Exposure to environmental oxidative stress-triggering factors, especially cigarette smoke (CS), is an important risk factor for COPD development and also alters the lung defense mechanisms against microbes. To address this problem, we established a model of COPD exacerbation triggered by bacterial infection in mice chronically exposed to CS. Animals with COPD develop exacerbated lung infection in response to Streptococcus pneumoniae and non-typable Haemophilus influenza, two bacteria colonizing COPD patients. Interestingly, this is associated with a defective production of an anti-infectious cytokine called IL-22 and an altered phenotype of lung antigen-presenting cells (Pichavant et al, 2015; Sharan et al, 2017). Local administration of recombinant IL-22 or treatment with an immune-adjuvant boosting the IL-22 response such as flagellin allow to prevent the development of acute exacerbation in mice (Koné et al., 2020, Perez-Cruz et al, submitted ). Thus, exposure to CS reduces the production of IL-22 induced by bacteria, a phenomenon that might explain the increased susceptibility to bacterial infections. Currently, we are investigating the upstream mechanisms leading to this inhibitory pathway. This research has allowed to characterize an immune receptor involved in the control of lung bacterial infection (Madouri et al, 2018). A clinical study in COPD patients hospitalized for AE is ongoing (COPD1722) in order to evaluate the expression of these different factors in relation with the cause of the exacerbation and of the clinical characteristics of these patients.

In collaboration with the University of Reims and the Pasteur institute of Paris, we have initiated a program aiming to analyzed the role of genetic polymorphisms of the nicotinic receptor (nAChR) in the development of COPD and during the exacerbation. We have preliminary data showing that a polymorphism of  alpha5 subunit of nAChR induced important airway epithelium remodeling and lung inflammation that potentially mimick a COPD disease (Routhier et al, submitted) Our present objective is now to demonstrate that α5SNP directly contribute to COPD pathology, sensitizing the lung to oxidative stress, and altering lung defence mechanisms (project PINAChRAECOPD, IRESP).

However, AEs in COPD patients are not only related to bacterial infections but also involve viruses and fungi. Infection by respiratory viruses including influenza A, rhinovirus and respiratory syncytial virus are also implicated in exacerbation of COPD potentially by favoring the development of bacterial superinfection. We have developed an original model of superinfection in COPD mice infected first with Influenza A virus and second with SP (Le Roux M and Gosset P). We are currently using this model to determine the potential implications of the factors previously identified for bacterial infection.

Regarding filamentous fungi colonization and infection, we have first evaluated the frequency and the role of fungi in COPD patients during AE (Dr E. Fréalle). Our data showed frequent colonization and sensitization by Aspergillus in COPD patients (Dauchy et al, 2018), associated with modulation of the lung and systemic inflammation. Sensitization and inflammation were also related with mould exposure in dwellings. Experimental models are currently developed in order to identify the physiopathologic mechanisms involved in the colonization and the development of invasive aspergillosis during COPD.►

Cigarette smoking and unhealthy diet (SCUD) are major behavioural risk factors that contribute to the alarming rise in non-communicable inflammatory diseases including COPD. Cigarette smoking is often associated with unhealthy patterns of nutrient intake thus increasing the risk of developing cardiovascular and metabolic disorders notably through its impact on intestinal homeostasis. These comorbidities strongly alter the quality of life of COPD patients and participate to the progression of the disease. Importantly, obesity and smoking promote inflammatory disorders including metabolic syndrome, cardiovascular diseases and pathologies of the intestinal tract and the lungs. The association of both risk factors synergistically accelerate the development of metabolic, cardiovascular, intestinal and lung dysfunction thereby markedly exacerbating the aging process. Recent data underline that these diseases are associated with gut and lung microbiota alteration (refered to dysbiosis). However, the impact of the association of smoking and poor diet on health and longevity has never been investigated yet.

In this context we developed an experimental model combining a high fat diet and a chronic exposure to cigarette smoke to explore (by multiple omics' approaches) the synergistic effects of the combined exposure on lifespan potentially through their impact on cardiovascular, metabolic, intestinal and respiratory function. Our research is presently focused on the role of oxidative stress (Commonly) and of the balance between pro- and anti-inflammatory cytokines in relation with gut dysbiosis (TheraSCUD2022). This model constitutes an original and unique model of COPD comorbidities. In this context, it is essential to define the physiopathologic mechanism responsible of organ dysfunction in order to prevent them. Our final goal is to propose new tools able to slowdown the aging process as well as the comorbidities associated to unhealthy lifestyle.

Both asthma and COPD have their origins in early childhood. The early life factors that have been implicated in poor future lung health include environmental factors, antenatal nutrition, premature birth and respiratory infections in early life. Beside the role of environmental exposures, birth cohort studies have highlighted potential pediatric roots of COPD with a role of early inflammation and small lung infections. In addition, viral infections in prescholar children trigger asthma development and exacerbation. However, the early life factors which determine clinical and functional evolution of children, have not been clearly identified. Moreover, there is an urgent need for markers of development and progression of these diseases as well as future respiratory health.

