STAPHEX II: Dissecting Staphylococcus aureus macrophage exit

点击翻译按钮获取中文摘要

Nasal carriage of Staphylococcus aureus is a major risk factor for severe and invasive infections. Clinical infection relapse even after state-of-the-art antibiotic therapy is not uncommon, suggesting that bacteria may hide inside cells. Recent studies in murine experimental models indicate that S. aureus persistence in intracellular reservoirs in macrophages in the liver or the peritoneum is critical for the pathology of sepsis development. During chronic infections such as osteomyelitis, S. aureus may also persist within cells for prolonged time. On a molecular and cellular level S. aureus dissemination and host cell exit or persistence are not well understood. After entering the bloodstream, S. aureus is readily phagocytosed by multiple types of phagocytes, e.g. macrophages. However, the pathogen is able to survive within human macrophages and escape from within. We could previously show that phenol soluble modulins (PSMs) and human-specific two component leukocidins LukAB and/or PVL are crucial for this process. PSMs can lyse cells receptor-independently, mediate the escape of S. aureus from phagosomes into the cytosol and function in mouse and humans. Conversely, LukAB and PVL are highly receptor dependent and restricted to humans, hampering analysis of these toxins in conventional mouse models. Our data indicate that LukAB promotes human macrophage escape and cell death in a non-conventional manner: although the NLRP3 inflammasome is activated resulting in IL-1beta release, pyroptosis or apoptosis are not involved; rather MLKL/necroptosis features are activated but are not sufficient for toxin-dependent cell death and exit. Using novel genetically labeled bacteria and cell lines features of exit can be monitored and may involve direct spread to uninfected macrophages by efferocytosis. In good agreement with the SPP’s key aims three resulting questions will be addressed here: 1) Which mechanisms induced by LukAB in ExitStaph synergize with MLKL or act independently? How is the host cell reprogrammed? 2) Is the activity of LukAB from within strictly dependent on classical CD11b binding and/or signaling or involves other bacterial and/or host factors? 3) Does cell-to-cell spread involve bona fide exit and release of free bacteria from cells for subsequent re-infection or does it rather entail uptake of bacteria in combination with cellular debris (efferocytosis)? What are the differences of the two alternative routes of bacterial transfer? By combining our expertise in the molecular and cellular immune cell signaling (Weber) and S. aureus physiology and genetic engineering (Wolz), we will define the key determinants driving cell death or S. aureus persistence. Understanding the mechanisms employed by S. aureus to evade intracellular killing, survive and escape could pave the way for better classification and treatment of clinical S. aureus phenotypes using novel anti-infective treatment approaches.