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 park...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-02-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011993&type=printable |
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| author | Andrés F Londoño Jennifer M Farner Marlon Dillon Dennis J Grab Yuri Kim Diana G Scorpio J Stephen Dumler |
| author_facet | Andrés F Londoño Jennifer M Farner Marlon Dillon Dennis J Grab Yuri Kim Diana G Scorpio J Stephen Dumler |
| author_sort | Andrés F Londoño |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-25T00:14:19Z |
| format | Article |
| id | doaj.art-303aaa7626214e9fa6ff891afd627703 |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-04-25T00:14:19Z |
| publishDate | 2024-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-303aaa7626214e9fa6ff891afd6277032024-03-13T05:31:47ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352024-02-01182e001199310.1371/journal.pntd.0011993Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis.Andrés F LondoñoJennifer M FarnerMarlon DillonDennis J GrabYuri KimDiana G ScorpioJ Stephen DumlerSpotted 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.https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011993&type=printable |
| spellingShingle | Andrés F Londoño Jennifer M Farner Marlon Dillon Dennis J Grab Yuri Kim Diana G Scorpio J Stephen Dumler Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis. PLoS Neglected Tropical Diseases |
| title | Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis. |
| title_full | Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis. |
| title_fullStr | Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis. |
| title_full_unstemmed | Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis. |
| title_short | Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis. |
| title_sort | benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis |
| url | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011993&type=printable |
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