Inhibition of Cyclooxygenase-1 and Cyclooxygenase-2 Impairs Trypanosoma cruzi Entry into Cardiac Cells and Promotes Differential Modulation of the Inflammatory Response

Abstract

fThe intracellular protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas disease, a serious disorder that affects millions of people in Latin America. Cell invasion by T. cruzi and its intracellular replication are essential to the parasite's life cycle and for the development of Chagas disease. Here, we present evidence suggesting the involvement of the host's cyclooxygenase (COX) enzymes during T. cruzi invasion. Pharmacological antagonists for COX-1 (aspirin) and COX-2 (celecoxib) caused marked inhibition of T. cruzi infection when rat cardiac cells were pretreated with these nonsteroidal anti-inflammatory drugs (NSAIDs) for 60 min at 37°C before inoculation. This inhibition was associated with an increase in the production of NO and interleukin-1␤ and decreased production of transforming growth factor ␤ (TGF-␤) by cells. Taken together, these results indicate that COX-1 more than COX-2 is involved in the regulation of anti-T. cruzi activity in cardiac cells, and they provide a better understanding of the influence of TGF-␤-interfering therapies on the innate inflammatory response to T. cruzi infection and may represent a very pertinent target for new therapeutic treatments of Chagas disease.

Modulation of host cell SUMOylation facilitates efficient development of Plasmodium berghei and Toxoplasma gondii

“…PTGS2/COX‐2 is responsible for production of the inflammatory prostaglandins, which plays important roles in resistance to apoptosis and proliferation (Greenhough et al, ). In Trypanosoma cruzi , celecoxib‐mediated downregulation of COX‐2 impairs parasite entry into cardiac cells (Malvezi et al, ), and in Leishmania infantum , production of the Prostagalandin E2 mediated by COX2 benefits the parasite survival (Saha et al, ). Thus, in Plasmodium hepatic stages, it may be envisaged that a similar strategy for modulation of host COX2 pathway occurs to establish successful infection.…”

Myenteric neuroprotective role of aspirin in acute and chronic experimental infections with Trypanosoma cruzi

“…Both ASA Early (20 mg/kg) and ASA Delayed (50 mg/kg) treatments were capable of reducing the intensity of inflammatory foci in the colonic wall, protecting myenteric neurons against cell death and plastic changes, and recovering the gastrointestinal transit in mice infected with the Y strain of T. cruzi . Therefore, the use of low doses of ASA may represent a therapeutic alternative against the evolution of Chagas disease and should be evaluated in combined treatment with trypanocidal drugs.…”

“…Thus, other strategies that affect the pathophysiological processes of the disease to facilitate current antiparasitic therapy are very welcome. In this sense, evidence suggests that the cyclooxygenase enzyme (COX) is involved in the T. cruzi invasion process . It is known that the use of aspirin (ASA) and celecoxib, respective COX‐1/COX‐2 and COX‐2 inhibitors, can modulate the infection with T. cruzi .…”

“…In this sense, evidence suggests that the cyclooxygenase enzyme (COX) is involved in the T. cruzi invasion process . It is known that the use of aspirin (ASA) and celecoxib, respective COX‐1/COX‐2 and COX‐2 inhibitors, can modulate the infection with T. cruzi . The effects of ASA have been shown to be dose‐dependent, as low doses (20‐50 mg/kg) have a protective effect and doses above 50 mg/kg increase host parasitemia and mortality in mice .…”

“…20 It is known that the use of aspirin (ASA) and celecoxib, respective COX-1/COX-2 and COX-2 inhibitors, can modulate the infection with T. cruzi. 20,21 The effects of ASA have been shown to be dose-dependent, as low doses (20-50 mg/kg) have a protective effect and doses above 50 mg/kg increase host parasitemia and mortality in mice. [22][23][24][25] Despite its importance, few studies have been evaluated the effect of COX inhibitors for myenteric neurons of T. cruzi infected mice.…”