Francisella tularensis induces extensive caspase-3 activation and apoptotic cell death in the tissues of infected mice.
Although Francisella tularensis subsp. tularensis is known to cause extensive tissue necrosis, the pathogenesis of tissue injury has not been elucidated. To characterize cell death in tularemia, C57BL/6 mice were challenged by the intranasal route with type A F. tularensis, and the pathological changes in infected tissues were characterized over the next 4 days. At 3 days postinfection, well-organized inflammatory infiltrates developed in the spleen and liver following the spread of infection from the lungs. By the next day, extensive cell death, characterized by the presence of pyknotic cells containing double-strand DNA breaks, was apparent throughout these inflammatory foci. Cell death was not mediated by activated caspase-1, as has been reported for cells infected with other Francisella subspecies. Mouse macrophages and dendritic cells that had been stimulated with type A F. tularensis did not release interleukin-18 in vitro, a response that requires the activation of procaspase-1. Dying cells within type A F. tularensis-infected tissues expressed activated caspase-3 but very little activated caspase-1. When caspase-1-deficient mice were challenged with type A F. tularensis, pathological changes, including extensive cell death, were similar to those seen in infected wild-type mice. In contrast, type A F. tularensis-infected caspase-3-deficient mice showed much less death among their F4/80+ spleen cells than did infected wild-type mice, and they retained the ability to express tumor necrosis factor alpha and inducible NO synthase. These findings suggest that type A F. tularensis induces caspase-3-dependent macrophage apoptosis, resulting in the loss of potentially important innate immune responses to the pathogen.
Wickstrum
Jason R
JR
Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Bokhari
Sirosh M
SM
Fischer
Jeffrey L
JL
Pinson
David M
DM
Yeh
Hung-Wen
HW
Horvat
Rebecca T
RT
Parmely
Michael J
MJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D005604:Francisella tularensis / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D014406:Tularemia / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*
D016207:Cytokines; C505409:Casp3 protein, mouse; D053148:Caspase 3
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