Toxoplasma gondii infection induces apoptosis in noninfected macrophages: Role of nitric oxide and other soluble factors

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, Japan.
Parasite Immunology (Impact Factor: 2.14). 08/2007; 29(7):375-85. DOI: 10.1111/j.1365-3024.2007.00956.x
Source: PubMed


Apoptosis has been found to help in the defence against pathogens. Infection with the obligate intracellular parasite Toxoplasma gondii is known to trigger host-cell apoptosis. When using a T. gondii-infected macrophage cell line, J774A.1, treatment with IFN-gamma significantly enhanced apoptosis in noninfected bystander cells while parasitized cells became relatively resistant. Infection and IFN-gamma treatment activated the expression of inducible nitric oxide synthase (iNOS), and the production of nitric oxide (NO) and treatment of cells with an iNOS inhibitor, N(G)-monomethlyl-L-arginine acetate (L-NMMA) reduced the apoptosis frequency. However, the reversal was only partial suggesting that not only NO, but also other, as of yet, unknown factors are induced. Finally, we studied the effect in vivo by infecting mice with either a virulent or an avirulent strain. Challenge with the virulent strain lead to a higher parasite burden, induced host-cell apoptosis in peritoneal cells, and produced higher levels of IFN-gamma and NO. Moreover, treatment of mice with a NO synthase inhibitor, aminoguanidine, partially inhibited the host-cell apoptosis induced by the parasite infection. Altogether, our findings indicate that apoptosis in bystander host cells is due to the secretion of NO and other soluble factors released by parasite-infected cells.

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    • "These results are consistent with the results by Li and colleagues (Li et al. 2012) that they demonstrated that a lower concentration of NO in the rodent peritoneal macrophages is strongly linked to their susceptibility to T. gondii infection. Some studies demonstrated that T. gondii infection could decrease NO production in the peritoneal macrophages (Nishikawa et al. 2007) and it was suggested as one of the reasons for the development of acute toxoplasmosis from chronic infection. Our results also showed that T. gondii infection could partially decrease NO production in the infected cells which was suggested as one of the pathways used by the parasite to enable to escape the immune reaction in the host (Seabra et al. 2002). "
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    • "T. gondii-infected cells were initially reported to be resistant to apoptosis, which benefits the parasite as it requires a living host cell for replication (Nash et al. 1998). However, several subsequent studies have demonstrated that T. gondii infection can induce apoptosis, mostly in neighboring, uninfected host cells (Liesenfeld et al. 1997; Mordue et al. 2001; Nishikawa et al. 2007). Bannai et al. (2008) investigated a T. gondii analog to the human protein Programmed Cell Death 5 (TgPDCD5) during apoptosis and during interactions with host cells. "
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    • "Therefore, if 14-3-3 proteins are involved in prevention of parasite replication, this remains to be determined. T. gondii infection leads to alteration or inhibition of key cell signaling pathways (Heussler et al., 2001; Butcher et al., 2001; Tato et al., 1993; ) and cellular processes (Luder et al., 2003; Payne et al., 2003; Nishikawa et al., 2007) resulting in increased parasite survival. Although, these studies were performed in well characterized human colonic epithelial cells; these cells are derived from colorectal adenocarcinomas, and expression of 14-3-3 proteins in cancer cells is commonly altered (Qi et al., 2005). "
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