• E. Pallasch, D. Wozniak, L. Oestereich, A. Thielebein, J. Müller, S. Bockholt, C. Hoffmann

Overview

Lassa virus (LASV) is a zoonotic pathogen that is endemic in several West African countries. It causes annual outbreaks of Lassa fever (LF) with a case fatality rate of 20-30% in hospitalized patients. LASV belongs to the family of Arenaviridae and is transmitted from it’s wildly distributed natural rodent host Mastomys natalensis to humans through the direct contact with infected animals or via contaminated household items or food. However human-to human transmission is possible and occurs mostly in hospital settings. LASV causes annual outbreaks of Lassa fever (LF) with 100.000 – 300.000 estimated infections and 5.000 deaths per year based on seroprevalence studies. The pathogenesis of LF is poorly understood, although deregulated host responses presumably play a key role. The projects in this junior research group focus on furthering the understanding of the role of antigen presenting cells (APC) and T cells in triggering the pathophysiological cascade. A second focus is deepening the understanding of the relationship of Lassa virus with it’s natural host.

 

Applications of motivated students are always welcome! If you are interested in immunology and virus research, please apply via email to oestereich(at)bnitm.de.

Research Projects

Pathological host responses to Lassa virus infection – from mice to men

Hemorrhagic fever viruses (VHFs) like Lassa virus (LASV), Ebola virus (EBOV) or Crimean- Congo hemorrhagic fever virus (CCHFV) can cause severe diseases in humans that are characterized by high morbidity and mortality. LASV is a zoonotic pathogen that was discovered in 1969 in Nigeria and is endemic in Nigeria and several other West African countries.

Despite the importance of LASV as a human pathogen, very little is known about the pathophysiology of LASV. Severe LF is characterized by high virus concentrations, inflammation, terminal shock and multi organ failure. The extent of the organ damage however is insufficient to account for death, which is mirrored in non human primate (NHP) experiments. Despite many years of research, the exact cause of death during LF is still completely unclear. The data from humans and NHPs indicates that deregulated host responses plays a key role in LASV pathophysiology but no all-encompassing model outlining beneficial and pathological immune responses exists so far, highlighting the urgent need to address the role of immune responses during LF.

We have previously developed a lethal, immune competent mouse model that is susceptible to the infection with LASV and that reproduces key features of severe human LF. This model allowed mechanistic studies of the host response to LASV in a small animal model for the first time. This model allows us to determine the role of antigen presenting cells (APC) and lymphocytes in LASV pathogenesis.

 

In vivo experiments in NHPs and mouse models as well as preliminary findings from human samples, identified APCs such as macrophages and dendritic cells (DCs) as target cells during infection. Migratory APCs, such as DCs might play an important role spreading the infection as they migrate to lymph nodes to prime naïve T cells and might transport the virus along. In vitro experiments with infected DCs and macrophages revealed a lack of maturation and no release of inflammatory cytokines or upregulation of activation molecules on their surface. In vivo data however showed that survival is correlated with a robust activation of the immune response. To this end, we investigate virus replication in APC, their functional status, their participation in virus dissemination, and their contribution to activation and regulation of innate and adaptive immune responses.

Due to the late appearance of neutralizing antibodies and the ambivalent results of treatments with convalescent plasma, T cells are considered to play a major role in the clearance of the virus. NHP experiments and data from humans support the importance of the early and strong activation of CD4+ and CD8+ T cells. Many vaccines are thus designed to induce a robust T cell response as well as a humeral response. Previous experiments however revealed CD8+ T cells as a major pathogenicity factor. The depletion of CD8+ T cells prevented death, reduced amount of proinflammatory cytokines in serum and prevented vascular leakage. These findings emphasize that further research is needed to understand the role of T cells in LF.

Lassa virus immunology in the natural host

No adequate data exist on the mode of transmission (vertical, perinatal, in adulthood, sexual) of Lassa virus or any other Old World arenavirus among the natural host population (Mastomys natalensis), the period of infectivity (persistent for life or limited) and the relation between rodent density and the prevalence of the virus in the rodent population. These parameters have dramatic effects on the outcome of ecological disease models. Knowing how a virus is transmitted is crucial to develop useful models that can predict how, how fast and when the infection will spread in a host population.

