RTX Toxins Ambush Immunity’s First Cellular Responders

The repeats-in-toxin (RTX) family represents a unique class of bacterial exoproteins. The first family members described were toxins from Gram-negative bacterial pathogens; however, additional members included exoproteins with diverse functions. Our review focuses on well-characterized RTX family toxins from <i>Aggregatibacter</i><i>actinomycetemcomitans</i> (LtxA), <i>Mannheimia</i><i>haemolytica</i> (LktA), <i>Bordetella pertussis</i> (CyaA), uropathogenic <i>Escherichia coli</i> (HlyA), and <i>Actinobacillus pleuropneumoniae</i> (ApxIIIA), as well as the studies that have honed in on a single host cell receptor for RTX toxin interactions, the β₂ integrins. The β₂ integrin family is composed of heterodimeric members with four unique alpha subunits and a single beta subunit. β₂ integrins are only found on leukocytes, including neutrophils and monocytes, the first responders to inflammation following bacterial infection. The LtxA, LktA, HlyA, and ApxIIIA toxins target the shared beta subunit, thereby targeting all types of leukocytes. Specific β₂ integrin family domains are required for the RTX toxin's cytotoxic activity and are summarized here. Research examining the domains of the RTX toxins required for cytotoxic and hemolytic activity is also summarized. RTX toxins attack and kill phagocytic immune cells expressing a single integrin family, providing an obvious advantage to the pathogen. The critical question that remains, can the specificity of the RTX-β₂ integrin interaction be therapeutically targeted?