Arbeitgruppe: Laborgruppe Lotter: 
Jill Noll, Corinna Lender, Siew-Ling Choy,  
Hanna Lotter, Hannah Bernin, Claudia Marggraff
Laborgruppe Lotter: Jill Noll, Corinna Lender, Siew-Ling Choy, Hanna Lotter, Hannah Bernin, Claudia Marggraff

Overview

  • Immune processes underlying amebic liver abscess (ALA) formation and regeneration
  • Background for the sex bias in invasive amebias
  • In vivo imaging of Entamoeba histolytica

Research Projects

Immune processes underlying ALA formation and regeneration

Jill Noll, Hannah Bernin, Elena Helk

Human amebiasis results from intestinal infections with the protozoan parasite Entamoeba histolytica (E. histolytica). The two major clinical symptoms that derive from the infections, the amebic colitis and the amebic liver abscess (ALA), represent major health problems in subtropical and tropical areas as well as in travellers. The parasite usually asymptomatically colonizes the bowel system, but occasionally it invades the mucosa and spreads via the blood stream into other organs, mainly in the liver. To investigate immunological backgrounds for the development of ALA, we have established a mouse model that resembles the human disease in terms of a comparable pathology and a similar sex distribution. Using highly selective depletion strategies and various knockout mutant mice, we were able to show that innate immune cells like the inflammatory monocytes, but also liver resident Kupffer cells substantially contribute to the liver destruction during ALA, and tissue damage was mediated primarily by TNFα. The data indicated that besides direct antiparasitic drug treatment, modulating innate immune responses potentially be beneficial in limiting ALA pathogenesis. Presently we are investigating mechanisms that are involved in tissue repair. On the hand, we focus on immune cells and cytokines involved in the organ regeneration. On the other hand, we analyze sex hormones-lipid metabolism interactions of that might be relevant for initiation and termination of inflammatory processes.

Background for the sex bias in invasive amebiasis

Hannah Bernin

The major severe symptom of a human Infection with E. histolytica, the amebic liver abscess (ALA), occurs independent from the infection rate with a clear sex bias towards adult men. The course of ALA occurrence in men suggested an influence of the male sex hormone testosterone on disease susceptibility. Using the mouse model for ALA that displays the similar sex distribution as observed in human ALA patients, we investigated the input of estradiol and testosterone on ALA following castration and hormone substitution. We found that testosterone substitution decreases the ability of primary resistant female mice to control abscess formation and parasite load in the liver. We further demonstrated that the secretion of protective IFNγ by NKT cells was reduced upon testosterone treatment of female mice. Castration of male mice, in contrast, increased the resistance towards ALA, reduced parasite load of the liver and increased NKT cell specific IFNγ-production. To identify immunological markers for sex bias of ALA in humans, we investigated sera from ALA patients and individuals that were asymptomatically infected with E. histolytica from an amebiasis-endemic area in Vietnam. We focused on the specific E. histolytica antibody response including all four IgG subclasses as well as cytokines and chemokines. In conclusion we found that a Th2 type of immune response and the inhibition of protective innate immune mechanisms by IgG2 prevent an effective amebicidal immune response in males that are further prone towards immunopathology by CCL2- dependent recruitment of inflammatory monocytes. Resistance in females utilizes IgG1-mediated complement activation to combat spreading of the complement-sensitive amebic trophozoites

In vivo imaging of E. histolytica by Magnet resonance imaging (MRI)

Helena Fehling

According to its name giving activity, Entamoeba histolytica possesses a repertoire of pathogenicity factors that enables the parasite to invade into various tissues of the host. We have generated cell lines, which greatly differ in their ability to destroy tissue during abscess development in the liver. Beside the investigation of differentially expressed pathogenicity molecules, we want to analyze whether differences in the movement, velocity and organ spreading behavior of E. histolytica trophozoites contribute to the pathogenicity. In cooperation with the Department and Clinic for Diagnostic and Interventional Radiology, UKE, Hamburg, we have established a magnet resonance imaging (MRI)- based protocol to monitor the course of amoebic liver abscess formation using a small animal MR Scanner at 7.0 Tesla. To visualize E. histolytica trophozoites by MRI within the liver on a single cell level, trophozoites have to engulf superparamagnetic iron oxid particles (SPIO). SPIOs vary greatly in their composition and size. So far we have tested the influence of different SPIO formulations on amebic growth rate, erythrophagocytosis and cytopathogenicity. At present, the system allows us in vitro analysis of velocity and movement characteristics. Using optimal SPIO formulations, we expect that we are able to perform in vivo analysis of the spreading behaviour in the liver of C57BL/6 mice in the next future to get a better understanding of the origin of amoebic pathogenesis.

