczuk I, Faveeuw C, Le Goffic R, Thomas M, Ferreira S, Mauro M Teixeira MM and Trottein F (2020). Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production. Cell Reports. 30(9):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(1):237
Paget C, Deng S, Soulard D, Priestman DA, Speca S, von Gerichten J, Speak AO, Mallevaey, T, Pewzner-Jung Y, Futerman AH, Faveeuw C, Platt FM., Sandhoff R and Trottein F (2019). Mammalian ganglioside species with specific ceramide backbones activate invariant Natural Killer T cells. Plos Biology 17(3):e3000169.
Beshara R, Sencio V, Soulard D, Barthélémy A, Fontaine J, Pinteau T, Bachar Ismail M, Paget C, Sirard JC, Trottein F, Faveeuw C (2018). Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during severe influenza contributes to bacterial superinfection. Plos Pathogens. 14(10): e1007360
Barthelemy, A., Ivanov S., Fontaine, J., Bouabe, H., Paget, C., Faveeuw, C, and Trottein F (2017). Influenza A virus-induced release of interleukin-10 inhibits the antimicrobial activities of invariant natural killer T cells during invasive pneumococcal superinfection. Mucosal Immunol 10:460.