The Apicomplexan PathogenNeospora caninumInhibits Host Cell Apoptosis in the Absence of Discernible NF-κB Activation

Abstract

Neospora caninum, a causative agent of bovine abortions, is an apicomplexan parasite that is closely related to the human pathogen Toxoplasma gondii. Since a number of intracellular parasites, including T. gondii, have been shown to modulate host cell apoptosis, the present study was conducted to establish whether N. caninum is similarly capable of subverting apoptotic pathways in its host cells. Our results indicated that death receptor-mediated apoptosis is repressed during N. caninum infection, and the data further showed that the executioner caspase, caspase 3, does not become activated in the infected cells. Surprisingly, nuclear translocation of the NF-B subunit p65 was not detected in N. caninum-infected cells, although this host transcription factor has been shown to upregulate prosurvival genes in cells infected with T. gondii. Consistent with these findings, the distinct accumulation of phosphorylated IB that is seen at the parasitophorous vacuole membrane (PVM) of T. gondii was not apparent on the N. caninum PVM. Although a putative IB kinase activity was detected in N. caninum extracts, thereby implying that this parasite is capable of modulating NF-B translocation into the host cell nucleus, the data collectively suggest that a profound and sustained activation of the NF-B pathway is not central to the ability of N. caninum to prevent apoptosis of their host cells.

Effects of Neospora caninum infection on brain microvascular endothelial cells bioenergetics

“…Similar observations were reported when rat astrocytes were infected with N. caninum in vitro [20]. Taken together, OCR findings corroborate with the findings of the MTT assay and further substantiate previous findings [26] namely that of the capacity of the parasite to manipulate the host cell in order to prevent damage to the host cell and to allow its normal functioning during the early stage of infection. Whilst further studies are necessary to disclose the molecular mechanisms underlying N. caninum -induced cellular death, the groundwork established in the present work suggests that cell respirometry analysis for the investigation of mitochondrial bioenergetics of brain microvascular endothelial cells, especially at the early stage of infection, may be an important tool for understanding N. caninum -host cells interactions.…”

“…A similar finding was obtained in primary cultures of rat astrocytes infected with N. caninum , where LDH levels increased significantly in culture supernatants after 24 hr and 72 hr of infection, compared with non-infected controls, but without significant changes in cell viability determined by MTT assays [20]. N. caninum infection of mouse embryonic fibroblasts has been found to result in reduced caspase activity and thus, inhibition of apoptosis [26]. The same process may be occurring during N. caninum infection of HBMECs.…”

Host cell manipulation by the human pathogen Toxoplasma gondii

“…The closely related parasite Neospora caninum shares several properties with T. gondii, such as establishing an anti-apoptotic state in the infected host cell. However, cells infected with N. caninum do not show nuclear translocation NF-κB, even though this parasite exhibits endogenous IKK activity similarly to T. gondii [109]. These results suggest differential roles between the IKKs of T. gondii and N. caninum in the modulation of the NF-κB pathway and by extension the inhibition of apoptosis in the infected cell.…”

Toxoplasma gondiiRhoptry Discharge Correlates with Activation of the Early Growth Response 2 Host Cell Transcription Factor

“…For example, Toxoplasma interferes with gamma interferon-dependent gene expression while Neospora does not. In addition, Neospora is unable to modulate NF-B (29,35).…”