title: The liver stage of Plasmodium berghei inhibits host cell apoptosis.
abstract: Plasmodium berghei is the causative agent of rodent malaria and is widely used as a model system to study the liver stage of Plasmodium parasites. The entry of P. berghei sporozoites into hepatocytes has extensively been studied, but little is known about parasite-host interaction during later developmental stages of the intracellular parasite. Growth of the parasite far beyond the normal size of the host cell is an important stress factor for the infected cell. Cell stress is known to trigger programmed cell death (apoptosis) and we examined several apoptotic markers in P. berghei-infected cells and compared their level of expression and their distribution to that of non-infected cells. As none of the apoptotic markers investigated were found altered in infected cells, we hypothesized that parasite infection might confer resistance to apoptosis of the host cell. Treatment with peroxide or serum deprivation induced apoptosis in non-infected HepG2 cells, whereas P. berghei-infected cells appeared protected, indicating that the parasite interferes indeed with the apoptotic machinery of the host cell. To prove the physiological relevance of these results, mice were infected with high numbers of P. berghei sporozoites and treated with tumour necrosis factor (TNF)-alpha/D-galactosamine to induce massive liver apoptosis. Liver sections of these mice, stained for degraded DNA, confirmed that infected cells containing viable parasites were protected from programmed cell death. However, in non-treated control mice as well as in TNF-alpha-treated mice a small proportion of dead intracellular parasites with degraded DNA were detected. Most hepatocytes containing dead parasites provoked an infiltration of immunocompetent cells, indicating that these cells are no longer protected from cell death.
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str 74, 20359 Hamburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: van de Sand
authors.forename: Sebastian
authors.initials: S
authors.lastname: Horstmann
authors.forename: Anja
authors.initials: A
authors.lastname: Schmidt
authors.forename: Angelika
authors.initials: A
authors.lastname: Sturm
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bolte
authors.forename: Andreas
authors.initials: A
authors.lastname: Krueger
authors.forename: Marc
authors.initials: M
authors.lastname: Lütgehetmann
authors.forename: Jörg-Matthias
authors.initials: JM
authors.lastname: Pollok
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.forename: Volker T
authors.initials: VT
authors.lastname: Heussler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000469:parasitology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D034882:Lamins / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000469:parasitology* / Q000502:physiology; D008288:Malaria / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D034101:Sporozoites / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D034882:Lamins; D014409:Tumor Necrosis Factor-alpha; D019859:Proto-Oncogene Proteins c-met; D020169:Caspases