title: Crimean-Congo haemorrhagic fever replication interplays with regulation mechanisms of apoptosis.
abstract: Pathogenesis of viral haemorrhagic fevers is associated with alteration of vascular barrier function and haemorrhage. To date, the specific mechanism behind this is unknown. Programmed cell death and regulation of apoptosis in response to viral infection is an important factor for host or virus survival but this has not been well-studied in the case of Crimean-Congo hemorrhagic fever virus (CCHFV). In this study, we demonstrated that CCHFV infection suppresses cleavage of poly(ADP-ribose) polymerase (PARP), triggered by staurosporine early post-infection. We also demonstrated that CCHFV infection suppresses activation of caspase-3 and caspase-9. Most interestingly, we found that CCHFV N can suppress induction of apoptosis by Bax and inhibit the release of cytochrome c from the inner membrane of mitochondria to cytosol. However, CCHFV infection induces activation of Bid late post-infection, suggesting activation of extrinsic apoptotic signalling. Consistently, supernatant from cells stimulated late post-infection was found to induce PARP cleavage, most probably through the TNF-α death receptor pathway. In summary, we found that CCHFV has strategies to interplay with apoptosis pathways and thereby regulate caspase cascades. We suggest that CCHFV suppresses caspase activation at early stages of the CCHFV replication cycle, which perhaps benefits the establishment of infection. Furthermore, we suggest that the host cellular response at late stages post-infection induces host cellular pro-apoptotic molecules through the death receptor pathway.
authors.affiliation: Karolinska Institute, Stockholm SE-171 77, Sweden.|Public Health Agency of Sweden, SE-171 82, Sweden.
authors.forename: Helen
authors.initials: H
authors.lastname: Karlberg
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore.|Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System (NUHS), National University of Singapore, Singapore.
authors.forename: Yee-Joo
authors.initials: YJ
authors.lastname: Tan
authors.affiliation: National Veterinary Institute, Uppsala SE-756 51, Sweden.|Karolinska Institute, Stockholm SE-171 77, Sweden.|Public Health Agency of Sweden, SE-171 82, Sweden.
authors.forename: Ali
authors.initials: A
authors.lastname: Mirazimi
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D003225:Hemorrhagic Fever Virus, Crimean-Congo / Q000502:physiology*; D006801:Humans; D009698:Nucleoproteins / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D009698:Nucleoproteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053453:Caspase 9