899.1 - Pulmonary Endothelial Tau Aggregation After Infection
Sunday, April 3, 2022
9:45 AM – 10:00 AM
Room: 203 B - Pennsylvania Convention Center
Introduction: Mortality in critically ill patients has decreased due to improvements in hemodynamic support, mechanical ventilation strategies and bundled care. However, patients surviving to discharge have staggering rates of mortality, ~50%, during the next year of life. Furthermore, survivors have significant morbidity due to end-organ dysfunction. An NHBLI report suggests two erroneous paradigms that have limited our understanding of the role of pneumonia on health: that pneumonia is a 1) lt;emgt;localizedlt;/emgt; and 2) lt;emgt;acutelt;/emgt; disease. In fact, pneumonia causes end-organ injury by poorly understood mechanisms and the clinical manifestations persist long after resolution of the primary infection. Biological changes occurring during pneumonia that induce long-term morbidity are poorly understood. In summary, we propose to discuss exciting new mechanisms and hypotheses elucidating mechanisms of long-term morbidity and end-organ dysfunction in survivors of pneumonia that suffer from chronic critical illness.
Mike Lin (University of South Alabama), Chung-Sik Choi (University of South Alabama), Meredith Gwin (University of South Alabama), Sarah Voth (University of South Alabama), Claire Kolb (University of South Alabama), Chun Zhou (University of South Alabama), Amy Nelson (University of South Alabama), Althea deWeever (University of South Alabama), Anna Koloteva (University of South Alabama), Naga Annamdevula (University of South Alabama), James Murphy (University of South Alabama), Brant Wagener (University of Alabama at Birmingham), Jean-Francois Pittet (University of Alabama at Birmingham), Ssang-Taek Lim (University of South Alabama), Ron Balczon (University of South Alabama), Troy Stevens (University of South Alabama)
Patients who recover from nosocomial pneumonia oftentimes exhibit long-lasting cognitive impairment comparable to what is observed in Alzheimer’s Disease patients. We previously hypothesized that the lung endothelium contributes to infection-related neurocognitive dysfunction, since bacteria-exposed endothelial cells release a form(s) of cytotoxic tau that is sufficient to impair long-term potentiation in the hippocampus. However, lung endothelial tau isoform(s) have yet to be resolved and it remains unclear whether the infection-induced endothelial cytotoxic tau can trigger neuronal tau aggregation which is the major hallmark of several neuropathologies. Here, we demonstrate that lung endothelial cells express a big tau isoform and three additional tau isoforms that are similar to neuronal tau, each containing four microtubule-binding repeat domains, and that tau is expressed in lung capillaries in vivo. To test whether infection elicits endothelial tau capable of causing transmissible tau aggregation, cells were infected with P. aeruginosa. The infection-induced tau released from endothelium into the medium induced neuronal tau aggregation in reporter cells, including reporter cells that express either the four microtubule-binding repeat domains or the full-length tau. Infection-induced release of pathological tau variant(s) from endothelium, and the ability of the endothelial-derived tau to cause neuronal tau aggregation, was abolished using tau knockout cells. After bacterial lung infection, brain homogenates from wild-type mice, but not from tau knockout mice, initiated tau aggregation. Notably, plasma samples obtained from pneumonia-positive patients showed significantly higher tau aggregation activity when compared to pneumonia-negative plasma samples. Thus, bacterial pneumonia initiates the release of lung endothelial-derived cytotoxic tau into the circulation, which is capable of propagating a neuronal tauopathy.
This work was funded by NIH grants HL140182 and HL140182-S (to M.L.), GM127584 (to B.W.), HL66299 (to T.S. and R.B.), HL60024 (to T.S.), AHA 19PRE34380166 (to M.G.), F31 HL147512 (to S.V.), and S10RR027535 (to University of South Alabama BioImaging Core).
