The PNEUMONIA Times
Pore-Forming Toxins Induce Macrophage Necroptosis during Acute Bacterial Pneumonia
Various bacterial pathogens produce a pore-forming toxin (PFT) that induce necroptosis of macrophages and this can prevent protection against Serratia marcescens hemorrhagic pneumonia. Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, uropathogenic Escherichia coli (UPEC), and purified recombinant pneumolysin, macrophages pretreated with inhibitors of RIP1, RIP3, and MLKL are also protected against death. Necroptosis is a pro-inflammatory mode of programmed cell death that is marked by the intentional disruption of host membranes and the release of pro-inflammatory cytosolic components into the milieu. Necroptosis is the principle mode of cell death and is critical for immune activation following injury.
Serratia marcescens is a Gram-negative nosocomial pathogen that secretes a unique PFT called ShlA. S. marcescens causes a broad spectrum of infectious disease, including hemorrhagic pneumonia, and is an increasingly important cause of hospital and community-acquired infections. Importantly, some clinical isolates of S. marcescens have been reported to be Carbapenem-resistant. Necroptosis is the responsible mechanism for macrophage death following their exposure to ShlA. Specific cell signals induced by PFT intoxication that trigger necroptosis can be blocked for therapeutic intervention during hemorrhagic S. marcescens pneumonia.
PFTs are one of the most common virulence factors found in bacteria. Recently, limited research has shown that PFTs induce necroptosis. Research has shown that several of toxins released by S. aureus triggered necroptosis and this resulted in lung damage. Diverse PFT-producing pathogens regardless Gram-negative or positive, extracellular or intracellular, have the capacity to induce necroptosis of macrophages. Hence, necroptosis is the principle cell death pathway triggered in macrophages by sub-lytic but still lethal levels of a PFT.
The effects of PFTs will eventually induce necroptosis in macrophages via membrane disruption that results in ion dysregulation, ATP depletion, and the induction of cellular ROS. These alone are sufficient to induce macrophage necroptosis. These signaling molecules as viable targets to counteract bacterial infections from significant community and nosocomial pathogens.
References:
González-Juarbe N, Gilley RP, Hinojosa CA, Bradley KM, Kamei A, Gao G, Dube PH, Bergman MA, Orihuela CJ (2015). Pore-Forming Toxins Induce Macrophage Necroptosis during Acute Bacterial Pneumonia. Pubmed. Retrieved 23rd December 2015, from <http://www.ncbi.nlm.nih.gov/pubmed/26659062>