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Unique human immune signature of Ebola virus disease in Guinea.

ABSTRACT: Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD. In particular, very little is known about human immune responses to Ebola virus. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4(+) and CD8(+) T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.

SUBMITTER: Ruibal P

PROVIDER: S-EPMC4876960 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Unique human immune signature of Ebola virus disease in Guinea.

Ruibal Paula P Oestereich Lisa L Lüdtke Anja A Becker-Ziaja Beate B Wozniak David M DM Kerber Romy R Korva Miša M Cabeza-Cabrerizo Mar M Bore Joseph A JA Koundouno Fara Raymond FR Duraffour Sophie S Weller Romy R Thorenz Anja A Cimini Eleonora E Viola Domenico D Agrati Chiara C Repits Johanna J Afrough Babak B Cowley Lauren A LA Ngabo Didier D Hinzmann Julia J Mertens Marc M Vitoriano Inês I Logue Christopher H CH Boettcher Jan Peter JP Pallasch Elisa E Sachse Andreas A Bah Amadou A Nitzsche Katja K Kuisma Eeva E Michel Janine J Holm Tobias T Zekeng Elsa-Gayle EG García-Dorival Isabel I Wölfel Roman R Stoecker Kilian K Fleischmann Erna E Strecker Thomas T Di Caro Antonino A Avšič-Županc Tatjana T Kurth Andreas A Meschi Silvia S Mély Stephane S Newman Edmund E Bocquin Anne A Kis Zoltan Z Kelterbaum Anne A Molkenthin Peter P Carletti Fabrizio F Portmann Jasmine J Wolff Svenja S Castilletti Concetta C Schudt Gordian G Fizet Alexandra A Ottowell Lisa J LJ Herker Eva E Jacobs Thomas T Kretschmer Birte B Severi Ettore E Ouedraogo Nobila N Lago Mar M Negredo Anabel A Franco Leticia L Anda Pedro P Schmiedel Stefan S Kreuels Benno B Wichmann Dominic D Addo Marylyn M MM Lohse Ansgar W AW De Clerck Hilde H Nanclares Carolina C Jonckheere Sylvie S Van Herp Michel M Sprecher Armand A Xiaojiang Gao G Carrington Mary M Miranda Osvaldo O Castro Carlos M CM Gabriel Martin M Drury Patrick P Formenty Pierre P Diallo Boubacar B Koivogui Lamine L Magassouba N'Faly N Carroll Miles W MW Günther Stephan S Muñoz-Fontela César C

Nature 20160501 7601

Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD. In particular, very little is known about human immune responses to Ebola virus. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established b ...[more]

PMID: 27147028

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Project description:BackgroundIn the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea.MethodsIn this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group.ResultsA total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed.ConclusionsThe transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Project description:Ebola virus (EBOV) transmission is currently poorly characterized and is thought to occur primarily by direct contact with infectious material; however transmission from swine to nonhuman primates via the respiratory tract has been documented. To establish an EBOV transmission model for performing studies with statistical significance, groups of six guinea pigs (gps) were challenged intranasally (i.n.) or intraperitoneally (i.p.) with 10,000 times the 50% lethal dose (LD50) of gp-adapted EBOV, and naive gps were then introduced as cage mates for contact exposure at 1 day postinfection (p.i.). The animals were monitored for survival and clinical signs of disease and quantitated for virus shedding postexposure. Changes in the duration of contact of naive gps with infected animals were evaluated for their impact on transmission efficiency. Transmission was more efficient from i.n.- than from i.p.-challenged gps, with 17% versus 83% of naive gps surviving exposure, respectively. Virus shedding was detected beginning at 3 days p.i. from both i.n.- and i.p.-challenged animals. Contact duration positively correlated with transmission efficiency, and the abrogation of direct contact between infected and naive animals through the erection of a steel mesh was effective at stopping virus spread, provided that infectious animal bedding was absent from the cages. Histopathological and immunohistochemical findings show that i.n.-infected gps display enhanced lung pathology and EBOV antigen in the trachea, which supports increased virus transmission from these animals. The results suggest that i.n.-challenged gps are more infectious to naive animals than their systemically infected counterparts and that transmission occurs through direct contact with infectious materials, including those transported through air movement over short distances.Ebola is generally thought to be spread between humans though infectious bodily fluids. However, a study has shown that Ebola can be spread from pigs to monkeys without direct contact. Further studies have been hampered, because an economical animal model for Ebola transmission is not available. To address this, we established a transmission model in guinea pigs and determined the mechanisms behind virus spread. The survival data, in addition to microscopic examination of lung and trachea sections, show that mucosal infection of guinea pigs is an efficient model for Ebola transmission. Virus spread is increased with longer contact times with an infected animal and is possible without direct contact between an infected and a naive host but can be stopped if infectious materials are absent. These results warrant consideration for the development of future strategies against Ebola transmission and for a better understanding of the parameters involved in virus spread.

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Unique human immune signature of Ebola virus disease in Guinea.

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Unique human immune signature of Ebola virus disease in Guinea.

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