Bacterial pore‐forming toxin effects on myeloid DC are mediated through purinergic receptors

Abstract

Cholesterol‐dependent cytolysins (CDC), a class of gram‐positive bacterial exotoxins, bind cholesterol in cell membranes and oligomerize to form pores. While a small numbers of pores can be repaired by cells, the formation of many pores leads to cell death. Differences in susceptibility to CDC have been observed for various immune cells, suggesting potential differences downstream of CDC‐induced pore formation. In this study, we have addressed the mechanism by which exposure to CDC induces pores in myeloid lineage cells relative to their toxic effects. Using a cell line derived from fetal mouse skin with myeloid dendritic cell properties, we generated a toxin‐resistant cell line by selection with increasing amounts of CDC family member tetanolysin O. Using this variant cell line combined with pharmacologic inhibitor studies in primary myeloid cells, we show a process in which CDC‐induced pores allow rapid release of intracellular adenosine triphosphate (ATP) into the surrounding environment followed by activation of the cell surface ATP receptor P2X7, and subsequent pore formation and IL‐1beta release. Our study demonstrates that bacterial toxins can trigger an endogenous host cell inflammatory response that might both protect the host and induce tissue damage when excessive. Supported by R01 AI57168 and 5T32CA082084‐09 grants.