Immunology of Infectious Disease Research Unit

Current projects

Role of TNF and adhesion molecules in tuberculosis, schistosomiasis and malaria
In humans, the natural route of infection is by aerosol inhalation where M. tuberculosis establish mainly in the lung of infected persons.

In order to reflect the route of infection in man we have established an aerosol infection model in mice. Infection studies in several gene deficient mice showed the crucial importance of the soluble factor Tumor Necrosis Factor (TNF) in tuberculosis.

Absence of TNF lead to fatal outcome in BCG as well as aerosol M. tuberculosis infection due to the absence of an effective immune response and the development of dramatic pathology in infected organs (see publications).

Currently, the role of TNF and related factors are being studied in schistosomiasis and malaria. The role of adhesion molecules are being further investigated with the adhesion molecule ICAM having demonstrated importance in the prevention of cerebral malaria (see publication).

Tuberculosis Dormancy and reactivation
A major problem in efficient tuberculosis drug therapy is the potential of M. tuberculosis to hide and therefore avoid complete clearance in an infected person (dormancy). When cured patients experience phases of immunological weakness due to other diseases or aging, reactivation may occur with the development of active TB.

In order to obtain a better understanding of dormancy and reactivation, and define important host protective factors, a study is in progress to establish and characterise latent Mtb infection in mice as a model of reactivation of clinical tuberculosis.

These investigations should contribute towards the understanding of protective immunity and the development of novel vaccines. Furthermore, these experiments should lead to the development of human test systems to demonstrate immunity in Mtb infected and/or vaccinated patients

Identification of genes involved in protection to Tuberculosis
Mycobacterium tuberculosis and Listeria monocytogenes are intracellular living bacteria that mainly infect resident macrophages (phagocytes). They are the main target cells as well as the main effector cells due to their "killing" functions that eradicate the invader after IFN-g and TNF- stimulation.

Neither the signal cascade, nor the mechanisms of these "killing" functions are completely understood and most of the genes have not been identified.

We propose a genetic approach involving microarray technology in pathogen-infected macrophages from wild type and gene-deficient macrophages (the later with defective killing functions) to identify and isolate novel genes involved in the cascade leading to the crucial killing mechanisms. Genes of interest will be used to generate novel mouse models for further in vivo study.

The role of IL-4 and IL-13 in innate and adaptive immunity to tuberculosis, leishmaniasis and helminthic diseases
The objective of this proposal is to define the biological role more accurately of the cytokines, IL-4 and IL-13 in murine models for human infectious diseases such as leishmaniasis and tuberculosis.

Our approach is based on comparative infection studies using gene deficient mice with a null mutation for the ligands (IL-4 or IL-13) or the receptor (IL-4Ralpha) and their corresponding wild type controls, generated in our laboratory.

Here, we have shown that the production of IL-4 or IL-13 in response to L. major infection lead to susceptibility in acute murine leishmaniasis. However, we further demonstrated that later during infection IL-13 seems to be protective and prevents chronic leishmaniasis.

Further, in L. donovani infection, which also causes cutaneous leishmaniasis, prevalent in the African continent, IL-4 is of crucial importance for effective drug therapy and vaccination against the invader. The same holds true for vaccination in schistosomiasis (see publication).

These results suggest a dual role of IL-4 and IL-13. Early IL-4 or IL-13 which is induced by pathogenic antigens is detrimental, whereas late IL-4 seems to be beneficial for effective host immune responses (see publication). demonstrating a common principle of IL-4 which has to be considered in the development of effective vaccines.