The interplay between platelets and pathogenic bacteria

• Applicants: Professor Dr. Andreas Greinacher; Professor Dr. Sven Hammerschmidt
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523973396

Platelets are anucleated cells produced by megakaryocyte (MK) shedding in the bone marrow and the lungs. They are increasingly recognized as important components of the host immune system and can be considered as the first responding innate immune cells towards invading bacteria. Pathogenic bacteria spreading from the site of infection often cross host barriers and enter the circulatory system leading to bacteraemia and sepsis. Complications of bacteraemia associated with abnormal platelet functions are e.g., thrombocytopenia and the acute respiratory distress syndrome (ARDS). Interactions between platelets and bacteria are characterized by direct or indirect binding of bacteria to platelets or via released bacterial factors. Using Staphylococcus aureus and Streptococcus pneumoniae as model microorganisms, we have shown that platelets and pathogenic bacteria mutually affect each other with varying outcome. Both pathobionts cause severe pneumonia, however, the mechanisms and interplay with platelets are different. Whereas S. aureus induced platelet activation leads to killing of the pathogen by compounds in the platelet releasate (likely defensins), pneumococci kill platelets themselves via its pore-forming toxin pneumolysin. This renders platelets non-functional and their sealing function of the endothelium is impaired. Importantly, we showed in vitro that pharmaceutical immunoglobulin preparations such as IVIG neutralize the toxin and completely secured the platelet phenotype function as well as the function in the presence of pneumolysin. In our proposed project we will transfer the findings of our previous in vitro experiments into an in vivo mouse model and decipher the complex mechanisms of platelet-bacteria interplay and the consequences for sealing the lung barrier. We will investigate the influence of pneumococcal pneumolysin and neuraminidase on the development of respiratory distress in our acute pneumococcal mouse pneumonia model. Leakage over the pulmonary barrier will be analysed upon infection with the different strains and markers of inflammation as well as the infiltration of neutrophils, megakaryocytes (MKs), and platelets will be investigated. Using our pneumonia model and immunoglobulin preparations, we also aim to identify mechanisms of therapeutic interventions. We hypothesize that platelets will remain functional upon therapeutic intervention and that capillary leakage is avoided. These in vivo studies will be extended by elucidating the role of platelet glycoprotein VI (GPVI) in pneumococcal pneumonia, because GPVI is suggested to play a crucial role in dampening inflammation and infections. As exploratory experiment we will assess the interaction of S. aureus, pneumococci, their proteins and toxins with human megakaryocytes in vitro and in an ex vivo heart-lung model. Complementary to our in vivo studies, the interplay of pneumococci and bacterial proteins on the platelet-neutrophil axis will be investigated in vitro.

• DFG Programme: Research Grants