Project Portugal 2030

Summary

Streptococcus pneumoniae is the main cause of bacterial pneumonia posing a serious health threat especially to children and elderly (1). Through the release of its pore-forming toxin, pneumolysin (PLY), S. pneumoniae causes extensive damage on lung cell plasma membrane, leading to tissue damage and dissemination of infection (2). Therapies currently used to fight S. pneumoniae infection rely on antibiotic treatment and aim to eliminate the bacteria. This therapeutic approach has recognized drawbacks as it leads to the emergence of resistances (3) and does not necessarily promote the recovery from lung damage. However, in response to S. pneumoniae damage, the host triggers a series of events aiming to resolve the infection and restore lung function, recently reviewed by us in (2) (Figures 1, 2). Several cell autonomous repair events have been shown to respond to plasma membrane damage and the pharmacological stimulation of such intrinsic responses emerged as a promising strategy to fight plasma membrane damage associated disorders (4,5), including infections such as pneumonia. In this context, the overarching goal of PoreRepair is to unravel the mechanisms underlying the events that repair the pneumococcal-induced membrane damage, offering the potential for innovative therapeutic applications (Figure 3). PoreRepair aims to uncover new therapeutic targets which would allow new approaches centered in the enhancement of the intrinsic mechanisms of host defense. The PoreRepair research plan aims to tackle challenging issues in the field of plasma membrane repair and to identify the most promising therapeutic targets. Specifically, PoreRepair will investigate: 1) the contribution of plasma membrane remodeling to repair; 2) the cellular machinery involved in repair and 3) the impact of repair mechanisms on the outcome of S. pneumoniae infection. We have designed 4 interconnected but independent tasks, to approach plasma membrane repair components from two different perspectives. Collectively, these tasks seek to identify the cellular components (organelles and structures) supporting plasma membrane remodeling and to elucidate the role of calcium-binding proteins responding to damage in the outcome of S. pneumoniae infection (Figure 3). Given that repair mechanisms are anticipated to exhibit similarities in their response to different sources of damage, such as mechanical or biochemical factors, ultimately PoreRepair aims to highlight robust therapeutic targets that can be explored in the context of non-infectious damage, offering potential applications beyond S. pneumoniae infection.