Benznidazole Treatment following AcuteTrypanosoma cruziInfection Triggers CD8⁺T-Cell Expansion and Promotes Resistance to Reinfection

Abstract

Many studies have shed light on the mechanisms underlying both immunoprotection and immune dysregulation arising after Trypanosoma cruzi infection. However, little is known about the impact of benznidazole (N-benzyl-2-nitroimidazole acetamide), the drug available for clinical treatment of the infection, on the immune system in the infected host. In the present study we investigated the effect of benznidazole therapy on the lymphoid compartment during the course of experimental T. cruzi infection. Although amelioration of a variety of clinical and parasitological signs was observed in treated mice, amelioration of splenocyte expansion was not detected. Interestingly, this sustained splenomegaly observed in benznidazole-treated mice showed a preferential expansion of CD8 ؉ T lymphocytes. Moreover, although benznidazole treatment blocked the expansion of recently activated CD4؉ and CD8 ؉ T cells seen in infected hosts, benznidazole treatment led to a selective expansion of effector and memory CD8 ؉ T lymphocytes in association with a lower rate of apoptosis. In addition, the surviving treated animals were protected from reinfection. Together, these data suggest that, in addition to its well-known direct role in blocking parasite replication in vivo, benznidazole appears to directly affect immune regulation in T. cruzi-infected hosts.Chagas' disease, caused by the intracellular protozoan parasite Trypanosoma cruzi, is a human parasitosis affecting 16 million to 18 million people in Latin America (42). This disease is characterized by an acute phase with detectable parasitemia and acute myocarditis in 8% of cases (20) and a longlasting chronic phase in which most infected people remain asymptomatic. However, approximately 36% of chronically infected individuals develop digestive problems and/or cardiomyopathy (42) in association with parasitemia and some parasitism in tissues.

Benznidazole Therapy inTrypanosoma cruzi-Infected Mice Blocks Thymic Involution and Apoptosis of CD4+CD8+Double-Positive Thymocytes

“…Therapy with benznidazole employed from 7 to 21 days after infection led to a lower peak level of parasitemia, as well as early control of the circulating parasites (Fig. 1B) as formerly described (25). Such results are reinforced by the low mortality rate seen in treated mice compared to the lethal condition in the absence of trypanocidal treatment (Fig.…”

“…In a recent work in the same experimental infection and therapy model, we demonstrated a on May 12, 2018 by guest http://aac.asm.org/ different outcome concerning the host immune response on peripheral lymphoid tissues after benznidazole therapy (25). Following acute experimental infection, the expansion of CD8 ϩ T lymphocytes with an effector/memory phenotype intreated mice occurs concomitantly to the reduction of parasitemia and mortality (25). Accordingly, benznidazole treatment not only interrupted parasite replication but also induced new regulatory mechanisms, thus triggering a different host immune response.…”

“…This may be linked to the low mortality rate and better clinical condition seen in benznidazole-treated mice. In a recent work in the same experimental infection and therapy model, we demonstrated a on May 12, 2018 by guest http://aac.asm.org/ different outcome concerning the host immune response on peripheral lymphoid tissues after benznidazole therapy (25). Following acute experimental infection, the expansion of CD8 ϩ T lymphocytes with an effector/memory phenotype intreated mice occurs concomitantly to the reduction of parasitemia and mortality (25).…”

“…Mice were submitted to ad libitum treatment with the addition of 0.25 mg of N-benzyl-2-nitroimidazole acetamide (benznidazole; Rochagan, Roche, Rio de Janeiro, Brazil) per milliliter in the drinking water, from days 7 to 21 after infection. The daily volume drunk by the mice was monitored for calculation of the total amount of drug consumed, which corresponded to 62.5 mg of benznidazole/kg/day, as described previously (25).…”

Enalapril in Combination with Benznidazole Reduces Cardiac Inflammation and Creatine Kinases in Mice Chronically Infected with Trypanosoma cruzi

“…31,32 In this way, administration of benznidazole during chronic phase of experimental T. cruzi infection prevents the development of a more severe form of cardiopathy, 33 in part by the reduction of the parasite load, in part by affecting host immune regulation. 34 Indeed, previous in vitro study, demonstrated that benznidazole acts downregulating NOSII gene promoting nitric oxide inhibition and also promotes macrophage NF-κB inhibition after stimulation with lipopolysaccharide and IFN-γ. 35 Its immunomodulatory effect goes further through the observation that the benznidazole is able to inhibit inflammatory cytokines, autoantibodies, nitric oxide production, and also leukocyte recruitment into the heart during T. cruzi infection in human and experimental models.…”