We have recently established two cohorts of patients hospitalized for asthma exacerbation among scholar (Virasthma) and prescholar (Virasthma2) children. The objective was to identify the role of viral infections and markers of severity and prognosis in these patients. Altogether, our data showed that viral infection is highly prevalent particularly in prescholar children with a defective anti-viral response in the more severe patients (Deschildre et al, 2017). Moreover, we will follow-up these patients until adult age in order to determine the relationship between biological and clinical parameters in early life with adult respiratory health. In addition, an experimental model will be deciphered in order to determine early life factors affecting adult lung function.

Airway colonization by P. Aeruginaosa are very frequent in CF patients leading to frequent infections by this pathogen related to virulence acquirement and development of disease exacerbation. Adhesion of P. aeruginosa to the target host airway cells is the first step of infection, even leading to activation of major virulence factors such as the type 3 secretion system. Among P. aeruginosa adhesins, we demonstrated that secreted lectins, LecA and LecB have a role in virulence that is attenuated by inhibition through galactose or fucose derivatives that have an affinity for lectins (Chemani C et al, 2009). A collaborative project based on this approach showed that lectin-inhibiting glycoclusters decrease P. aeruginosa adhesion down to 10%, lung bacterial load and lung injury to baseline levels (Boukerb et al, 2014). This led to an academic-industrial project (Anti-Pyo- Fonds Unitaire Interministériel) to synthetize and screen glycoclusters to provide "leads" for the development of the most promising compounds.

Our team is currently testing these and newer compounds (Donnier-Maréchal et al, 2017) in cellular and animal models relevant to CF for their effects as adjuvants to antibiotics against multirésistant P. aeruginosa isolates from CF patients (projet Vaincre la Mucoviscidose: "Etude de glycoclusters anti-adhésion en tant qu'adjuvants aux bêta-lactamines contre Pseudomonas aeruginosa au cours de la mucoviscidose"). These compounds will provide candidates for developing treatments to prevent or decrease the colonization of airways of patients with cystic fibrosis by P. aeruginosa, decreasing exacerbations or to treat exacerbations caused by multi-resistant strains as adjuvants to antibiotics.

Patients with chronic lung diseases such as COPD or CF, are submitted to repeated contacts with healthcare environments (consults, hospitalizations, respiratory function testing, rehabilitation…) in which Multi-Drug Resistant (MDR) bacteria are increasingly prevalent worldwide, raising fears of severe infections without therapeutic options, particularly in these vulnerable patient populations. Furthermore, whilenormal microbiota provide colonization resistance against exogenous microorganisms, disruption by environmental factors such as antibiotics allows colonization (colonization resistance failure), and these patients share repeated exposure to antibiotics to treat acute exacerbations. We have already demonstrated that antibiotic-induced intestinal dysbiosis strongly induces (cellular immunosuppression in both lung and blood, predominating on antigen-presenting cells and favoring opportunistic pulmonary infections. Fecal microbiota transplantation as well as bon marrow activation  prevent these deleterious effects (Dessein et al, 2020). In order to better decipher the interactions between altered microbiota and mucosal immune response and the mechanism allowing development of opportunistic pulmonary infections, we have developped murine dysbiosis/colonization resistance failure models (Le Guern et al, 2019). These studies will establish the interactions between treating exacerbations with antibiotics, colonization resistance failure and responses to opportunistic infections and progression of underlying chronic lung diseases such as COPD or CF. The resulting data should provide insights into mitigating the consequences of environmental factors related to the management of acute exacerbations in these patients.        

Covid-19 represents the latest threat to global health with potential disastrous healthcare consequences and a potential saturation of the intensive care units in hospitals. A substantial number of SARS-CoV2-infected patients experienced critical disease mainly characterized by acute respiratory distress syndrome (ARDS) and multiple organ failure potentially leading to patient death. Several parameters have been proposed as promoting the complications of COVID-19 infection including the age, the presence of preexisting diseases, inflammatory and metabolic disorders. In order to decipher the physiopathology of the disease and to improve the follow-up of infected patients, it is necessary 1) to quickly detect the presence of SARS-CoV2, 2) to identify new markers allowing to guide management and therapy and to evaluate prognosis in hospitalized COVID-19 patients (Project CritiSARS2, ANR), 3) to identify new factors able to control the disease. For this, our projects underlies on the data showing the protective role of smoking habit on SARS-CoV2 (ANR project NirCOVID, Coll Dr Maskos IPParis, Dr V. Dormoy, Reims).

 Our data will allow to improve our knowledge of the natural history, the management and the follow-up in COVID-19 patients as well as to identify new physiopathologic mechanisms. These findings will be used in order to propose potential treatment options