Mitochondrial T-Cell reprogramming in virus-induced COPD exacerbation/emphysema progression
Chronic obstructive pulmonary disease (COPD) ranks among the top 3 global causes of death. Virus-induced exacerbations are heavily responsible for the prominent morbidity, mortality and associated health care costs. COPD patients suffer from increased susceptibility to- and decreased clearance from- respiratory viruses, as well as hyperinflammation in response to associated infections, which promotes lung injury and permanent lung remodelling. Enhanced susceptibility and immunopathology have been associated with distorted innate and adaptive immune responses, in particular with the crosstalk of macrophages and bronchial epithelial cells (BEC) with T cells. Mitochondria may be critically involved in this intercellular communication. Induction of the mitochondrial anti-viral signalling protein (MAVS) pathway in macrophages/BEC, mitochondrial localization at the immune synapse, regulation of cellular metabolism and release of mitochondrial reactive oxygen species (mtROS) collectively coordinate T cell activation, proliferation, differentiation and exhaustion.
We hypothesize that (i) chronic smoke exposure-induced mitochondrial dysfunction (including aberrant mtROS, MAVS) causes impaired T cell function (activation, proliferation, differentiation), which enhances susceptibility to respiratory virus infections in COPD, (ii) recurrent virus infections excessively activate mitochondrial signaling, promote hyperinflammation and T cell exhaustion, and ultimately emphysema and (iii) targeting mitochondrial reprogramming of T cells and mtROS/MAVS-signaling in macrophages/BEC will allow augmentation of antiviral immune responses and prevent disease exacerbations and progression of emphysema. In order to investigate our hypotheses, we aim on: 1) Characterization of smoke-induced mitochondrial alterations affecting T cell activation, proliferation, differentiation and contraction following infection with rhinovirus or influenza A virus in a murine cigarette smoke-induced emphysema model; 2) Determination of the role of mitochondrial pathways (including mtROS, MAVS) in virus-induced progression of emphysema; 3) Pharmacological and genetic interventions addressing pathways as identified in objectives 1 and 2 using in vitro and in vivo short- and long- term smoke exposure and viral infections. Interventions will be achieved by the use of mtROS inhibitors, T cell specific knockout mice and adoptive T cell transfer; 4) Translation to the human context by use of biosamples (peripheral blood mononuclear cells, bronchoalveolar lavage, lung tissue, precision cut lung slices) for molecular biological and functional analysis from control subjects, and COPD patients with or without a virus-induced exacerbation; 5) Transfer of key findings from the murine smoke-induced emphysema model regarding T-cell dysfunction and mitochondrial alterations to an e-cigarette mouse model, in order to investigate potential deleterious effects of e-cigarette vapour (with and without nicotine) on pulmonary immune responses.