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 application.

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.

Projects | Publications

Projects

Cardiac and renal organ manifestations in Plasmodium falciparum malaria
Stephan Ehrhardt

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.

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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 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.

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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, 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.

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Selected Publications Clinical Research

• 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.