The liver stage of Plasmodium berghei inhibits host cell apoptosis

Abstract

SummaryPlasmodium 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. bergheiinfected 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)-α α α α / 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 nontreated control mice as well as in TNF-α α α α -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.

Genetically Attenuated Parasite Vaccines Induce Contact-Dependent CD8+ T Cell Killing of Plasmodium yoelii Liver Stage-Infected Hepatocytes

“…This kind of condition is likely to operate among the populations that live in malaria endemic areas, thereby explaining the absence of protective immune responses against the infection even after repeated exposures to the parasite. It has also been shown earlier that infected cells are protected from apoptosis by hepatocyte growth factor/MET signaling (44,45). Our results are also supported by the findings of Bongfen et al, who demonstrated that CSP, an immunodominant spz surface protein, is processed and presented by both traversed and infected primary hepatocytes and that they were both efficiently lysed by CSP-specific CTLs, apparently via perforin/granzyme mobilization (16).…”

Plasmodium berghei-Infected Primary Hepatocytes Process and Present the Circumsporozoite Protein to Specific CD8+ T Cells In Vitro

“…This is in conformity with studies which have shown that infected cells are protected from apoptosis (42,43). In addition, the finding that Fas-and perforin-deficient mice could still be protected from P. berghei (44) and P. yoelii (45) infection suggests that other mechanisms are implicated in the destruction of hepatic forms.…”

Leishmania donovani Prevents Oxidative Burst-mediated Apoptosis of Host Macrophages through Selective Induction of Suppressors of Cytokine Signaling (SOCS) Proteins

“…Therefore, even though apoptosis, induced in infected cells by cytotoxic immune effector cells, is a critical defense against intracellular pathogens, many viral, bacterial, and protozoan pathogens have developed mechanisms to invade and multiply within host cells without inducing apoptosis (6 -10). Various parasites undermine the apoptotic progression that includes Chlamydia, Escherichia coli, Mycobacterium tuberculosis, Toxoplasma gondii, Plasmodium berghei, and Leishmania species (11)(12)(13)(14)(15)(16)(17). Leishmania donovani was the first parasite reported to enhance host cell viability by inhibiting growth factor deprivation-induced apoptosis.…”