title: Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection.
abstract: Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells.
authors.affiliation: Virology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.|Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Agrati
authors.affiliation: Virology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Castilletti
authors.affiliation: Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Casetti
authors.affiliation: Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sacchi
authors.affiliation: Microscopy Laboratory, INMI "L.Spallanzani", Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Falasca
authors.affiliation: Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Turchi
authors.affiliation: Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Tumino
authors.affiliation: Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Bordoni
authors.affiliation: Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Cimini
authors.affiliation: Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Viola
authors.affiliation: Virology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Lalle
authors.affiliation: Virology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bordi
authors.affiliation: Epidemiology Division, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lanini
authors.affiliation: Cellular Immunology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Martini
authors.affiliation: Clinical Division, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Nicastri
authors.affiliation: Clinical Division, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Petrosillo
authors.affiliation: Epidemiology Division, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Puro
authors.affiliation: Microscopy Laboratory, INMI "L.Spallanzani", Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Piacentini
authors.affiliation: Virology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Caro
authors.affiliation: National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Canada.
authors.forename: G P
authors.initials: GP
authors.lastname: Kobinger
authors.affiliation: Division of Infection and Immunity, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Zumla
authors.affiliation: Epidemiology Division, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ippolito
authors.affiliation: Virology Laboratory, INMI-IRCCS "L.Spallanzani", Rome, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: Capobianchi
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D029043:Ebolavirus / Q000502:physiology; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000378:metabolism; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000032:analysis; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D006684:HLA-DR Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C000594176:ZMapp; D019014:fas Receptor; D007371:Interferon-gamma; D051997:ADP-ribosyl Cyclase 1