Toxoplasma gondiiCyclophilin 18-Mediated Production of Nitric Oxide Induces Bradyzoite Conversion in a CCR5-Dependent Manner

Abstract

Toxoplasma gondii modulates pro-and anti-inflammatory responses to regulate parasite multiplication and host survival. Pressure from the immune response causes the conversion of tachyzoites into slowly dividing bradyzoites. The regulatory mechanisms involved in this switch are poorly understood. The aim of this study was to investigate the immunomodulatory role of T. gondii cyclophilin 18 (TgCyp18) in macrophages and the consequences of the cellular responses on the conversion machinery. Recombinant TgCyp18 induced the production of nitric oxide (NO), interleukin-12 (IL-12), and tumor necrosis factor alpha through its binding with cysteine-cysteine chemokine receptor 5 (CCR5) and the production of gamma interferon and IL-6 in a CCR5-independent manner. Interestingly, the treatment of macrophages with TgCyp18 resulted in the inhibition of parasite growth and an enhancement of the conversion into bradyzoites via NO in a CCR5-dependent manner. In conclusion, T. gondii possesses sophisticated mechanisms to manipulate host cell responses in a TgCyp18-mediated process.

Toxoplasma gondiiCyclophilin 18 Regulates the Proliferation and Migration of Murine Macrophages and Spleen Cells

“…In contrast, no significant proliferative response was demonstrated after stimulation with 25 150 ) of the TgCyp18 region abrogated this effect. This observation provides further evidence that TgCyp18 binding to CCR5 is antagonistic for spleen cell proliferation, but further study will be required to confirm this.…”

“…TgCyp18 has been shown to stimulate macrophages to produce IL-12 and NO in a CCR5-dependent manner (25). However, the dose-dependent effect of TgCyp18 has not yet been elucidated.…”

“…Lipopolysaccharide (LPS) from Escherichia coli (10-g/ml stock solution in RPMI 1640 medium), concanavalin A (ConA) from Canavalia ensiformis (5-mg/ml stock solution in RPMI 1640 medium) were obtained from Sigma (Sigma, St. Louis, MO). Recombinant mouse MIP-3␣ (25- , were performed as described previously (25). Wild-type and mutant TgCyp18s were expressed as glutathione S-transferase (GST) fusion proteins in the E. coli DH5␣ strain (Takara, Bio Inc., Japan).…”

Nitric oxide production increases during Toxoplasma gondii encephalitis in mice

“…Moreover, many studies have shown that nitric oxide (NO) triggers the conversion between tachyzoite to bradyzoite forms and has parasiticidal effects. In addition to its immunoregulatory functions (Sibley et al, 1991;Candolfi et al, 1994;Bohne et al, 1994;Hayashi et al, 1996;Ibrahim et al, 2009), NO has immunopathological effects (Khan et al, 1997;Hayashi et al, 1996;Scharton-Kersten et al, 1997;Liesenfeld et al, 1999).…”

Identification and co-localization of perforin-like (TgPLP1) protein in Toxoplasma gondii bradyzoites

“…Mechanisms of tissue cyst rupture and bradyzoite release in T. gondii have not yet been fully elucidated (Dzierszinski et al, 2004;Ibrahim et al, 2009). Once T. gondii infects humans and forms cysts during the chronic phase; encysted bradyzoites can rupture, reactivate into actively replicating and cytolytic tachyzoites, and cause symptomatic disease in immunocompromised individuals, such as people with HIV-AIDS or organ transplantation patients (Sullivan et al, 2009).…”