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 liquid application.
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

Projects

Cardiac and renal organ manifestations in Plasmodium falciparum malaria
Stephan Ehrhardt

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).

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GPI-induced apoptosis in murine cardiomyocytes and inhibition by caspase-inhibitors
Dominic Wichmann

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.

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Malaria, Toll-like receptors and GPI
Jakob Cramer

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.

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Selected Publications Clinical Research

• 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.