Arbeitgruppe: Arbeitsgruppe Jacobs (Protozoen-Immunologie), Foto: Jann Wilken
Arbeitsgruppe Jacobs (Protozoen-Immunologie), Foto: Jann Wilken

Overview

Protective and pathogenetic role of T cells in murine malaria

Malaria is characterized by two very distinct phases both of which with a unique interaction with immune system of the host. The liver phase is immunological silent i.e. no massive induction of the immune system occurs and no pathology is associated with this stage. However, during the liver stage CD8+ T cells that recognize malaria antigen on hepatocytes can mediate protection. Thus current vaccine strategies are concentrating on this stage. A major problem is the short duration of the liver stage. Therefore a vaccine-induced response must induce CD8+ T cells that persist in the liver and produce cytokines immediately after antigen encounter. This problem might be solved by using novel vaccine strategies that efficiently induce T effector/memory cells, which are known to persist in peripheral organs. Recently we have shown that fusion molecules of the adenylate cyclase toxin of Bordetella pertussis with liver stage specific antigens are potent tools to target antigen to dendritic cells in vivo, which is then followed by presentation on MHC class I. This, in combination with either a blockade of CTLA-4 or a heterologous boost immunization can confer a long-lasting and protective immune response.

The blood stage of malaria leads to a strong activation of cytokine-producing T cells, which are associated with inflammation and pathology in different organs e.g. the brain. Most of these T cells express negative costimulators like CTLA-4, PD-1 and BTLA. Ligands of these molecules were expressed in different organs upon inflammation and thus help to prevent an overwhelming pathology. Depending on the type of infection a blockade of these interactions lead to an increased parasite clearance or to an exacerbation of disease. However, the regulatory mechanisms that are induced during the blood stage are not only regulating the immune response that is triggered by the blood stage but they also influence liver stage immunity. Thus we are now concentrating on regulatory mechanisms at the interface between liver and blood stage immunity.

Research Projects

Protective and pathogenetic role of T cells in murine malaria

Malaria is characterized by two very distinct phases both of which with a unique interaction with immune system of the host. The liver phase is immunological silent i.e. no massive induction of the immune system occurs and no pathology is associated with this stage. However, during the liver stage CD8+ T cells that recognize malaria antigen on hepatocytes can mediate protection. Thus current vaccine strategies are concentrating on this stage. A major problem is the short duration of the liver stage. Therefore a vaccine-induced response must induce CD8+ T cells that persist in the liver and produce cytokines immediately after antigen encounter. This problem might be solved by using novel vaccine strategies that efficiently induce T effector/memory cells, which are known to persist in peripheral organs. Recently we have shown that fusion molecules of the adenylate cyclase toxin of Bordetella pertussis with liver stage specific antigens are potent tools to target antigen to dendritic cells in vivo, which is then followed by presentation on MHC class I. This, in combination with either a blockade of CTLA-4 or a heterologous boost immunization can confer a long-lasting and protective immune response.

The blood stage of malaria leads to a strong activation of cytokine-producing T cells, which are associated with inflammation and pathology in different organs e.g. the brain. Most of these T cells express negative costimulators like CTLA-4, PD-1 and BTLA. Ligands of these molecules were expressed in different organs upon inflammation and thus help to prevent an overwhelming pathology. Depending on the type of infection a blockade of these interactions lead to an increased parasite clearance or to an exacerbation of disease. However, the regulatory mechanisms that are induced during the blood stage are not only regulating the immune response that is triggered by the blood stage but they also influence liver stage immunity. Thus we are now concentrating on regulatory mechanisms at the interface between liver and blood stage immunity.

Protektive und pathogenetische Rolle von T-Zellen bei der Malaria (SFB 841 - Leberentzündung)

Publication Highlights

Arbeitsgruppe Jacobs (Protozoen Immunologie)

Acute Malaria Induces PD1+CTLA4+ Effector T Cells with Cell-Extrinsic Suppressor Function
Maria Sophia Mackroth, Annemieke Abel, Christiane Steeg, Julian Schulze zur Wiesch, Thomas Jacobs
PLoS Pathog. 2016 Nov 1;12(11):e1005909. doi: 10.1371/journal.ppat.1005909.

