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
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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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    ABSTRACT: It is well known that toxoplasmosis can be life threatening to immunocompromised individuals such as AIDS and organ transplantation patients. Glucocorticoids (GCs) are widely used in the clinic for the treatment of autoimmune diseases and organ transplantation resulting in acute toxoplasmosis in these patients. However, the interaction and mechanism between the development of acute toxoplasmosis and GC therapy are still unknown. The aims of this study were to investigate the infection of Toxoplasma gondii in the peritoneal macrophages of rats treated with glucocorticoids. Our results showed that the growth rate of T. gondii RH strain was significantly increased in the peritoneal macrophages of rats treated with glucocorticoids in vivo. For instance, 242 (±16) tachyzoites were found in 100 macrophages from the rats treated with methylprednisolone (MP), while only 16 (±4) tachyzoites were counted in the macrophages from the non-treated control rats 24 h after infection (P < 0.01). We also demonstrated that a significant inhibition of nitric oxide (NO) production was detected in the macrophages collected from the rats post-treated with GCs with 12.90 μM (±0.99 μM) of nitrite production from the rats treated with MP, while 30.85 μM (±1.62 μM) was found in the non-treated control rats 36 h after incubation (P < 0.01). Furthermore, glucocorticoids could significantly inhibit the expression of inducible nitric oxide synthase mRNA and its protein in the rat peritoneal macrophages. Our results strongly indicate that the decrease of NO in the rat peritoneal macrophages is closely linked to the cause of acute toxoplasmosis in the host. Additionally, there was a significant increase in the number of cysts produced by the naturally cyst forming, T. gondii Prugniaud strain with an average of 2,795 (±422) cysts of the parasite being detected in the brains of the rats treated with dexamethasone, while only 1,356 (±490) cysts were found in the non-treated control animals (P < 0.01). As rats and humans are both naturally resistant to T. gondii infection, these novel data could lead to a better understanding of the development of acute toxoplasmosis during glucocorticoid therapy in humans.
    Parasitology Research 11/2013; 113(1). DOI:10.1007/s00436-013-3661-3 · 2.10 Impact Factor
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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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    ABSTRACT: To cause infections, microbial pathogens elaborate a multitude of factors that interact with host components. Using these host–pathogen interactions to their advantage, pathogens attach, invade, disseminate, and evade host defense mechanisms to promote their survival in the hostile host environment. Many viruses, bacteria, and parasites express adhesins that bind to cell surface heparan sulfate proteoglycans (HSPGs) to facilitate their initial attachment and subsequent cellular entry. Some pathogens also secrete virulence factors that modify HSPG expression. HSPGs are ubiquitously expressed on the cell surface of adherent cells and in the extracellular matrix. HSPGs are composed of one or several heparan sulfate (HS) glycosaminoglycan chains attached covalently to specific core proteins. For most intracellular pathogens, cell surface HSPGs serve as a scaffold that facilitates the interaction of microbes with secondary receptors that mediate host cell entry. Consistent with this mechanism, addition of HS or its pharmaceutical functional mimic, heparin, inhibits microbial attachment and entry into cultured host cells, and HS-binding pathogens can no longer attach or enter cultured host cells whose HS expression has been reduced by enzymatic treatment or chemical mutagenesis. In pathogens where the specific HS adhesin has been identified, mutant strains lacking HS adhesins are viable and show normal growth rates, suggesting that the capacity to interact with HSPGs is strictly a virulence activity. The goal of this chapter is to provide a mechanistic overview of our current understanding of how certain microbial pathogens subvert HSPGs to promote their infection, using specific HSPG–pathogen interactions as representative examples.
    Glycans in Diseases and Therapeutics, 04/2011: pages 31-62;
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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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    ABSTRACT: 14-3-3 Proteins are expressed in most eukaryotes organisms and play varied and crucial roles in a wide range of regulatory processes. In mammalian cells, seven 14-3-3 isoforms have been identified. However, it is not known what effect infection has on 14-3-3 isoform expression. In this study human colonic carcinoma cell lines were infected with Toxoplasma gondii for 24h and expression of 14-3-3 proteins was determined by RT-PCR. HT-29 cells only expressed 3 out of the 7 isoforms while 5 and all 7 isoforms were found in HCT-116 and Caco-2 cells, respectively. Infection had little or no effect in the expression of 14-3-3gamma, epsilon, sigma, and xi; but in HCT-116 cells induced expression of 14-3-3eta and sigma, while 14-3-3beta, eta, and xi were induced in HT-29 cells. If 14-3-3 proteins are involved in cell survival and/or prevention of parasite replication, longer incubation times may be required as no differences in percentage of infection were found among the cell lines at 24h post-infection.
    Experimental Parasitology 02/2008; 118(1):134-8. DOI:10.1016/j.exppara.2007.07.008 · 1.64 Impact Factor
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