All Publications

Department of Virology

Kinetics of Soluble Mediators of the Host Response in Ebola Virus Disease.
Kerber R, Krumkamp R, Korva M, Rieger T, Wurr S, Duraffour S, Oestereich L, Gabriel M, Sissoko D, Anglaret X, Malvy D, May J, Županc TA, Muñoz-Fontela C, Günther S.
J Infect Dis. 2018 Nov 22;218(suppl_5):S496-S503. doi: 10.1093/infdis/jiy429.

T-Cell Receptor Diversity and the Control of T-Cell Homeostasis Mark Ebola Virus Disease Survival in Humans
Speranza E, Ruibal P, Port JR, Feng F, Burkhardt L, Grundhoff A, Günther S, Oestereich L, Hiscox JA, Connor JH, Muñoz-Fontela C
J Infect Dis. 2018 Nov 22;218(suppl_5):S508-S518. doi: 10.1093/infdis/jiy352

Antibodies to the Glycoprotein GP2 Subunit Cross-React between Old and New World Arenaviruses
Amanat F, Duehr J, Oestereich L, Hastie KM, Ollmann Saphire E, Krammer F
mSphere. 2018 May 2;3(3). pii: e00189-18. doi: 10.1128/mSphere.00189-18. eCollection 2018 May-Jun

Erratum for Madelain et al., "Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses"
Madelain V, Guedj J, Mentré F, Nguyen THT, Jacquot F, Oestereich L, Kadota T, Yamada K, Taburet AM, de Lamballerie X, Raoul H
Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: e02093-17. doi: 10.1128/AAC.02093-17. Print 2018 Jan

Determining Ribavirin's mechanism of action against Lassa virus infection
Carrillo-Bustamante P, Nguyen THT, Oestereich L, Günther S, Guedj J, Graw F
Sci Rep. 2017 Sep 15;7(1):11693. doi: 10.1038/s41598-017-10198-0

Novel Cross-Reactive Monoclonal Antibodies against Ebolavirus Glycoproteins Show Protection in a Murine Challenge Model
Duehr J, Wohlbold TJ, Oestereich L, Chromikova V, Amanat F, Rajendran M, Gomez-Medina S, Mena I, tenOever BR, García-Sastre A, Basler CF, Munoz-Fontela C, Krammer F
J Virol. 2017 Jul 27;91(16). pii: e00652-17. doi: 10.1128/JVI.00652-17. Print 2017 Aug 15

Different features of Vδ2 T and NK cells in fatal and non-fatal human Ebola infections
Cimini E, Viola D, Cabeza-Cabrerizo M, Romanelli A, Tumino N, Sacchi A, Bordoni V, Casetti R, Turchi F, Martini F, Bore JA, Koundouno FR, Duraffour S, Michel J, Holm T, Zekeng EG, Cowley L, Garcia Dorival I, Doerrbecker J, Hetzelt N, Baum JHJ, Portmann J, Wölfel R, Gabriel M, Miranda O, Díaz G, Díaz JE, Fleites YA, Piñeiro CA, Castro CM, Koivogui L, Magassouba N, Diallo B, Ruibal P, Oestereich L, Wozniak DM, Lüdtke A, Becker-Ziaja B, Capobianchi MR, Ippolito G, Carroll MW, Günther S, Di Caro A, Muñoz-Fontela C, Agrati C
PLoS Negl Trop Dis. 2017 May 30;11(5):e0005645. doi: 10.1371/journal.pntd.0005645. eCollection 2017 May

Ebola virus infection kinetics in chimeric mice reveal a key role of T cells as barriers for virus dissemination
Lüdtke A, Ruibal P, Wozniak DM, Pallasch E, Wurr S, Bockholt S, Gómez-Medina S, Qiu X, Kobinger GP, Rodríguez E, Günther S, Krasemann S, Idoyaga J, Oestereich L, Muñoz-Fontela C
Lüdtke A, Ruibal P, Wozniak DM, Pallasch E, Wurr S, Bockholt S, Gómez-Medina S, Qiu X, Kobinger GP, Rodríguez E, Günther S, Krasemann S, Idoyaga J, Oestereich L, Muñoz-Fontela C

Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study
Sissoko D, Duraffour S, Kerber R, Kolie JS, Beavogui AH, Camara AM, Colin G, Rieger T, Oestereich L, Pályi B, Wurr S, Guedj J, Nguyen THT, Eggo RM, Watson CH, Edmunds WJ, Bore JA, Koundouno FR, Cabeza-Cabrerizo M, Carter LL, Kafetzopoulou LE, Kuisma E, Michel J, Patrono LV, Rickett NY, Singethan K, Rudolf M, Lander A, Pallasch E, Bockholt S, Rodríguez E, Di Caro A, Wölfel R, Gabriel M, Gurry C, Formenty P, Keïta S, Malvy D, Carroll MW, Anglaret X, Günther S
Lancet Glob Health. 2017 Jan;5(1):e80-e88. doi: 10.1016/S2214-109X(16)30243-1

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses
Madelain V, Guedj J, Mentré F, Nguyen TH, Jacquot F, Oestereich L, Kadota T, Yamada K, Taburet AM, de Lamballerie X, Raoul H
Antimicrob Agents Chemother. 2016 Dec 27;61(1). pii: e01305-16. doi: 10.1128/AAC.01305-16. Print 2017 Jan

Analysis of Diagnostic Findings From the European Mobile Laboratory in Guéckédou, Guinea, March 2014 Through March 2015
Kerber R, Krumkamp R, Diallo B, Jaeger A, Rudolf M, Lanini S, Bore JA, Koundouno FR, Becker-Ziaja B, Fleischmann E, Stoecker K, Meschi S, Mély S, Newman EN, Carletti F, Portmann J, Korva M, Wolff S, Molkenthin P, Kis Z, Kelterbaum A, Bocquin A, Strecker T, Fizet A, Castilletti C, Schudt G, Ottowell L, Kurth A, Atkinson B, Badusche M, Cannas A, Pallasch E, Bosworth A, Yue C, Pályi B, Ellerbrok H, Kohl C, Oestereich L, Logue CH, Lüdtke A, Richter M, Ngabo D, Borremans B, Becker D, Gryseels S, Abdellati S, Vermoesen T, Kuisma E, Kraus A, Liedigk B, Maes P, Thom R, Duraffour S, Diederich S, Hinzmann J, Afrough B, Repits J, Mertens M, Vitoriano I, Bah A, Sachse A, Boettcher JP, Wurr S, Bockholt S, Nitsche A, Županc TA, Strasser M, Ippolito G, Becker S, Raoul H, Carroll MW, De Clerck H, Van Herp M, Sprecher A, Koivogui L, Magassouba N, Keïta S, Drury P, Gurry C, Formenty P, May J, Gabriel M, Wölfel R, Günther S, Di Caro A
J Infect Dis. 2016 Oct 15;214(suppl 3):S250-S257. Epub 2016 Sep 16

Ebola Virus Disease Is Characterized by Poor Activation and Reduced Levels of Circulating CD16+ Monocytes
Lüdtke A, Ruibal P, Becker-Ziaja B, Rottstegge M, Wozniak DM, Cabeza-Cabrerizo M, Thorenz A, Weller R, Kerber R, Idoyaga J, Magassouba N, Gabriel M, Günther S, Oestereich L, Muñoz-Fontela C
J Infect Dis. 2016 Oct 15;214(suppl 3):S275-S280. Epub 2016 Aug 11

Chimeric Mice with Competent Hematopoietic Immunity Reproduce Key Features of Severe Lassa Fever
Oestereich L, Lüdtke A, Ruibal P, Pallasch E, Kerber R, Rieger T, Wurr S, Bockholt S, Pérez-Girón JV, Krasemann S, Günther S, Muñoz-Fontela C
PLoS Pathog. 2016 May 18;12(5):e1005656. doi: 10.1371/journal.ppat.1005656. eCollection 2016 May