Publication Highlights

Laborgruppe Lotter

IL-23 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]

Sex bias in the outcome of human tropical infectious diseases: influence of steroid hormones.
Bernin H, Lotter H.
J Infect Dis. 2014 Jul 15;209 Suppl 3:S107-13. doi: 10.1093/infdis/jit610.

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.

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 AJ, Holst O, Tannich E, Jacobs T.
PLoS Pathog. 2009 May;5(5):e1000434. doi: 10.1371/journal.ppat.1000434. Epub 2009 May 15.

All Publications

2016
2016

Overexpression of Differentially Expressed Genes Identified in Non-pathogenic and Pathogenic Entamoeba histolytica Clones Allow Identification of New Pathogenicity Factors Involved in Amoebic Liver Abscess Formation.
Meyer M, Fehling H, Matthiesen J, Lorenzen S, Schuldt K, Bernin H, Zaruba M, Lender C, Ernst T, Ittrich H, Roeder T, Tannich E, Lotter H, Bruchhaus I.
PLoS Pathog. 2016 Aug 30;12(8):e1005853. doi: 10.1371/journal.ppat.1005853.

The cytokine profile of human NKT cells and PBMCs is dependent on donor sex and stimulus.
Bernin H, Fehling H, Marggraff C, Tannich E, Lotter H.
Med Microbiol Immunol. 2016 Aug;205(4):321-32. doi: 10.1007/s00430-016-0449-y.

IL-23 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 May;64(5):1147-57. doi: 10.1016/j.jhep.2016.01.013.

2015
2015

Sex differences in H7N9 influenza A virus pathogenesis.
Hoffmann J, Otte A, Thiele S, Lotter H, Shu Y, Gabriel G.
Vaccine. 2015 Dec 8;33(49):6949-54. doi: 10.1016/j.vaccine.2015.08.044. Epub 2015 Aug 25.

Magnetic resonance imaging of pathogenic protozoan parasite Entamoeba histolytica labeled with superparamagnetic iron oxide nanoparticles.
Ernst TM, Fehling H, Bernin H, Zaruba MD, Bruchhaus I, Adam G, Ittrich H, Lotter H.
Invest Radiol. 2015 Oct;50(10):709-18. doi: 10.1097/RLI.0000000000000175.

2014

Sex bias in the outcome of human tropical infectious diseases: influence of steroid hormones.
Bernin H, Lotter H.
J Infect Dis. 2014 Jul 15;209 Suppl 3:S107-13. doi: 10.1093/infdis/jit610.

The cell surface proteome of Entamoeba histolytica.
Biller L, Matthiesen J, Kühne V, Lotter H, Handal G, Nozaki T, Saito-Nakano Y, Schümann M, Roeder T, Tannich E, Krause E, Bruchhaus I.
Mol Cell Proteomics. 2014 Jan;13(1):132-44. doi: 10.1074/mcp.M113.031393. Epub 2013 Oct 17.

2013

Overexpression of specific cysteine peptidases confers pathogenicity to a nonpathogenic Entamoeba histolytica clone.
Matthiesen J, Bär AK, Bartels AK, Marien D, Ofori S, Biller L, Tannich E, Lotter H, Bruchhaus I.
MBio. 2013 Mar 26;4(2). pii: e00072-13. doi: 10.1128/mBio.00072-13.

Testosterone increases susceptibility to amebic liver abscess in mice and mediates inhibition of IFNγ secretion in natural killer T cells.
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.

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.

2010

Differences in the transcriptome signatures of two genetically related Entamoeba histolytica cell lines derived from the same isolate with different pathogenic properties.
Biller L, Davis PH, Tillack M, Matthiesen J, Lotter H, Stanley SL Jr, Tannich E, Bruchhaus I.
BMC Genomics. 2010 Jan 26;11:63. doi: 10.1186/1471-2164-11-63.

