Mannose receptor-derived peptides neutralize pore-forming toxins and reduce inflammation and development of pneumococcal disease

Cholesterol-dependent cytolysins (CDCs) are essential virulence factors for human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes (streptolysin O, SLO), and Listeria monocytogenes (Listeriolysin, LLO). Recently, we identified that PLY interacts with the mannose receptor (MRC-1) on specific immune cells thereby evoking anti-inflammatory responses. Here, we identified the interaction sites between MRC-1 and CDCs using computational docking. We designed peptides from the CTLD4 domain of MRC-1 that binds to PLY, SLO and LLO, respectively. In vitro, the peptides blocked CDC-induced cytolysis and inflammatory cytokine production by human macrophages, and reduced PLY-induced damage of the epithelial barrier integrity and blocked bacterial invasion into the epithelium in a 3D lung tissue model. Pre-treatment of human DCs with peptides blocked bacterial uptake via MRC-1 and reduced intracellular bacterial survival by targeting intracellular bacteria to autophagosomes. Calcium-phosphate-nanoparticles loaded with peptides installed intranasally during infection improved survival and bacterial clearance in both zebrafish and mice models of pneumococcal infection. We suggest that MRC-1 peptides can be employed as adjunctive therapeutics with antibiotics to treat bacterial infections by countering CDC actions.