Sex-specific responses of monocytes to infectious challenges
Dr. Marco ER-Lukowiak, Charlotte Hansen, Stefanie Tewes
Monocytes play an important role in immune control of infections and in the success of vaccination. Like other cells of the immune system, monocytes are influenced by biological, sex-specific factors. For example, many parasitic diseases such as leishmaniasis and amebiasis occur more frequently in males. The mouse model for hepatic amebiasis mimics the sex difference as observed in humans and substitution of females with testosterone abolished their resistance. As key mediators of inflammation, monocytes must be tightly regulated, but when this is not the case, as in amebiasis, excessive activation can result in immunopathology and destruction of host tissue. Our previous investigations revealed that TNFα and recruitment of classical, inflammatory monocytes and neutrophils substantially contribute to liver damage during parasitic infection. The underlying immune cascade involves the IL-23/IL-17 immune axis and monocyte/neutrophil-attracting cytokines like chemokine ligand (CCL) 2 and the C-X-C motif ligand 1 (CXCL1). Intriguingly, TNFα and both chemokines are higher in male compared to female mice and partially also in humans upon infectious challenge. The production of these proinflammatory cytokines is further increased by treatment with the most active androgen, dihydrotestosterone. On the other hand, the prerequisites to recognize a foreign antigen are stronger in monocytes of female individuals. This also leads, for example, to a stronger vaccination response in women than in men. Among other mechanisms, certain Fcgamma receptors on the surface of monocytes are responsible for this.
We hypothesize that sex hormones substantially modulate monocyte functions and aim to investigate essentially underlying androgen-dependent signaling pathways
The immune response to foreign agents differs between women and men.
We will study the influence of sex hormones on cells of the innate immune system and the impact on the efficacy of vaccination and the outcome of parasitic infection.
Forschergruppe 5068; "Sexdifference in Immunity" (Deutsche Forschungsgemeinschaft)
Beating parasites with their own weapons
Dr. Helena Fehling, Annika Bea
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 Mtbin vitro (Patent BNI002).
Organoids as host models for parasitic infections
Parasitic infections of the liver are the subject of extensive research projects, but much of the knowledge gained is based on the use of mouse models. Advantages and limitations of these models have long been known. As an alternative, we use liver organoids for our research work.
These are in vitro cultures that enable the long-term cultivation of human liver cells in a 3D composite. In this way, both functional and structural properties of the liver can be recreated in miniature. The required liver cells can be obtained from the excess tissue of biopsies or tumour resections.
We use the liver organoids to model parasitic infections using human cells and to study the interaction with immune cells in detail in the form of
Extracellular vesicles as communicators between parasite and host immune system
Extracellular vesicles (EVs) are small particles released by cells that contain protein or microRNA (miRNA), among other types of cargo. For many parasitic disease models, it is known that EVs can play a role in the interaction between parasite and host and contribute to immune responses.
In this project, we investigate EVs secreted by Entamoeba histolytica, causative agent of the disease amebiasis. EVs are analyzed with regard to their biological properties as well as their immune-stimulatory capacities. In order to determine to which extent EVs play a role in communication with the host immune system, EVs isolated from parasite cultures are used to stimulate monocytes and neutrophils in vitro. Both immune cell types are known to be involved in the immune pathology of amebiasis. Immune cells derived from both male and female mice are used in order to investigate putative sex differences in response to EV stimulation. Furthermore, two clonal parasitic cell lines differing in their pathogenicity are used in order to elucidate pathogenicity mechanisms of the parasite.
Immune processes underlying ALA formation and regeneration
Stefan Hoenow, 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.
SFB841, " Leberentzündung: Infektion, Immunregulation und Konsequenzen" Project A2
Sex dimorphisms in the immune system
Julie Sellau, Marie Groneberg, Svenja Kühl
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.
Landesforschungsförderung Hamburg; "Geschlechtsdimorphismus im Immunsystem: Bedeutung für Erkrankung und Immunität" (LFF-FV45)