Unique human immune signature of Ebola virus disease in Guinea
Ruibal P, Oestereich L, Lüdtke A, Becker-Ziaja B, Wozniak DM, Kerber R, Korva M, Cabeza-Cabrerizo M, Bore JA, Koundouno FR, Duraffour S, Weller R, Thorenz A, Cimini E, Viola D, Agrati C, Repits J, Afrough B, Cowley LA, Ngabo D, Hinzmann J, Mertens M, Vitoriano I, Logue CH, Boettcher JP, Pallasch E, Sachse A, Bah A, Nitzsche K, Kuisma E, Michel J, Holm T, Zekeng EG, García-Dorival I, Wölfel R, Stoecker K, Fleischmann E, Strecker T, Di Caro A, Avšič-Županc T, Kurth A, Meschi S, Mély S, Newman E, Bocquin A, Kis Z, Kelterbaum A, Molkenthin P, Carletti F, Portmann J, Wolff S, Castilletti C, Schudt G, Fizet A, Ottowell LJ, Herker E, Jacobs T, Kretschmer B, Severi E, Ouedraogo N, Lago M, Negredo A, Franco L, Anda P, Schmiedel S, Kreuels B, Wichmann D, Addo MM, Lohse AW, De Clerck H, Nanclares C, Jonckheere S, Van Herp M, Sprecher A, Xiaojiang G, Carrington M, Miranda O, Castro CM, Gabriel M, Drury P, Formenty P, Diallo B, Koivogui L, Magassouba N, Carroll MW, Günther S, Muñoz-Fontela C
Nature. 2016 May 5;533(7601):100-4. doi: 10.1038/nature17949

Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever
Oestereich L, Rieger T, Lüdtke A, Ruibal P, Wurr S, Pallasch E, Bockholt S, Krasemann S, Muñoz-Fontela C, Günther S
J Infect Dis. 2016 Mar 15;213(6):934-8. doi: 10.1093/infdis/jiv522. Epub 2015 Nov 3.

Development of an antibody capture ELISA using inactivated Ebola Zaire Makona virus
Krähling V, Becker D, Rohde C, Eickmann M, Eroğlu Y, Herwig A, Kerber R, Kowalski K, Vergara-Alert J, Becker S; European Mobile Laboratory consortium
Med Microbiol Immunol. 2016 Apr;205(2):173-83. doi: 10.1007/s00430-015-0438-6. Epub 2015 Oct 16

Ebola virus dynamics in mice treated with favipiravir
Madelain V, Oestereich L, Graw F, Nguyen TH, de Lamballerie X, Mentré F, Günther S, Guedj J
Antiviral Res. 2015 Nov;123:70-7. doi: 10.1016/j.antiviral.2015.08.015. Epub 2015 Sep 2

Temporal and spatial analysis of the 2014-2015 Ebola virus outbreak in West Africa
Carroll MW, Matthews DA, Hiscox JA, Elmore MJ, Pollakis G, Rambaut A, Hewson R, García-Dorival I, Bore JA, Koundouno R, Abdellati S, Afrough B, Aiyepada J, Akhilomen P, Asogun D, Atkinson B, Badusche M, Bah A, Bate S, Baumann J, Becker D, Becker-Ziaja B, Bocquin A, Borremans B, Bosworth A, Boettcher JP, Cannas A, Carletti F, Castilletti C, Clark S, Colavita F, Diederich S, Donatus A, Duraffour S, Ehichioya D, Ellerbrok H, Fernandez-Garcia MD, Fizet A, Fleischmann E, Gryseels S, Hermelink A, Hinzmann J, Hopf-Guevara U, Ighodalo Y, Jameson L, Kelterbaum A, Kis Z, Kloth S, Kohl C, Korva M, Kraus A, Kuisma E, Kurth A, Liedigk B, Logue CH, Lüdtke A, Maes P, McCowen J, Mély S, Mertens M, Meschi S, Meyer B, Michel J, Molkenthin P, Muñoz-Fontela C, Muth D, Newman EN, Ngabo D, Oestereich L, Okosun J, Olokor T, Omiunu R, Omomoh E, Pallasch E, Pályi B, Portmann J, Pottage T, Pratt C, Priesnitz S, Quartu S, Rappe J, Repits J, Richter M, Rudolf M, Sachse A, Schmidt KM, Schudt G, Strecker T, Thom R, Thomas S, Tobin E, Tolley H, Trautner J, Vermoesen T, Vitoriano I, Wagner M, Wolff S, Yue C, Capobianchi MR, Kretschmer B, Hall Y, Kenny JG, Rickett NY, Dudas G, Coltart CE, Kerber R, Steer D, Wright C, Senyah F, Keita S, Drury P, Diallo B, de Clerck H, Van Herp M, Sprecher A, Traore A, Diakite M, Konde MK, Koivogui L, Magassouba N, Avšič-Županc T, Nitsche A, Strasser M, Ippolito G, Becker S, Stoecker K, Gabriel M, Raoul H, Di Caro A, Wölfel R, Formenty P, Günther S
Nature. 2015 Aug 6;524(7563):97-101. doi: 10.1038/nature14594. Epub 2015 Jun 17

