Cooperative Cytotoxins: A New Look at an Old Observation of Bacterial Crosstalk

Cooperative (or synergistic) hemolysis, the ability of two bacterial species to jointly lyse erythrocytes, has long been recognized as a helpful tool in the identification of common pathogens (i.e. the CAMP reaction between Streptococcus agalactiae and Staphylococcus aureus). However, to examine these biological partnerships separately from their use in the diagnostic lab provides new perspectives on toxicity to host tissue during infections and in health. Many examples of such pairings exist, and typically reflect the sequential action of a phospholipase (e.g., PLC from Staphylococcus aureus or Clostridium perfringens), followed by a second bacterial toxin acting on the altered membrane, e.g. the CAMP protein of group B streptococci, or the cholesterol oxidase of Rhodococcus equi. Commonly occurring cooperative cytotoxic partnerships are reviewed, along with their biochemical mechanisms of action. Newly reported is the ability of hemolytic collaborations to accommodate a midcourse change in conditions of oxygenation. Thus, erythrocytes altered by PLC of C. perfringens grown anaerobically, are lysed following exposure to the strict aerobe R. equi, in air. Why does this matter? Microbial communities on tissue (i.e. the microbiome) are increasingly understood to impact the health of hosts. Pathogenesis, especially in anaerobic infections, often reflects the combined actions of microbial pathogens, commensal (resident) microorganisms, and metabolites from the host. Products of some cooperative reactions (i.e., ceramide and oxysterol) are directly toxic, e.g., to the immune system. Host environments include a range of oxygenation not intuitively evident, i.e., extreme anaerobiosis in the mouth, creating ideal conditions for cooperative cytotoxicity to occur in vivo. To appreciate the impact of common hydrolytic enzymes and other proteins from diverse sources deepens our understanding of the host and its complex microbial community.