AUTHOR=Pereira Ana Carolina Alcântara , Silva Rafaela José , Franco Priscila Silva , de Oliveira Gomes Angelica , Souza Guilherme , Milian Iliana Claudia Balga , Ribeiro Mayara , Rosini Alessandra Monteiro , Guirelli Pâmela Mendonça , Ramos Eliézer Lucas Pires , Mineo Tiago Wilson Patriarca , Mineo José Roberto , Silva Neide Maria , Ferro Eloisa Amália Vieira , Barbosa Bellisa Freitas 

TITLE=Cyclooxygenase (COX)-2 Inhibitors Reduce Toxoplasma gondii Infection and Upregulate the Pro-inflammatory Immune Response in Calomys callosus Rodents and Human Monocyte Cell Line

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.00225

DOI=10.3389/fmicb.2019.00225

ISSN=1664-302X

ABSTRACT=<p><italic>Toxoplasma gondii</italic> 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 <italic>Trypanosoma cruzi</italic>. However, the role of COX-2 during <italic>T. gondii</italic> 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 <italic>T. gondii</italic> in <italic>Calomys callosus</italic> rodents and human THP-1 cells. <italic>C. callosus</italic> were infected with 50 cysts of <italic>T. gondii</italic> (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 <italic>T. gondii</italic> 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 E<sub>2</sub> in COX-2 mechanism, THP-1 cells were infected, treated with meloxicam or celecoxib plus PGE<sub>2</sub>, and analyzed to parasite proliferation and cytokine production. The data showed that body weight and morbidity of the animals changed after infection by <italic>T. gondii</italic>, under both treatments. Immunohistochemistry and real-time PCR showed a reduction of <italic>T. gondii</italic> in brains of animals treated with both COX-2 inhibitors. Additionally, it was observed that both COX-2 inhibitors controlled the <italic>T. gondii</italic> proliferation in peritoneal macrophages and THP-1 cells, and the treatment with PGE<sub>2</sub> restored the parasite growth in THP-1 cells blocked to COX-2. In the serum of <italic>Calomys</italic>, 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, PGE<sub>2</sub> 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 <italic>T. gondii</italic> regardless of strain or cell types, since inhibition of this enzyme induced control of infection by upregulating important pro-inflammatory mediators against <italic>Toxoplasma</italic>.</p>