Ebola virus disease in mice with transplanted human hematopoietic stem cells
Lüdtke A, Oestereich L, Ruibal P, Wurr S, Pallasch E, Bockholt S, Ip WH, Rieger T, Gómez-Medina S, Stocking C, Rodríguez E, Günther S, Muñoz-Fontela C
J Virol. 2015 Apr;89(8):4700-4. doi: 10.1128/JVI.03546-14. Epub 2015 Feb 11

Zika virus infections imported to Italy: clinical, immunological and virological findings, and public health implications
Zammarchi L, Stella G, Mantella A, Bartolozzi D, Tappe D, Günther S, Oestereich L, Cadar D, Muñoz-Fontela C, Bartoloni A, Schmidt-Chanasit J
J Clin Virol. 2015 Feb;63:32-5. doi: 10.1016/j.jcv.2014.12.005. Epub 2014 Dec 12

Gairo virus, a novel arenavirus of the widespread Mastomys natalensis: Genetically divergent, but ecologically similar to Lassa and Morogoro viruses
Gryseels S, Rieger T, Oestereich L, Cuypers B, Borremans B, Makundi R, Leirs H, Günther S, Goüy de Bellocq J
Virology. 2015 Feb;476:249-256. doi: 10.1016/j.virol.2014.12.011. Epub 2015 Jan 2

Evaluation of antiviral efficacy of ribavirin, arbidol, and T-705 (favipiravir) in a mouse model for Crimean-Congo hemorrhagic fever
Oestereich L, Rieger T, Neumann M, Bernreuther C, Lehmann M, Krasemann S, Wurr S, Emmerich P, de Lamballerie X, Ölschläger S, Günther S
PLoS Negl Trop Dis. 2014 May 1;8(5):e2804. doi: 10.1371/journal.pntd.0002804. eCollection 2014 May.

Emergence of Zaire Ebola virus disease in Guinea
Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N, Soropogui B, Sow MS, Keïta S, De Clerck H, Tiffany A, Dominguez G, Loua M, Traoré A, Kolié M, Malano ER, Heleze E, Bocquin A, Mély S, Raoul H, Caro V, Cadar D, Gabriel M, Pahlmann M, Tappe D, Schmidt-Chanasit J, Impouma B, Diallo AK, Formenty P, Van Herp M, Günther S
N Engl J Med. 2014 Oct 9;371(15):1418-25. doi: 10.1056/NEJMoa1404505. Epub 2014 Apr 16

Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model
Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S
Antiviral Res. 2014 May;105:17-21. doi: 10.1016/j.antiviral.2014.02.014. Epub 2014 Feb 26

Entry of bunyaviruses into mammalian cells
Lozach PY, Mancini R, Bitto D, Meier R, Oestereich L, Overby AK, Pettersson RF, Helenius A
Cell Host Microbe. 2010 Jun 25;7(6):488-99. doi: 10.1016/j.chom.2010.05.007

Contact

Dr. Lisa Oestereich

Phone: +49 40 42818-940
Fax: +49 40 42818-931
E-Mail: oestereich(at)bnitm.de


PhD Students

Olivia Blake

Olivia Blake (-940)

Anke Thielebein

Anke Thielebein (-940)

Chris Hoffmann

Chris Hoffmann (-940)

Technical Staff

Sabrina Bockholt

Sabrina Bockholt (-947)

Jonas Müller

Jonas Müller (-946)

Elisa Pallasch

Elisa Pallasch (-947)

Other Staff Members

Thomas Brehm (DZIF Clinical Leave)

Thomas Brehm (DZIF Clinical Leave)