IL-22 dampens the T cell response in experimental malaria
Sellau J, Alvarado CF, Hoenow S, Mackroth MS, Kleinschmidt D, Huber S., Jacobs T
Sci. Rep. (2016) 6; 28058; doi: 10.1038/srep28058

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, Christopher H. Logue, 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, Fabrizio Carletti F, Portmann J, Wolff S, Castilletti C, Schudt G, Fizet F, 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) 533; 100–104

Cutting Edge: The BTLA-HVEM Regulatory Pathway Interferes with Protective Immunity to Intestinal Helminth Infection
Breloer M., Hartmann W., Blankenhaus B., Eschbach ML., Pfeffer K. & Jacobs T.
J. Immunol. (2015) pii: 1402510. Epub ahead of print

Plasmodium berghei sporozoite challenge of vaccinated BALB/c mice leads to the induction of humoral immunity and improved function of CD8(+) memory T cells
Tartz S., Deschermeier C., Retzlaff S., Heussler V., Sebo P., Fleischer B. & Jacobs T.
Eur. J. Immunol. (2013) 43: 693-704.

All Publications

Arbeitsgruppe Jacobs (Protozoen Immunologie)
2016

IL-22 dampens the T cell response in experimental malaria
Sellau J, Alvarado CF, Hoenow S, Mackroth MS, Kleinschmidt D, Huber S, & Jacobs T
Sci. Rep. (2016) 6, 28058; doi: 10.1038/srep28058

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, Christopher H. Logue, 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, Fabrizio Carletti F, Portmann J, Wolff S, Castilletti C, Schudt G, Fizet F, 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) 533; 100–104

Mycobacterium tuberculosis Coinfection Has No Impact on Plasmodium berghei ANKA-Induced Experimental Cerebral Malaria in C57BL/6 Mice.
Blank J, Behrends J, Jacobs T, Schneider BE.
Infect Immun. 2015 Dec 7;84(2):502-10.

EBI3 suppresses Th1, Th17 and Th2 immune responses after Trypanosoma cruzi infection and inhibits parasite replication by interfering with alternative macrophage activation
Böhme J, Roßnagel C, Jacobs T, Behrends J, Hölscher C, Erdmann H.
Immunology. 2015 Dec 23. doi: 10.1111/imm.12565. [Epub ahead of print]

IL-23 promotes immunopathology and prevents IL-13-dependent tissue repair associated with Ly6Clo monocytes in Entamoeba histolytica-induced liver damage.
Noll J, Helk E, Fehling H, Bernin H, Marggraff C, Jacobs T, Huber S, Pelczar P, Ernst T, Ittrich H, Otto B, Mittrücker HW, Hölscher C, Tacke F, Bruchhaus I, Tannich E, Lotter H.
J Hepatol. 2016 Jan 22. pii: S0168-8278(16)00019-2. doi: 10.1016/j.jhep.2016.01.013. [Epub ahead of print]

Laborgruppe Jacobs
2015

The Application of Anti-Toso Antibody Enhances CD8+ T Cell Responses in Experimental Malaria Vaccination and Disease
Lapke N., Tartz S., Lee KH. & Jacobs T.
Vaccine 2015, accepted for publication

Cutting Edge: The BTLA-HVEM Regulatory Pathway Interferes with Protective Immunity to Intestinal Helminth Infection
Breloer M., Hartmann W., Blankenhaus B., Eschbach ML., Pfeffer K. & Jacobs T.
J Immunol. 2015 Feb 15;194(4):1413-6. doi: 10.4049/jimmunol.1402510. Epub 2015 Jan 16.

Involvement of sulfates from cruzipain, a major antigen of Trypanosoma cruzi, in the interaction with immunomodulatory molecule Siglec-E.
Ferrero MR., Heins AM., Soprano LL., Acosta DM., Esteva MI., Jacobs T.*, Duschak VG.* *shared senior authors
Med Microbiol Immunol. 2015 Jun 6. [Epub ahead of print]

Laborgruppe Jacobs
2014

Depletion of regulatory T cells augments a vaccine-induced T effector cell response against the liver-stage of malaria but fails to increase memory
Espinoza Mora R, Steeg C, Tartz S, Heussler V, Sparwasser T, Link A, Fleischer B & Jacobs T
PLoS One 2014; 12:e104627

Immune markers characteristic for asymptomatically infected and diseased Entamoeba histolytica individuals and their relation to sex
Bernin H, Marggraff C, Jacobs T, Brattig N, An L, Blessmann J & Lotter H.
BMC Infect Dis. 2014 Nov 25;14:621. doi: 10.1186/s12879-014-0621-1.

