Abstract
Toxoplasma gondii is able to infect a wide range of vertebrates, including humans. Studies show that cyclooxygenase-2 (COX-2) is a modulator of immune response in multiple types of infection, such as Trypanosoma cruzi. However, the role of COX-2 during T. gondii infection is still unclear. The aim of this study was to investigate the role of COX-2 during infection by moderately or highly virulent strains of T. gondii in Calomys callosus rodents and human THP-1 cells. C. callosus were infected with 50 cysts of T. gondii (ME49), treated with COX-2 inhibitors (meloxicam or celecoxib) and evaluated to check body weight and morbidity. After 40 days, brain and serum were collected for detection of T. gondii by real-time PCR and immunohistochemistry or cytokines by CBA. Furthermore, peritoneal macrophages or THP-1 cells, infected with RH strain or uninfected, were treated with meloxicam or celecoxib to evaluate the parasite proliferation by colorimetric assay and cytokine production by ELISA. Finally, in order to verify the role of prostaglandin E2 in COX-2 mechanism, THP-1 cells were infected, treated with meloxicam or celecoxib plus PGE2, and analyzed to parasite proliferation and cytokine production. The data showed that body weight and morbidity of the animals changed after infection by T. gondii, under both treatments. Immunohistochemistry and real-time PCR showed a reduction of T. gondii in brains of animals treated with both COX-2 inhibitors. Additionally, it was observed that both COX-2 inhibitors controlled the T. gondii proliferation in peritoneal macrophages and THP-1 cells, and the treatment with PGE2 restored the parasite growth in THP-1 cells blocked to COX-2. In the serum of Calomys, upregulation of pro-inflammatory cytokines was detected, while the supernatants of peritoneal macrophages and THP-1 cells demonstrated significant production of TNF and nitrite, or TNF, nitrite and MIF, respectively, under both COX-2 inhibitors. Finally, PGE2 treatment in THP-1 cells triggered downmodulation of pro-inflammatory mediators and upregulation of IL-8 and IL-10. Thus, COX-2 is an immune mediator involved in the susceptibility to T. gondii regardless of strain or cell types, since inhibition of this enzyme induced control of infection by upregulating important pro-inflammatory mediators against Toxoplasma.
Highlights
Toxoplasmosis is an infectious disease caused by the protozoan parasite Toxoplasma gondii, which can invade and replicate in any type of nucleated cell, including macrophages, cells from the nervous system and muscle tissue (Montoya and Liesenfeld, 2004; Dubey, 2010; Robert-Gangneux and Dardé, 2012)
It is important to emphasize that C. callosus has a mean body weight around 40 g, ME49 strain does not cause severe disease in these animals, and Calomys are widely used as toxoplasmosis model study (Ferro et al, 2002; Barbosa et al, 2007, 2012; Franco et al, 2014, 2015)
Many studies demonstrate the role of COX-2 and prostaglandin E2 (PGE2) during infections triggered by pathogens (Michelin et al, 2005; Abdalla et al, 2008; Tatakihara et al, 2008; Moraes et al, 2015), there are no studies demonstrating association between COX-2 and susceptibility to T. gondii infection
Summary
Toxoplasmosis is an infectious disease caused by the protozoan parasite Toxoplasma gondii, which can invade and replicate in any type of nucleated cell, including macrophages, cells from the nervous system and muscle tissue (Montoya and Liesenfeld, 2004; Dubey, 2010; Robert-Gangneux and Dardé, 2012). When the infection is established in immunocompromised patients or during pregnancy, severe manifestations can be observed, especially in newborns or in children congenitally infected, such as retinochoroiditis, encephalitis, and miscarriage (Dubey et al, 2012). Programs of prevention of congenital toxoplasmosis in pregnant women can be only found in a limited number of countries. A French screening program established since 1992 requires monthly testes in pregnant women until delivery, in order to reduce significantly the rate of congenital transmission (Peyron et al, 2017). New strategies to prevent or treat the toxoplasmosis are welcome, in order to minimize the public health problem and to improve the quality of life of children and immunocompromised individuals infected by the parasite
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