Prof. Dr. Gerd-D.
Bernhard-Nocht-Institut für Tropenmedizin
Dr. Dominic Wichmann
Dr. Stephan Ehrhardt
Dr. Jakob Cramer
Pathogenesis and significance of cardiac
and renal organ manifestations in Plasmodium falciparum infection
Organ manifestations in Plasmodium falciparum
infections are representing an important pathophysiological factor in
the course of the disease. Up to now there was not much attention paid
to heart failure in malaria infection. There is actually no knowledge
to what extent possible plasmodia-induced heart failure is contributing
to pulmonary oedema which is often lethal in severe malaria. The question
of possible left heart failure in malaria is, however, very important
as far as practice is concerned. Better evaluation of the danger of occurring
pulmonary oedema will have effects on the liquid equilibration as well
as on the decision for blood transfusions in view of anaemia often occurring
at the same time in these cases. First investigations show that in complicated
malaria - in comparison with uncomplicated cases - myocardial markers
are set free. i.e. there is obviously myocardial damage occurring. We
are actually planning to correlate these results with echocardiographic
results and subsequently investigating heart function before and after
Up to now, the mechanisms leading to myocardial damage in malaria is unknown,
there does not seem to be myocardial ischaemia. Direct myocardial damage
by lipopolysaccharide was seen in cases of sepsis. We are actually carrying
out trials in view of the question if plasmodia GPI does have a similar
effect and might lead to apoptosis of cardiomyocytes in a rodent model.
Aim of the investigator group is to contribute to the understanding of
pathomechanisms in complicated malaria in order to define attempts for
a better clinical management. Special attention is directed to the cardiac
and renal aspects of the disease.
Projects | Publications
Cardiac and renal organ manifestations in Plasmodium falciparum
To look for myocardial impairment in falciparum malaria at first an unmatched
case control study was conducted in 63 non-immune patients with uncomplicated
(n=52) and complicated (n=11) malaria. We measured the serum levels of
N-terminal pro-brain natriuretic peptide (NT-proBNP) as a sensitive marker
of impaired left ventricular function, and heart-type fatty acid-binding
protein (H-FABP) as a sensitive and specific marker of acute myocardial
injury. Additionally we assessed myoglobin, creatine kinase muscle-brain
and troponin T as established markers. Cardiac impairment, as defined
by elevated levels of cardiac specific markers was found to be common
in complicated malaria.
These results were confirmed by an extensive study carried out in Ghana
in 200 children with uncomplicated and 200 children with complicated malaria.
Further investigations shall find out if this proof obtained in laboratory
chemistry testing of a myocardial damage is apt to be correlated with
echocardiographic findings. Further aim of investigation is to find out
if myocardial damage is likely to be worsened by infusions or transfusions.
In the scope of the German MIM-Initiative, the BNI is carrying out an
intervention study at the KCCR in Kumasi/Ghana. The Clinical Department
is contributing a study basing on the question if asymptomatic parasitaemia
in children is likely to lead to renal failure (and thus being the reason
for renal failure being 10 to 50 times higher in Africa in comparison
to industrial countries). Furthermore the Clinical Department is taking
part in a multicentric study working on the effectiveness and reliability
of Artemether/Lumefantrin (sponsored by pharmaceutical suppliers).
back to top
GPI-induced apoptosis in murine cardiomyocytes and inhibition by caspase-inhibitors
Aim of the study is to investigate, if Plasmodium falciparum GPI
is playing a similar part as LPS does in case of sepsis caused by gram-negative
bacteriae. This might be the case as apoptosis in endothelial cells is
likely to be induced by direct contact with plasmodia infected erythrocytes.
In the scope of this trial, GPI purifying was taken up in co-operation
with Prof. Schwartz, University of Marburg.
The purified GPI was injected in C57BL/6-mice, the animals were killed
2 days later. Actually the myocardium (as well as other organs) are examined
by means of histological methods, TUNEL-assay and DNA-fragmentation assay.
In the course of the investigations, the intracellular signal conduct
shall be decoded by injection of selective caspase-inhibitors. Modified
GPI will used at the investigation of functional domains.
back to top
Malaria, Toll-like receptors and GPI
Cytokines and pro-inflammatory mediators are important for
parasite elimination but also contribute to host pathology. Toll-like
receptors (TLRs) on human mononuclear cells play an important role in
recognising conserved antigen structures and initiating innate immune
mechanisms in the host. Glykosylphosphatidylinositol (GPI), a surface
antigen of protozoan parasites, activates host innate immunity via TLR2
and may form the basis for an anti-disease vaccine. Little is known about
Plasmodium falciparum GPI and its interaction with human TLRs.
