Determining how age-related dysfunction of the circadian cycle influences innate immune defenses against respiratory infections
Description: Bacterial respiratory tract infections are a major cause of morbidity and mortality in older adults, and thus have huge medical and socio-economic impacts. As the population ages, it is essential to gain a better understanding of the causes of age-induced bacterial pneumonia and then to develop innovative treatments. Circadian rhythms regulate a wide variety of physiological, metabolic, and immune processes. For instance, the circadian clock in immune cells controls the intensity of inflammatory-immune responses during infection. Importantly, circadian rhythms are disrupted in the elderly, predisposing them to metabolic/inflammatory diseases and cancers. Our data in elderly mice indicate a link between circadian clock dysfunction in the lungs and altered antibacterial pulmonary defenses. We showed that the expression of the nuclear receptor Rev-erba (a major regulator of the clock machinery and a potent repressor of gene expression) is elevated in elderly lungs and does not show a circadian variation. We also demonstrated that Rev-erba downregulates the lung’s innate immune defenses against Streptococcus pneumoniae, the leading cause of bacterial pneumonia in older adults. We hypothesize that the uncontrolled Rev-erba expression in aged lungs might lead to a clock-dependent alteration in innate immunity and thus result in defective antibacterial defenses. Our first objective is to determine (i) the cause of altered Rev-erba expression during ageing, (ii) the cell type(s) in which Rev-erba expression is abnormal, and (iii) the innate immune genes targeted by Rev-erba in elderly mice. We postulate that cellular senescence - a cellular process leading to chronic low-grade inflammation and ageing - has a role in altered clock gene (Rev-erba)-dependent pulmonary immunity. To test this hypothesis, we shall use a unique elderly mouse model (p16-ATTAK) that allows the depletion of senescent cells. For translational perspectives, we shall define the link between age-induced circadian rhythm dysfunction, cellular senescence, and altered defenses in humans. This will be assessed by measuring clock components (including Rev-erba) as well as cellular senescence and innate immune markers in surgical lung specimens collected from older adults. Our second objective is to determine the function and mechanisms of Rev-erba with regard to impaired pulmonary defenses against pneumococcal infection. A genetic approach (cell-specific gene deletion) and the use of Rev-erba agonist (to manipulate its repressor activity) will be pursued. To gain additional mechanistic insights, the effect of cell-specific Rev-erba deletion will be studied. We will focus on epithelial cells and myeloid cells because these cell types are known to coordinate the circadian cycle in lungs and have a critical role in the daily control of pulmonary inflammation. We seek to demonstrate the potential link between Rev-erba expression/repressor activity and impaired innate immunity in young adult mice. Molecular signatures and immune profiles (cell counts/functions) with regard to Rev-erba expression and activity, circadian rhythms and antibacterial immunity will be determined in the lungs of naïve and S. pneumoniae-infected mice. Our third objective is to pharmacologically manipulate Rev-erba activity and thus enhance immunological defenses in elderly mice. The latter will be treated with a potent Rev-erba antagonist to restore robust circadian oscillations of innate immunity. The treatment’s impact on pulmonary immune defenses against pneumococcal infection will be measured. The project has the potential to provide important scientific knowledge and a rationale for new interventional methods for reinforcing the immune system in older adults. Considering the socio-economic impact of bacterial pneumonia, this project might benefit society in general.
Funder: Agence Nationale de la Recherche
Amount: €393,200
Funding type: research
Funder scheme: AAPG2019
Start date: 2020-03-01
Investigator: Serge ADNOT
Institution: Institut Mondor de recherche biomédicale
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Funded outputs count: 7
Funder award ID: ANR-19-CE15-0033
OpenAlex ID: G8929508171