Laborgruppe Jacobs
2013

Plasmodium berghei sporozoite challenge of vaccinated BALB/c mice leads to the induction of humoral immunity and improved function of CD8(+) memory T cells.
Tartz S., Deschermeier C., Retzlaff S., Heussler V., Sebo P., Fleischer B. & Jacobs T.
Eur J Immunol. 2013 Mar;43(3):693-704. doi: 10.1002/eji.201142262. Epub 2013 Jan 18.

Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells.
Burghardt S., Erhardt A., Claass B., Huber S., Jacobs T., Stevanovic M., Schmidt-Arras D., Rose-John S., Karimi K. & Tiegs G.
J Immunol. 2013 Dec 1;191(11):5574-82. doi: 10.4049/jimmunol.1300826. Epub 2013 Oct 18.

TNFα-mediated liver destruction by kupffer cells and Ly6Chi monocytes during Entamoeba histolytica infection.
Helk E., Bernin H., Ernst T., Ittrich H., Jacobs T., Heeren J., Tacke F., Tannich E. & Lotter H.
PLoS Pathog. 2013 Jan;9(1):e1003096. doi: 10.1371/journal.ppat.1003096. Epub 2013 Jan 3.

Testosterone increases susceptibility to amebic liver abscess in mice and mediates inhibition of IFNγ secretion in natural killer T cells.
Lotter H., Helk E., Bernin H., Jacobs T., Prehn C., Adamski J., González-Roldán N., Holst O. & Tannich E.
PLoS One. 2013;8(2):e55694. doi: 10.1371/journal.pone.0055694. Epub 2013 Feb 12.

A new approach to generate a safe double-attenuated Plasmodium liver stage vaccine.
Nagel A., Prado M., Heitmann A., Tartz S., Jacobs T., Deschermeier C., Helm S., Stanway R. & Heussler V.
Int J Parasitol. 2013 May;43(6):503-14. doi: 10.1016/j.ijpara.2013.01.010. Epub 2013 Mar 13.

Laborgruppe Jacobs
2012

Dissection of minimal sequence requirements for rhoptry membrane targeting in the malaria parasite.
Cabrera A., Herrmann S., Warszta D., Santos JM., John Peter AT., Kono M., Debrouver S., Jacobs T., Spielmann T., Ungermann C., Soldati-Favre D. & Gilberger TW.
Traffic. 2012 Oct;13(10):1335-50. doi: 10.1111/j.1600-0854.2012.01394.x. Epub 2012 Aug 1.

Efficient control of Plasmodium yoelii infection in BALB/c and C57BL/6 mice with pre-existing Strongyloides ratti infection
Kolbaum J., Eschbach M.-L., Steeg C., Jacobs T., Fleischer B. & Breloer M.
Parasite Immunol. 2012 Jul;34(7):388-93. doi: 10.1111/j.1365-3024.2012.01369.x.

Nematode-induced interference with the anti-Plasmodium CD8+ T-cell response can be overcome by optimizing antigen administration.
Kolbaum J., Tartz S., Helm S., Nagel A., Heussler V., Sebo P., Fleischer B., Jacobs T.* & Breloer M.* *contributed equally
Eur J Immunol. 2012 Apr;42(4):890-900. doi: 10.1002/eji.201141955. Epub 2012 Jan 19.

Laborgruppe Jacobs
2011

B and T Lymphocyte Attenuator (BTLA) Restricts the Protective Immune Response Against Experimental Malaria
Adler G., Steeg C., Pfeffer K., Murphy T.L., Murphy K.M., Langhorne J. & Jacobs T.
J Immunol. 2011 Nov 15;187(10):5310-9. doi: 10.4049/jimmunol.1101456. Epub 2011 Oct 12.