2009

Comparison of two genetically related Entamoeba histolytica cell lines derived from the same isolate with different pathogenic properties.
Biller L, Schmidt H, Krause E, Gelhaus C, Matthiesen J, Handal G, Lotter H, Janssen O, Tannich E, Bruchhaus I.
Proteomics. 2009 Sep;9(17):4107-20. doi: 10.1002/pmic.200900022.

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 AJ, Holst O, Tannich E, Jacobs T.
PLoS Pathog. 2009 May;5(5):e1000434. doi: 10.1371/journal.ppat.1000434. Epub 2009 May 15.

2008

Attenuated recombinant Yersinia as live oral vaccine carrier to protect against amoebiasis.
Lotter H, Rüssmann H, Heesemann J, Tannich E.
Int J Med Microbiol. 2008 Jan;298(1-2):79-86. Epub 2007 Sep 27.

2006

Increased expression of the major cysteine proteinases by stable episomal transfection underlines the important role of EhCP5 for the pathogenicity of Entamoeba histolytica.
Tillack M, Nowak N, Lotter H, Bracha R, Mirelman D, Tannich E, Bruchhaus I.
Mol Biochem Parasitol. 2006 Sep;149(1):58-64. Epub 2006 May 19.

The current status of an amebiasis vaccine.
Lotter H, Tannich E.
Arch Med Res. 2006 Feb;37(2):292-6.

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

2004

Oral vaccination with recombinant Yersinia enterocolitica expressing hybrid type III proteins protects gerbils from amebic liver abscess.
Lotter H, Rüssmann H, Heesemann J, Tannich E.
Infect Immun. 2004 Dec;72(12):7318-21.

Resistance of Entamoeba histolytica to the cysteine proteinase inhibitor E64 is associated with secretion of pro-enzymes and reduced pathogenicity.
Nowak N, Lotter H, Tannich E, Bruchhaus I.
J Biol Chem. 2004 Sep 10;279(37):38260-6. Epub 2004 Jun 23.

2002

Differential gene expression in Entamoeba histolytica isolated from amoebic liver abscess.
Bruchhaus I, Roeder T, Lotter H, Schwerdtfeger M, Tannich E.
Mol Microbiol. 2002 May;44(4):1063-72.

Alumni

Doctoral Thesis

Dr. Helena Fehling (2012-2015) : Analyse der Unterschiede pathogener und apathogener Entmoeba histolytica (SCHAUDINN, 1903) Klone in der Parasit-Wirt Interaktion

Dr. Hannah Bernin (2011-2014) : Evaluierung des immuntherapeutischen Potentials eines Lipopeptidphosphoglykans aus Entamoeba histolytica

Dr. Elena Helk (2010-2013) : Charakterisierung der Immunantwort im Mausmodell für den Amöbenleberabszess

Diploma and Master Thesis

Sarah Corinna Lender (2015) : Immunstimulatorische Eigenschaften des Entamoeba histolytica Lipopeptidpshosphoglykans und davon abgeleiteten synthetischen Analoga

Karolin Hildebrandt (2014) : Die Rolle des Lipidstoffwechsels bei der Immunaktivierung und der Regeneration des Amöbenleberabszesses

Jill Kracht (2013) : Die Rolle der Zytokine IL-22 und IL-23 bei der Entstehung und Regeneration des Amöbenleberabszesses

Mareen Zaruba (2012) : Charakterisierung verschieden pathogener Entamoeba histolytica (Schaudinn, 1903) Klone im immunkomtetenten Tiermodell Mus musculus

Hannah Bernin (2011) : Die Rolle von neutrophilen Granulozyten und Makrophagen während der Amöbenleberabszessentstehung ausgelöst durch Entamoeba histolytica (Schaudinn, 1903)

Helena Dobbeck (2011) : Untersuchung der geschlechtsspezifischen Zytokinsekretion humaner iNKT-Zellen in Bezug auf die Amöbiasis des Menschen

Contact

PD Dr. Hannelore Lotter

Phone: +49 40 42818-476, -475
Fax: +49 40 42818-512
E-Mail: lotter@bnitm.de


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