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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ftdoajarticles:oai:doaj.org/article:303aaa7626214e9fa6ff891afd627703 2024-09-09T19:27:22+00:00 Benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis. Andrés F Londoño Jennifer M Farner Marlon Dillon Dennis J Grab Yuri Kim Diana G Scorpio J Stephen Dumler 2024-02-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0011993 https://doaj.org/article/303aaa7626214e9fa6ff891afd627703 EN eng Public Library of Science (PLoS) https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011993&type=printable https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0011993 https://doaj.org/article/303aaa7626214e9fa6ff891afd627703 PLoS Neglected Tropical Diseases, Vol 18, Iss 2, p e0011993 (2024) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2024 ftdoajarticles https://doi.org/10.1371/journal.pntd.0011993 2024-08-05T17:49:49Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 18 2 e0011993 |
institution |
Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 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. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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. |
format |
Article in Journal/Newspaper |
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 |
title |
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_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_sort |
benidipine impairs innate immunity converting sublethal to lethal infections in a murine model of spotted fever rickettsiosis. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2024 |
url |
https://doi.org/10.1371/journal.pntd.0011993 https://doaj.org/article/303aaa7626214e9fa6ff891afd627703 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 18, Iss 2, p e0011993 (2024) |
op_relation |
https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011993&type=printable https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0011993 https://doaj.org/article/303aaa7626214e9fa6ff891afd627703 |
op_doi |
https://doi.org/10.1371/journal.pntd.0011993 |
container_title |
PLOS Neglected Tropical Diseases |
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18 |
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2 |
container_start_page |
e0011993 |
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1809896805786189824 |