Invasion of Trypanosoma cruzi into host cells is impaired by N-propionylmannosamine and other N-acylmannosamines.
Lieke T., Gröbe D., Blanchard V., Grunow D., Tauber R., Zimmermann-Kordmann M., Jacobs T. & Reutter W.
Glycoconj J. 2011 Jan;28(1):31-7. doi: 10.1007/s10719-010-9321-2. Epub 2011 Jan 15.

Strongyloides ratti infection induces expansion of Foxp3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice.
Blankenhaus B., Klemm U., Eschbach M.-L., Sparwasser T., Huehn J., Kühl A.A., Loddenkemper C., Jacobs T. & Breloer M.
J Immunol. 2011 Apr 1;186(7):4295-305. doi: 10.4049/jimmunol.1001920. Epub 2011 Feb 18.

Laborgruppe Jacobs
2010

Differential effects of C3d on the immunogenicity of gene gun vaccines encoding Plasmodium falciparum and Plasmodium berghei MSP1.
Weiss R., Gabler M., Jacobs T., Gilberger T.W., Thalhamer J. & Scheiblhofer S.
Vaccine. 2010 Jun 17;28(28):4515-22. doi: 10.1016/j.vaccine.2010.04.054. Epub 2010 May 15.

Molecular interaction of Siglecs (sialic acid-binding Ig-like lectins) with sialylated ligands on Trypanosoma cruzi.
Jacobs T., Erdmann H. & Fleischer B.
Eur J Cell Biol. 2010 Jan;89(1):113-6. doi: 10.1016/j.ejcb.2009.10.006. Epub 2009 Nov 11.

Laborgruppe Jacobs
2009

Limited role of CD4+Foxp3+ regulatory T cells in the control of experimental cerebral malaria.
Steeg C., Adler A., Sparwasser T., Fleischer B. & Jacobs T.
J Immunol. 2009 Dec 1;183(11):7014-22. doi: 10.4049/jimmunol.0901422. Epub 2009 Nov 4.

Sialylated ligands on pathogenic Trypanosoma cruzi interact with Siglec-E (sialic acid-binding Ig-like lectin-E).
Erdmann H., Steeg C., Koch-Nolte F., Fleischer B. & Jacobs T.
Cell Microbiol. 2009 Nov;11(11):1600-11. doi: 10.1111/j.1462-5822.2009.01350.x. Epub 2009 Jun 22.

Natural killer T cells activated by a lipopeptidophosphoglycan from Entamoeba histolytica are critically important to control amebic liver abscess.
Lotter H., González-Roldán N., Lindner B., Winau F., Isibasi A., Moreno-Lafont M., Ulmer A. J., Holst O., Tannich E. & Jacobs T.
PLoS Pathog. 2009 May;5(5):e1000434. doi: 10.1371/journal.ppat.1000434. Epub 2009 May 15.

Laborgruppe Jacobs
2008

MyD88/IL-18-dependent pathways rather than TLRs control early parasitaemia in non-lethal Plasmodium yoelii infection.
Cramer J. P., Kamena F., Lepenies B., Hölscher C., Freudenberg M. A., Burchard Gerd D., Kirschning C. J., Seeberger P. H. & Jacobs T.
Microbes Infect. 2008 Oct;10(12-13):1259-65. doi: 10.1016/j.micinf.2008.07.024. Epub 2008 Jul 22.

Complete protection against P. berghei malaria upon heterologous prime/boost immunization against circumsporozoite protein employing Salmonella type III secretion system and Bordetella adenylate cyclase toxoid.
Tartz S., Rüssmann H., Kamanova J., Sebo P., Sturm A., Heussler V., Fleischer B. & Jacobs T.
Vaccine. 2008 Nov 5;26(47):5935-43. doi: 10.1016/j.vaccine.2008.08.057. Epub 2008 Sep 17.

Liposome-encapsulated antigens induce a protective CTL response against Listeria monocytogenes independent of CD4+ T cell help.
Grenningloh R., Darji A., Bauer H., zur Lage S., Chakraborty T., Jacobs T. & Weiss S.
Scand J Immunol. 2008 Jun;67(6):594-602. doi: 10.1111/j.1365-3083.2008.02112.x. Epub 2008 Apr 21.

