Oral Bacille Calmette-Guérin (BCG) vaccination induces long-term potentiation of memory immune response to Ovalbumin airway challenge in mice.

The Bacille Calmette-Guérin (BCG) is a potent immunomodulator. It was initially used by oral administration, but it is mostly used subcutaneously nowadays. This study shows that oral BCG vaccination modifies the immune response to a second non-related antigen (Ovalbumin) systemic immunization. Airway Ovalbumin challenge six months after the systemic intraperitoneal immunization resulted in a potent γδ+ T cell response in the lungs biased to IFN-γ and IL-17 production ex vivo and a mixed TH1, TH2, and TH17 T cells upon further stimulation with anti-CD3 mAb in vitro. Higher percentages of CD4+ T cells accompanied the augmented T cell response in oral BCG vaccinated mice. Also, the proportion of Foxp3+ Tregs was diminished compared to PBS-gavaged and OVA-immunized mice. The anti-OVA-specific antibody response was also influenced by oral exposure to BCG so that these mice produced more IgG2a and less IgE detected in the sera. These results suggest that oral BCG vaccination can modify future immune responses to vaccines and improve immunity to pathogen infections, especially in the mucosal interfaces.

Immunity and immune modulation in Trypanosoma cruzi infection.

Chagas disease is caused by the protozoan Trypanosoma cruzi. The parasite reaches the secondary lymphoid organs, the heart, skeletal muscles, neurons in the intestine and esophagus among other tissues. The disease is characterized by mega syndromes, which may affect the esophagus, the colon and the heart, in about 30% of infected people. The clinical manifestations associated with T. cruzi infection during the chronic phase of the disease are dependent on complex interactions between the parasite and the host tissues, particularly the lymphoid system that may either result in a balanced relationship with no disease or in an unbalanced relationship that follows an inflammatory response to parasite antigens and associated tissues in some of the host organs and/or by an autoimmune response to host antigens. This review discusses the findings that support the notion of an integrated immune response, considering the innate and adaptive arms of the immune system in the control of parasite numbers and also the mechanisms proposed to regulate the immune response in order to tolerate the remaining parasite load, during the chronic phase of infection. This knowledge is fundamental to the understanding of the disease progression and is essential for the development of novel therapies and vaccine strategies.

Epoxy-α-lapachone has in vitro and in vivo anti-leishmania (Leishmania) amazonensis effects and inhibits serine proteinase activity in this parasite.

Leishmania (Leishmania) amazonensis is a protozoan that causes infections with a broad spectrum of clinical manifestations. The currently available chemotherapeutic treatments present many problems, such as several adverse side effects and the development of resistant strains. Natural compounds have been investigated as potential antileishmanial agents, and the effects of epoxy-α-lapachone on L. (L.) amazonensis were analyzed in the present study. This compound was able to cause measurable effects on promastigote and amastigote forms of the parasite, affecting plasma membrane organization and leading to death after 3 h of exposure. This compound also had an effect in experimentally infected BALB/c mice, causing reductions in paw lesions 6 weeks after treatment with 0.44 mM epoxy-α-lapachone (mean lesion area, 24.9 ± 2.0 mm(2)), compared to untreated animals (mean lesion area, 30.8 ± 2.6 mm(2)) or animals treated with Glucantime (mean lesion area, 28.3 ± 1.5 mm(2)). In addition, the effects of this compound on the serine proteinase activities of the parasite were evaluated. Serine proteinase-enriched fractions were extracted from both promastigotes and amastigotes and were shown to act on specific serine proteinase substrates and to be sensitive to classic serine proteinase inhibitors (phenylmethylsulfonyl fluoride, aprotinin, and antipain). These fractions were also affected by epoxy-α-lapachone. Furthermore, in silico simulations indicated that epoxy-α-lapachone can bind to oligopeptidase B (OPB) of L. (L.) amazonensis, a serine proteinase, in a manner similar to that of antipain, interacting with an S1 binding site. This evidence suggests that OPB may be a potential target for epoxy-α-lapachone and, as such, may be related to the compound's effects on the parasite.

Production of MMP-9 and inflammatory cytokines by Trypanosoma cruzi-infected macrophages.

Matrix metalloproteinases (MMPs) constitute a large family of Zn(2+) and Ca(2+) dependent endopeptidases implicated in tissue remodeling and chronic inflammation. MMPs also play key roles in the activation of growth factors, chemokines and cytokines produced by many cell types, including lymphocytes, granulocytes, and, in particular, activated macrophages. Their synthesis and secretion appear to be important in a number of physiological processes, including the inflammatory process. Here, we investigated the interaction between human and mouse macrophages with T. cruzi Colombian and Y strains to characterize MMP-9 and cytokine production in this system. Supernatants and total extract of T. cruzi infected human and mouse macrophages were obtained and used to assess MMP-9 profile and inflammatory cytokines. The presence of metalloproteinase activity was determined by zymography, enzyme-linked immunosorbent assay and immunoblotting assays. The effect of cytokines on MMP-9 production in human macrophages was verified by previous incubation of cytokines on these cells in culture, and analyzed by zymography. We detected an increase in MMP-9 production in the culture supernatants of T. cruzi infected human and mouse macrophages. The addition of IL-1ß or TNF-α to human macrophage cultures increased MMP-9 production. In contrast, MMP-9 production was down-modulated when human macrophage cultures were treated with IFN-γ or IL-4 before infection. Human macrophages infected with T. cruzi Y or Colombian strains produced increased levels of MMP-9, which was related to the production of cytokines such as IL-1ß, TNF-α and IL-6.

Evidences for leishmanicidal activity of the naphthoquinone derivative epoxy-α-lapachone.

In this work, we analyze the leishmanicidal effects of epoxy-α-lapachone on Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis. Promasigotes and amastigotes (inhabiting human macrophages) from both species were assayed to verify the compound's activity over the distinct morphological stages. The incubation with epoxy-α-lapachone led to a significant decrease in the numbers of promastigotes from both species in the cultures, in a dose-and time-dependent fashion. The survival of amastigotes inhabiting human macrophages was also drastically affected by the compound, as shown by the variations in the endocytic index. Our results indicate that the epoxy-α-lapachone has an antiparasitic effect over Leishmania in both morphological stages and may potentially affect a range of species in two distinct subgenera of this parasite.