Leitung Prof. Dr. Gerd-D.
Bernhard-Nocht-Institut für Tropenmedizin
Mitarbeiter Dr. Dominic Wichmann
Dr. Stephan Ehrhardt
Dr. Jakob Cramer
Pathogenesis and significance of cardiac
and renal organ manifestations in Plasmodium falciparum infection
Organ manifestation in Plasmodium falciparum
infections represents an important pathophysiological factor in the course
of the disease. Yet, not much attention has been paid to myocardial impairment
in malaria infection. There is little knowledge to what extent possible
plasmodia-induced heart failure contributes to pulmonary oedema, a severe
and often lethal complication in severe malaria. Knowledge on factors
contributing to pulmonary oedema will have considerable impact on liquid
management and transfusion criteria in patients with anaemia. First investigations
revealed that in complicated malaria as compared to uncomplicated cases,
myocardial peptides are released from cardiomyocytes indicating myocardial
damage. Our group is currently substantiating these results with echocardiography
and is subsequently investigating heart function before and after liquid
Up to now, the mechanisms leading to myocardial
damage in malaria are unknown. Direct myocardial damage by lipopolysaccharide
was observed in patients with sepsis. We are currently carrying out trials
to examine if plasmodia GPI does have a similar effect and might lead
to apoptosis in rodent cardiomyocytes.
Aim of the investigator group is to contribute
to the understanding of pathomechanisms in complicated malaria in order
to define methods for improved clinical management. Special attention
is directed to the heart and kidneys as these organs seem to be prone
to impairment during the course of the disease.
Cardiac and renal organ manifestations in Plasmodium falciparum
Myocardial impairment in falciparum malaria was first observed in an
unmatched case control study, conducted in 63 non-immune patients with
uncomplicated (n=52) and complicated (n=11) malaria. We assessed 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 indicator of acute myocardial
injury. Additionally we measured myoglobin, creatine kinase muscle-brain
and troponin T as established markers. Cardiac impairment, as defined
by elevated levels of cardiac specific peptides, 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 substantiate if our results are apt to be
correlated with echocardiographic findings. Furthermore, we aim at investigating
transfusion and infusion criteria in the light of myocardial damage found
in severe malaria patients.
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
contributes a study examining if asymptomatic parasitaemia in children
is likely to lead to renal failure (thus explaining 10 to 50 times higher
rates of renal failure in Africa compared to industrialised countries).
Furthermore the Clinical Department is taking part in a multicenter study
on the effectiveness and safety of Artemether/Lumefantrin in the treatment
of uncomplicated Plasmodium falciparum malaria.
GPI-induced apoptosis in murine cardiomyocytes and inhibition by caspase-inhibitors
Aim of the study is to investigate if Plasmodium falciparum GPI
triggers similar pathophysiological host resonses as LPS in sepsis caused
by gram-negative bacteriae. Apoptosis in endothelial cells is likely to
be induced by direct contact with pasitized red blood cells. In the scope
of this trial, GPI purifying was performed in co-operation with the group
of Prof. Schwartz, University of Marburg.
C57BL/6-mice were exposed to purified GPI and the animals were subsequently
examined for signs of apoptosis. In more detail, the myocardium (as well
as other organs) are examined by means of histological methods, TUNEL-assay
and DNA-fragmentation assay. In addition, the intracellular signal transduction
shall be investigated. To identify functional domains, modified GPI will
be examined with respect to biological activity in macrophage assays.
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, respective TLRs as well as genes coding for the intracellular
signalling pathway shall be genotyped in African children with and without
malaria. 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 important to assess individual disease susceptibility
and to deduce future options for malaria treatment.
Stephan Ehrhardt, Frank P. Mockenhaupt, Sylvester D. Anemana, Rowland
N. Otchwemah, Dominic Wichmann, Jakob P. Cramer, Ulrich Bienzle, Gerd
D. Burchard, Norbert W. Brattig (2005). High levels of circulating cardiac
proteins indicate cardiac impairment in African children with severe
/Plasmodium falciparum/ malaria. Microbes Infect 7(11-12):1204-10.
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.