The antimicrobial peptide NK-2, the core region of mammalian NK-lysin, kills intraerythrocytic Plasmodium falciparum.
Gelhaus C., Jacobs T., Andrä J. & Leippe M.
Antimicrob Agents Chemother. 2008 May;52(5):1713-20. doi: 10.1128/AAC.01342-07. Epub 2008 Mar 10.

Simvastatin treatment shows no effect on the incidence of cerebral malaria or parasitemia during experimental malaria.
Kobbe R., Schreiber N., May J. & Jacobs T.
Antimicrob Agents Chemother. 2008 Apr;52(4):1583-4. doi: 10.1128/AAC.01428-07. Epub 2008 Feb 11.

Induction of experimental cerebral malaria is independent of TLR2/4/9.
Lepenies B., Cramer J. P., Burchard G. D., Wagner H., Kirschning C. J., Fleischer B., & Jacobs T.
Med Microbiol Immunol. 2008 Mar;197(1):39-44. Epub 2007 Aug 1.

Laborgruppe Jacobs
2007

Ligation of B and T lymphocyte attenuator (BTLA) prevents the genesis of experimental cerebral malaria.
Lepenies B., Pfeffer K., Hurchla M. A., Murphy T. L., Murphy K. M., Oetzel J., Fleischer B. & Jacobs T.
J Immunol. 2007 Sep 15;179(6):4093-100.

CTLA-4 blockade differentially influences the outcome of non-lethal and lethal Plasmodium yoelii infections.
Lepenies B., Gaworski I., Tartz S., Langhorne J., Fleischer B. & Jacobs T.
Microbes Infect. 2007 May;9(6):687-94. Epub 2007 Feb 23.

Laborgruppe Jacobs
2006

Interaction of natural killer cells with Trypanosoma cruzi-infected fibroblasts.
Lieke T., Graefe S. E.B., Steeg C., Fleischer B. & Jacobs T.
Clin Exp Immunol. 2006 Aug;145(2):357-64.

Immunization with a circumsporozoite epitope fused to Bordetella adenylate cyclase in conjunction with CTLA-4 blockade confers protection against P. berghei liver stage malaria.
Tartz S., Kamanova J., Sebo P., Bolte S., Heussler V., Fleischer B. & Jacobs T.
Infect Immun. 2006 Apr;74(4):2277-85.

Sexual dimorphism in the control of amebic liver abscess in a mouse model of disease.
Lotter H.*, Jacobs T.*, Gaworski I. & Tannich E. *contributed equally
Infect Immun. 2006 Jan;74(1):118-24.

Spontaneous recovery of pathogenicity by Leishmania major hsp100-/- alters the immune response in mice.
Reiling L.*, Jacobs T.*, Gaworski I., Kroemer K., Graefe G.& Clos J. *contributed equally.
Infect Immun. 2006 Nov;74(11):6027-36.

Laborgruppe Jacobs
2005

The cholesterol dependent cytolysin Listeriolysin O, aggregates rafts via oligomerization
Gekara N. O., Jacobs, T., Chakraborty, T. & Weiss, S.
Cell Microbiol. 2005 Sep;7(9):1345-56.

Complement C3 is required for progression of cutaneous lesions and parasite dissemination in Leishmania major infection.
Jacobs T., Andrä J., Gaworski I., Graefe S.E.B., Mellenthin K., Krömer M, Halter R., Borlak J. & Clos J.
Med Microbiol Immunol. 2005 May;194(3):143-9. Epub 2004 Sep 17.

Contact

PD Dr. Thomas Jacobs

Phone: +49 40 42818-850
Fax: +49 40 42818-400
E-Mail: tjacobs@bnitm.de


PhD Students

Franziska Muscate (-852)
Yanina Arana (-852)
Rosa Isela Grote-Galvez (-852)

Graduate Students

Bastian Kruse (-854)
Mona Tabel (-853)
Lea Kaminski (-855)
Vera Brackrock (freiwilliges Jahr) -853

Technical Staff

Christiane Steeg (-853)
Birgit Hüsing (-854)
Ulricke Richardt (-855)

Videoabstract: Tartz et al. Eur J Immunol 2013; 43:693-704.

Unsere Projekte als Video:

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Malaria - Feldforschung in Ghana:

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