Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis

Spotted fever group rickettsiae are tick-borne obligate intracellular bacteria that infect microvascular endothelial cells. Humans and mammalian infection results in endothelial cell barrier dysfunction and increased vascular permeability. We previously demonstrated that treatment of Rickettsia parkeri-infected cells with the calcium channel blocker benidipine significantly delayed vascular barrier permeability. Thus, we hypothesized that benidipine, known to be safe and effective for other clinical processes, could reduce rickettsia-induced vascular permeability in vivo in an animal model of spotted fever rickettsiosis. Based on liver, lung and brain vascular FITC-dextran extravasation studies, benidipine did not reliably impact vascular permeability. However, it precipitated a deleterious effect on responses to control sublethal R. parkeri infection. Animals treated with benidipine alone had no clinical signs or changes in histopathology and splenic immune cell distributions. Benidipine-treated infected animals had marked increases in tissue and blood bacterial loads, more extensive inflammatory histopathologic injury, and changes in splenic architecture and immune cell distributions potentially reflecting diminished Ca2+ signaling, reduced innate immune cell activation, and loss of rickettsial propagation control. Impaired T cell activation by R. parkeri antigen in the presence of benidipine was confirmed in vitro with the use of NKT cell hybridomas. The unexpected findings stand in stark contrast to recent discussions of the benefits of calcium channel blockers for viral infections and chronic infectious or inflammatory diseases. A role for calcium channel blockers in exacerbation of human rickettsiosis and acute inflammatory infections should be evaluated by a retrospective review of patient’s outcomes and medications.Author summary: Spotted fever group rickettsiae infect endothelial cells of humans and animals with spotted fever rickettsiosis. Severe infection is associated with marked blood vessel permeability. We showed in vitro that certain calcium-active drugs, such as calcium channel blockers can stabilize or reverse vascular permeability in vitro. This prompted a preclinical study of the calcium channel blocker benidipine in a spotted fever rickettsiosis mouse model designed to yield 50% deaths. While benidipine did not reliably stabilize vascular permeability in this model, it’s use led to a significant dose-dependent increase in animal deaths and a marked loss in the control of rickettsial infections, also associated with a significant reduction in the ability to mount an early innate immune response. Hypothetically, this reflected diminished Ca2+ signaling and reduced innate immune cell activation. Thus, we also showed impaired R. parkeri antigen T cell activation in the presence of benidipine in vitro providing support. These findings are distinct in outcome from recent discussions of calcium channel blocker benefits in viral and chronic infectious or inflammatory diseases. A role for calcium channel blockers in exacerbation of human rickettsiosis and acute inflammatory infections should be evaluated.