Furthermore, TLR gene variants may influence disease susceptibility and
severity in P. falciparum malaria.
We propose to perform gene expression analysis in a rodent model and in
malaria patients to investigate the specific TLR signalling pathway. In
addition, we plan to genotype respective TLRs as well as genes coding
for the intracellular signalling pathway in a case-control-study of Ghanaian
children. Finally, TLR signalling patterns and gene variants are to be
correlated with disease pathology in rodents and human malaria patients.
We expect to gain insight into the mechanisms triggering innate immune
mechanisms in malaria disease and their contribution to host pathology.
This information may be useful to assess individual disease susceptibility
and to deduce future options for malaria treatment.
back to top
- Cramer JP, Mockenhaupt FP, Ehrhardt S, Burkhardt J, Otchwemah RN,
Dietz E, Gellert S and Bienzle U (2004). iNOS promoter variants and
severe malaria in Ghanaian children. Trop Med Int Health 9(10): 1074-80.
- Ehrhardt S, Wichmann D, Hemmer CJ, Burchard GD and Brattig NW (2004).
Circulating concentrations of cardiac proteins in complicated and uncomplicated
Plasmodium falciparum malaria. Trop Med Int Health 9(10): 1099-103.
- Mockenhaupt FP, Ehrhardt S, Burkhardt J, Bosomtwe SY, Laryea S, Anemana
SD, Otchwemah RN, Cramer JP, Dietz E, Gellert S and Bienzle U (2004).
Manifestation and outcome of severe malaria in children in northern
Ghana. Am J Trop Med Hyg 71(2): 167-72.
- Muehlen M, Schreiber J, Ehrhardt S, Otchwemah R, Jelinek T, Bienzle
U and Mockenhaupt FP (2004). Short communication: Prevalence of mutations
associated with resistance to atovaquone and to the antifolate effect
of proguanil in Plasmodium falciparum isolates from northern
Ghana. Trop Med Int Health 9(3): 361-3.
- Burchard GD, Ehrhardt S, Mockenhaupt FP, Mathieu A, Agana-Nsiire P,
Anemana SD, Otchwemah RN, Abel W and Brattig N (2003). Renal dysfunction
in children with uncomplicated Plasmodium falciparum malaria
in Tamale, Ghana. Ann Trop Med Parasitol 97(4): 345-50.
- Gunther A, Grobusch MP, Slevogt H, Abel W and Burchard GD (2003).
Myocardial damage in falciparum malaria detectable by cardiac troponin
T is rare. Trop Med Int Health 8(1): 30-2.
- Manegold C, Schmiedel S, Chiwakata CB and Dietrich M (2003). Procalcitonin
serum levels in tertian malaria. Malar J 2(1): 34.
- Muhlberger N, Jelinek T, Behrens R, Gjorup I, Coulaud J, Clerinx J,
Puente S, Burchard G, Gascon J, Grobusch MP, Weitzel T, Zoller T, Kollaritsch
H, Beran J, Iversen J, Hatz C, Schmid ML, Bjorkman A, Fleischer K, Bisoffi
Z, Guggemos W, Knobloch J, Matteelli A, Schulze M, Laferl H, Kapaun
A, McWhinney P, Lopez-Velez R, Fatkenheuer G, Kern P, Zieger BW, Kotlowski
A, Fry G, Cuadros J and Myrvang B (2003). Age as a risk factor for severe
manifestations and fatal outcome of falciparum malaria in European patients:
observations from TropNetEurop and SIMPID Surveillance Data. Clin Infect
Dis 36(8): 990-5.
- Wichmann O, Jelinek T, Peyerl-Hoffmann G, Muhlberger N, Grobusch
MP, Gascon J, Matteelli A, Hatz C, Laferl H, Schulze M, Burchard G,
da Cunha S, Beran J, McWhinney P, Kollaritsch H, Kern P, Cuadros J,
Alifrangis M and Gjorup I (2003). Molecular surveillance of the antifolate-resistant
mutation I164L in imported African isolates of Plasmodium falciparum
in Europe: sentinel data from TropNetEurop. Malar J 2(1): 17.