title: Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses.
abstract: Chikungunya virus (CHIKV) surprised medical workers by a massive outbreak in the Indian Ocean region, reaching Europe in 2007, with exceptional pathologies in infants and elderly patients. Although CHIKV was recently shown to persist in myoblasts, monocytes, and macrophages, we argued that robust antiviral mechanisms, including apoptosis, are essential to ward off the virus. Herein, we tested the capacity of CHIKV to mobilize the apoptotic machinery in HeLa cells as well as primary fibroblasts, making use of several inhibitors of caspases, cell blebbing, and engulfment of the apoptotic blebs by neighboring cells. CHIKV triggered apoptosis through intrinsic and extrinsic pathways. Bystander apoptosis was also evidenced in neighboring cells in a caspase-8-dependent manner. Remarkably, by hiding in apoptotic blebs, CHIKV was able to infect neighboring cells. In HeLa cells, these events were inhibited specifically by zVAD-fmk and DEVD-cho (caspase inhibitors), blebbistatin, Y-27632 (ROCK inhibitor), and genistein, annexin V, and cytochalasin B (inhibitors of blebbing and engulfment). These CHIKV-apoptotic blebs were also capable of infecting macrophages (primary cultures, MM6- and THP1-PMA differentiated cells) otherwise refractory to infection by CHIKV alone. Remarkably, viral replication in macrophages did not yield a proinflammatory response. We describe a novel infectious mechanism by which CHIKV invades host cells and escapes the host response.
authors.affiliation: GRI/IRG Immunopathology and Infection Research Grouping, University of La Réunion, CYROI, 2 rue Maxime Rivière, 97491, Ste Clotilde, Reunion. pascale.krejbich-trotot@chr-reunion.fr
authors.forename: Pascale
authors.initials: P
authors.lastname: Krejbich-Trotot
authors.forename: Melanie
authors.initials: M
authors.lastname: Denizot
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Hoarau
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Jaffar-Bandjee
authors.forename: Trina
authors.initials: T
authors.lastname: Das
authors.forename: Philippe
authors.initials: P
authors.lastname: Gasque
mesh_terms: D018354:Alphavirus Infections / Q000821:virology; D000577:Amides / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D024201:Bystander Effect / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002646:Chikungunya virus / Q000502:physiology*; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D019833:Genistein / Q000494:pharmacology; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D014709:Vero Cells; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000577:Amides; D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D009842:Oligopeptides; D011725:Pyridines; C108637:aspartyl-glutamyl-valyl-aspartal; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C108830:Y 27632; C472645:blebbistatin; D019833:Genistein; D053181:Caspase 8