Trypanosoma cruzi infection triggers substantial production of nitric oxide (NO), which has been shown to have protective and toxic effects on the host's immune system. Sensing of trypomastigotes by phagocytes activates the inducible NO-synthase (NOS2) pathway, which produces NO and is largely responsible for macrophage-mediated killing of T. cruzi. NO is also responsible for modulating virtually all steps of innate and adaptive immunity. However, NO can also cause oxidative stress, which is especially damaging to the host due to increased tissue damage. The cytokines IFN-gamma and TNF-alpha, as well as chemokines, are strong inducers of NOS2 and are produced in large amounts during T. cruzi acute infection. Conversely, TGF-beta and IL-10 negatively regulate NO production. Here we discuss the recent evidence describing the mechanisms by which NO is able to exert its antimicrobial and immune regulatory effects, the mechanisms involved in the oxidative stress response during infection and the implications of NO for the development of therapeutic strategies against T. cruzi.

An effective innate immune recognition of the intracellular protozoan parasite Trypanosoma cruzi is critical for host resistance against Chagas disease, a severe and chronic illness that affects millions of people in Latin America. In this study, we evaluated the participation of nucleotide-binding oligomerization domain (Nod)-like receptor proteins in host response to T. cruzi infection and found that Nod1-dependent, but not Nod2-dependent, responses are required for host resistance against infection. Bone marrow-derived macrophages from Nod1^−/− mice showed an impaired induction of NF-κB–dependent products in response to infection and failed to restrict T. cruzi infection in presence of IFN-γ. Despite normal cytokine production in the sera, Nod1^−/− mice were highly susceptible to T. cruzi infection, in a similar manner to MyD88^−/− and NO synthase 2^−/− mice. These studies indicate that Nod1-dependent responses account for host resistance against T. cruzi infection by mechanisms independent of cytokine production.

Considering that little is known about the epidemiology ofNeospora caninuminfection in humans, particularly in populations with highToxoplasma gondiiinfection rates, the present study aimed to investigate the presence of antibodies toN. caninuminT. gondii-seropositive and -seronegative individuals. A total of 256 serum samples divided into four groups (61 samples from human immunodeficiency virus [HIV]-positive patients, 50 samples from patients with neurological disorders, 91 samples from newborns, and 54 samples from healthy subjects) were assessed forN. caninumandT. gondiiserologies by indirect fluorescent-antibody test, enzyme-linked immunosorbent assay, and immunoblotting (IB). Immunoglobulin G antibodies toN. caninumwere predominantly detected in HIV-infected patients (38%) and patients with neurological disorders (18%), while newborns and healthy subjects showed lower seropositivity rates (5% and 6%, respectively). Seropositivity toN. caninumwas significantly associated with seropositivity toT. gondiiin both HIV-infected patients and patients with neurological disorders. Seroreactivity toN. caninumwas confirmed by IB, with positive sera predominantly recognizing the 29-kDa antigen ofN. caninum. The results of this study indicate the presence ofN. caninuminfection or exposure in humans, particularly in HIV-infected patients or patients with neurological disorders, who could have opportunistic and concurrent infections withT. gondii. These findings may bring a new concern for the unstable clinical health of HIV-infected patients and the actual role ofN. caninuminfection in immunocompromised patients.

Protozoan parasites of the genus Leishmania are the causative agents of Leishmaniasis, a disease that can be lethal and affects 12 million people worldwide. Leishmania replicates intracellularly in macrophages, a process that is essential for disease progression. Although the production of reactive oxygen species (ROS) accounts for restriction of parasite replication, Leishmania is known to induce ROS upon macrophage infection. We have recently demonstrated NLRP3 inflammasome activation in infected macrophages, a process that is important for the outcome of infection. However, the molecular mechanisms responsible for inflammasome activation are unknown. In this article, we demonstrate that ROS induced via NADPH oxidase during the early stages of L. amazonensis infection is critical for inflammasome activation in macrophages. We identified that ROS production during L. amazonensis infection occurs upon engagement of Dectin-1, a C-type lectin receptor that signals via spleen tyrosine kinase (Syk) to induce ROS. Accordingly, inflammasome activation in response to L. amazonensis is impaired by inhibitors of NADPH oxidase, Syk, focal adhesion kinase, and proline-rich tyrosine kinase 2, and in the absence of Dectin-1. Experiments performed with Clec7a^−/− mice support the critical role of Dectin-1 for inflammasome activation, restriction of parasite replication in macrophages, and mouse resistance to L. amazonensis infection in vivo. Thus, we reported that activation of the Dectin-1/Syk/ROS/NLRP3 pathway during L. amazonensis phagocytosis is important for macrophage restriction of the parasite replication and effectively accounts for host resistance to Leishmania infection.