title: Impact of caspase-1/11, -3, -7, or IL-1β/IL-18 deficiency on rabies virus-induced macrophage cell death and onset of disease.
abstract: Rabies virus is a highly neurovirulent RNA virus, which causes about 59000 deaths in humans each year. Previously, we described macrophage cytotoxicity upon infection with rabies virus. Here we examined the type of cell death and the role of specific caspases in cell death and disease development upon infection with two laboratory strains of rabies virus: Challenge Virus Standard strain-11 (CVS-11) is highly neurotropic and lethal for mice, while the attenuated Evelyn-Rotnycki-Abelseth (ERA) strain has a broader cell tropism, is non-lethal and has been used as an oral vaccine for animals. Infection of Mf4/4 macrophages with both strains led to caspase-1 activation and IL-1βand IL-18 production, as well as activation of caspases-3, -7, -8, and -9. Moreover, absence of caspase-3, but not of caspase-1 and -11 or -7, partially inhibited virus-induced cell death of bone marrow-derived macrophages. Intranasal inoculation with CVS-11 of mice deficient for either caspase-1 and -11 or -7 or both IL-1βand IL-18 led to general brain infection and lethal disease similar to wild-type mice. Deficiency of caspase-3, on the other hand, significantly delayed the onset of disease, but did not prevent final lethal outcome. Interestingly, deficiency of caspase-1/11, the key executioner of pyroptosis, aggravated disease severity caused by ERA virus, whereas wild-type mice or mice deficient for either caspase-3, -7, or both IL-1βand IL-18 presented the typical mild symptoms associated with ERA virus. In conclusion, rabies virus infection of macrophages induces caspase-1- and caspase-3-dependent cell death.In vivocaspase-1/11 and caspase-3 differently affect disease development in response to infection with the attenuated ERA strain or the virulent CVS-11 strain, respectively. Inflammatory caspases seem to control attenuated rabies virus infection, while caspase-3 aggravates virulent rabies virus infection.
authors.affiliation: National Reference Centre of Rabies, Viral Diseases, Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP), Brussels, Belgium; Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Kip
authors.affiliation: National Reference Centre of Rabies, Viral Diseases, Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP) , Brussels, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Nazé
authors.affiliation: National Reference Centre of Rabies, Viral Diseases, Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP) , Brussels, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Suin
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Inflammation Research Center, Molecular Signalling and Cell Death Unit, VIB, Ghent, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Vanden Berghe
authors.affiliation: National Reference Centre of Rabies, Viral Diseases, Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP) , Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Francart
authors.affiliation: National Reference Centre of Rabies, Viral Diseases, Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP) , Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Lamoral
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Inflammation Research Center, Molecular Signalling and Cell Death Unit, VIB, Ghent, Belgium.
authors.forename: P
authors.identifier: 0000-0002-6669-8822
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: National Reference Centre of Rabies, Viral Diseases, Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP), Brussels, Belgium; Laboratory of Virology, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium.
authors.forename: S
authors.identifier: 0000-0002-8150-9372
authors.initials: S
authors.lastname: Van Gucht
authors.affiliation: National Reference Centre of Rabies, Viral Diseases, Communicable and Infectious Diseases, Scientific Institute of Public Health (WIV-ISP) , Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Kalai