Arbeitgruppe: Laborgruppe Lotter: 
Marie Groneberg, Corinna Lender, Jill Noll, Siew-Ling Choy, Julie Sellau, Hanno Niss, Hanna Lotter, Claudia Marggraff
Laborgruppe Lotter: Marie Groneberg, Corinna Lender, Jill Noll, Siew-Ling Choy, Julie Sellau, Hanno Niss, Hanna Lotter, 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, Marie Groneberg, Claudia Marggraff

 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 selective depletion strategies and various knockout mutant mice, we were able to show that innate immune cells like the inflammatory Ly6Chi monocytes, but also liver resident Kupffer cells substantially contribute to the liver destruction via production of TNFα. IL-23 further contributes to immunopathology of ALA by stabilizing IL-17 production and CCL2 expression. On the other hand, tissue repair is initiated by the presence of anti-inflammatory Ly6Clo monocytes in the liver that produce IL-13 and further develop into alternative activated M2 macrophages expressing Arginase 1.

 

Funding:

SFB841, " Leberentzündung: Infektion, Immunregulation und Konsequenzen" Project A2

Sex dimorphisms in the immune system

Julie Sellau

 An increasing body of evidence suggests an involvement of sex-based influences on the outcome of infectious, autoimmune and tumor diseases. This could be either attributed to X- or Y-chromosome linked-genes, environmental risk factors or sex hormones that act on immune responses involved in the outcome of a disease. Amebic liver abscess, a major severe symptom arising from human infections with the protozoan parasite Entamoeba  (E.)  histolytica, occurs independent from the infection rate with a clear sex bias towards adult men. With the aid of a mouse model that reflects the same sex dimorphism as observed in human, we found that testosterone significantly influenced the outcome of the disease. Female mice treated with testosterone lost their ability to control the abscess development and the parasite burden in the liver and Natural killer T cells, which were crucial for the control of the disease, produced less amounts of the protective cytokine IFNγ. In contrast, abscess development in male individuals was enabled by an immunopathology mediated by a C-C chemokine ligand  (CCL) 2-dependent recruitment of inflammatory monocytes and the production of TNFα and Nitric Oxide. Interestingly, we found higher CCL2 serum levels in the serum of men and male mice infected with the parasite compared to female individuals. In a larger consortium consisting of groups from the UKE, the Heinrich Pette Institute and the BNITM and funded by the BWFG we now want to identify common immune mechanisms that might underlie the sex-dependent outcome in a variety of diseases.

Funding:

Landesforschungsförderung Hamburg; "Geschlechtsdimorphismus im Immunsystem: Bedeutung für Erkrankung und Immunität" (LFF-FV45)

Beating parasites with their own weapons

Siew-Ling Choy, Corinna Lender, Hanno Niss

Intracellular microorganisms that target immune cells can circumvent their clearance by manipulating the innate and the acquired immune response of the host. Two major human pathogens, parasites of the genus Leishmania and bacteria of the genus Mycobacterium, enter professional phagocytes like macrophages and dendritic cells (DC) where they survive and multiply. Through induction of immune evasion mechanisms the pathogen alter immune cell function and dampen protective immune responses. Therefore, immune ­stimulatory molecules that activate or re-activate target cells represent promising therapeutic tools for the treatment of these diseases. We recently isolated such an immunostimulatory molecule from the membrane of Entamoeba (E.) histolytica, a lipopeptidephosphoglycan (EhLPPG). The native molecule exhibited considerable immune cell stimulation leading to the reduction of the intracellular load of leishmania parasites in vitro and in a mouse model for the disease. In cooperation with Prof. Yukari Fujimoto from the Keio University in Japan and Prof. Chris Meier from the University of Hamburg we developed a series of synthetic analogs deduced from the two Phosphatidylinositol anchors of EhLPPG. So far, several analogs reproduced the anti-leishmanial activity of the parent compound in vitro and in vivo, presumably by inducing production of pro-inflammatory cytokines, and exhibited bactericidal activity against Mtb in vitro (Patent BNI002).

Funding:

DZIF  “Development of a new immunostimulatory compound for the treatment of Leishmaniasis and Tuberculosis.” (TTU02.902_00)       

 

DZIF-MD Stipendium (TI07.003)                                 

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.

<