Research Group Heussler (Malaria I) - Bernhard-Nocht-Institut für ...

Introduction
tion contains the Departments of Molecular Medicine
mainly concerned with the elucidation of host determinants
of pathogenesis and clinical outcome, the Department
of Pathology, an international reference laboratory
for AIDS pathology and the Kumasi Centre for Collaborative
Research in Tropical Medicine in Kumasi, Ghana.
The presence of a Clinical Department that performs
clinical research in addition to performing diagnosis
and treatment of patients provides a distinctive advantage
to the BNI. It is a valuable addition to clinical research
performed in the tropics because patients seen in
Hamburg usually have primary infections with only one
infecting agent, and intensive and long-term studies applying
high technology are possible in Hamburg.
Major Areas of Research
In its research work the BNI has to concentrate on a limited
number of important tropical infections due to its
limited ressources. These infections are addressed in a
multidisciplinary way by institute-wide collaborations, a
prominent feature of the scientific work at the BNI. Most
scientific work directly or indirectly leads to projects
participating in one of these areas. In all these studies
the BNI tries to span the research from the bench to the
field, i.e. from the molecular details to studies in the tropics.
During the reported time period this were filariasis,
malaria and amoebiasis. Other major topics of research
are viral haemorrhagic fever, AIDS and leishmaniasis.
Malaria research has become the largest research
area with institute-wide cooperations ranging from the
characterization of plasmodial molecules to clinical studies
about treatment of malaria in Ghanaian children.
Projects at the Department of Parasite Biochemistry
characterize key enzymes of the glutathione metabolism
and polyamine synthesis of Plasmodium falciparum
at the molecular level for a possible exploitation
for chemotherapy The complete cycle of P. berghei is
available and allows access to sporozoites and liver stages.
Downregulation of apoptosis of infected hepatocytes
by sporozoites during the hepatic phase is studied
as well as the immune response to liver stages.
Work is also performed on the identification of molecules
involved in cell invasion and on mechanisms of sorting
and trafficking of parasite molecules in infected
erythrocytes. Studies in Ghana are concerned with the
identification genes involved in susceptibility for or resistance
to severe malaria by a genome-wide linkage analysis
within the German National Genome Network and
with the effect of intermittent treatment with sulfadoxine-pyromethamine
for malaria control within the German
Malaria Initiative.
Filariasis research has a long history at the BNI having
started already in the 1960ies. The main topic was onchocerciasis
(river blindness) caused by the filaria Onchocerca
volvulus but work on lymphatic filariasis is
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also performed. Adult filaria worms develop from infective
larval stages transmitted by blackflies or mosquitos
release microfilariae (MF) that migrate within the skin
(in onchocerciasis) or circulate in the blood (in lymphatic
filariasis). Patients with generalized onchocerciasis
show a profound suppression of cellular immune responses
against filarial antigens whereas patients with
the hyperergic form of the disease that presents with
heavy skin pathology have high T cell responses.
Again the studies reach from the molecular tailoring
of antifilarial compounds to treatment studies in the tropics.
Proteases of filaria are cloned and characterized
that allow the developing worm and the microfilariae
the migration through the skin and biochemical pathways
exploitable for the design of new antifilarial
drugs are studied. Immunological effector mechanisms
were analysed in the Departments of Helminthology
and Immunology and regulatory T cells were identified
in patients with generalized onchocerciasis that are
able to specifically suppress the response of normal T
cells to onchocercal antigens. The genetic differences
underlying the various manifestations of the infection
are identified in a genome-wide linkage analysis to identify
host genes relevant to protection.
The previous finding by Achim Hoerauf and colleagues
that endosymbiotic Rickettsia-like bacteria of the
genus Wolbachia present in most filarial species can
serve as a target for chemotherapy has been further exploited
in many studies. Treatment studies of onchocerciasis
patients were conducted in Ghana and have now
shown that depletion of endobacteria that can be achieved
by tetracycline treatment has a dramatic effect on
fertility and also viability of adult filariae. Several studies
were performed to show that anti-Wolbachia therapy is
an option for the treatment of all types of filariasis.
Thus, a combination therapy of doxycycline and ivermectin
resulted in a significantly prolonged absence of
microfilariae compared to sole ivermectin treatment. Ultrasound
investigations show that in lymphatic filariasis
tetracycline treatment has a macrofilaricidal effect since
after treatment adult worms do not move any more.
Wolbachia are not only essential symbionts for the filariae
but also play a role in the pathology since Wolbachia
surface proteins are a major stimulant for the innate
immune system. This has a bearing for therapeutical
interventions.
Amoebiasis research was established as the first institute-wide
research area in 1988, covering a variety of
aspects concerning the biology and pathogenicity of
Entamoeba histolytica. In 1989, the group of Egbert
Tannich had first described that pathogenic and apathogenic
amoeba can be distinguished by molecular
genetic methods, a finding that had enormous impact
on diagnosis and therapy. The work in the last years
concerned the analysis of molecules involved in pathogenicity,
the genome organization of Entamoeba including
the genetic comparison between E. histolytica and
E. dispar, the epidemiology of the infection (a collabora-