Trypanosomes are the extracellular protozoan parasites that cause human African trypanosomiasis disease in humans and nagana disease in animals. Tsetse flies act as a vector for the transmission of the disease in African countries. Animals infected with these parasites become useless or workless, and if not treated, disease can be fatal. There are many side effects associated with old treatments and some of them result in death in 5% of cases. There is a major surface glycoprotein in the parasite known as variant surface glycoprotein. The immune system of the host develops antibodies against this antigen but due to antigenic variation, parasites evade the immune response. Currently, no vaccine is available that provides complete protection. In murine models, only partial protection was observed using certain antigens. In order to develop vaccines against trypanosomes, molecular biology and immunology tools have been used. Immunization is the sole method for the control of disease because the eradication of the vector from endemic areas is an impossible task. Genetic vaccines can carry multiple genes encoding different antigens of the same parasite or different parasites. DNA immunization induces the activation of both cellular immune response and humoral immune response along with the generation of memory. This review highlights the importance of DNA vaccines and advances in the development of DNA vaccines against T. brucei.

Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?

Three new lignan glucosides, namely, justisecundosides A (1), B (2a), and C (2b), were isolated from the whole plant of Justicia secunda together with seven known compounds (3-9). Their structures were established based on a comprehensive analysis of HR-ESI-MS, IR, UV, and CD, in conjunction with their 1D and 2D-NMR data. A putative biogenetic pathway of compounds 1-2a,b from coniferyl alcohol was proposed. In addition, the antimicrobialactivities of the extract, fractions, and some isolated compounds were assessed against multiresistant bacterial and fungal strains. Furthermore, the antiplasmodial, antileishmanial, and antitrypanosomal activities were assessed against the sensitive (3D7) and multidrug-resistant (Dd2) strains of P. falciparum, promastigote and bloodstream forms of L. donovani, and Trypanosoma brucei, respectively. Compound 4 exhibited moderate antibacterial activity against Staphylococcus aureus SA RN 46003 with a MIC value of 62.5 μg/mL. Besides, compound 6 demonstrated a very good activity against sensitive (IC50Pf3D7: 0.81 μg/mL) and multidrug-resistant (IC50PfDd2: 14.61 μg/mL) strains of P. falciparum while compound 4 displayed good antitrypanosomal activity (IC50: 1.19 μg/mL). Also, compound 1 was the most active on the promastigote form of L. donovani with an IC50 of 13.02 μg/mL.

Flaviviridae infections, such as those caused by hepatitis C (HCV) and dengue viruses (DENVs), represent global health risks. Infected people are in danger of developing chronic liver failure or hemorrhagic fever, both of which can be fatal if not treated. The tropical parasites Trypanosoma brucei and Trypanosoma cruzi cause enormous socioeconomic burdens in Sub-Saharan Africa and Latin America. Anti-HCV chemotherapy has severe adverse effects and is expensive, whereas dengue has no clinically authorized treatment. Antiparasitic medicines are often toxic and difficult to administer, and treatment failures are widely reported. There is an urgent need for new chemotherapies. Based on our previous research, we have undertaken structural modification of lead compound V with the goal of producing derivatives with both antiviral and trypanocidal activity. The novel spirocarbocyclic-substituted hydantoin analogs were designed, synthesized, and tested for antiviral activity against three HCV genotypes (1b, 3a, 4a), DENV, yellow fever virus (YFV), and two trypanosome species (T. brucei, T. cruzi). The optimization was successful and led to compounds with significant antiviral and trypanocidal activity and exceptional selectivity. Several modifications were made to further investigate the structure-activity relationships (SARs) and confirm the critical role of lipophilicity and conformational degrees of freedom.

Infections cause catabolism of fat and muscle stores. Traditionally, studies have focused on understanding how the innate immune system contributes to energy stores wasting, while the role of the adaptive immune system remains elusive. In the present study, we examine the role of the adaptive immune response in adipose tissue wasting and cachexia using a murine model of the chronic parasitic infection Trypanosoma brucei, the causative agent of sleeping sickness. We find that the wasting response occurs in two phases, with the first stage involving fat wasting caused by CD4+ T cell-induced anorexia and a second anorexia-independent cachectic stage that is dependent on CD8+ T cells. Fat wasting has no impact on host antibody-mediated resistance defenses or survival, while later-stage muscle wasting contributes to disease-tolerance defenses. Our work reveals a decoupling of adaptive immune-mediated resistance from the catabolic response during infection.

Human trypanosomiasis affects nearly eight million people worldwide, causing great economic and social impact, mainly in endemic areas. T. cruzi and T. brucei are protozoan parasites that present efficient mechanisms of immune system evasion, leading to disease chronification. Currently, there is no vaccine, and chemotherapy is effective only in the absence of severe clinical manifestations. Nevertheless, resistant phenotypes to chemotherapy have been described in protozoan parasites, associated with cross-resistance to other chemically unrelated drugs. Multidrug resistance is multifactorial, involving: (i) drug entry, (ii) activation, (iii) metabolism and (iv) efflux pathways. In this context, ABC transporters, initially discovered in resistant tumor cells, have drawn attention in protozoan parasites, owing to their ability to decrease drug accumulation, thus mitigating their toxic effects. The discovery of these transporters in the Trypanosomatidae family started in the 1990s; however, few members were described and functionally characterized. This review contains a brief history of the main ABC transporters involved in resistance that propelled their investigation in Trypanosoma species, the main efflux modulators, as well as ABC genes described in T. cruzi and T. brucei according to the nomenclature HUGO. We hope to convey the importance that ABC transporters play in parasite physiology and chemotherapy resistance.

African trypanosomes are extracellular flagellated unicellular protozoan parasites transmitted by tsetse flies and causing Sleeping Sickness disease in humans and Nagana disease in cattle and other livestock. These diseases are usually characterized by the development of a fatal chronic inflammatory disease if left untreated. During African trypanosome infection and many other infectious diseases, the immune response is mediating a see-saw balance between effective/protective immunity and excessive infection-induced inflammation that can cause collateral tissue damage. African trypanosomes are known to trigger a strong type I pro-inflammatory response, which contributes to peak parasitaemia control, but this can culminate into the development of immunopathologies, such as anaemia and liver injury, if not tightly controlled. In this context, the macrophage migration inhibitory factor (MIF) and the interleukin-10 (IL-10) cytokines may operate as a molecular \"Yin-Yang\" in the modulation of the host immune microenvironment during African trypanosome infection, and possibly other infectious diseases. MIF is a pleiotropic pro-inflammatory cytokine and critical upstream mediator of immune and inflammatory responses, associated with exaggerated inflammation and immunopathology. For example, it plays a crucial role in the pro-inflammatory response against African trypanosomes and other pathogens, thereby promoting the development of immunopathologies. On the other hand, IL-10 is an anti-inflammatory cytokine, acting as a master regulator of inflammation during both African trypanosomiasis and other diseases. IL-10 is crucial to counteract the strong MIF-induced pro-inflammatory response, leading to pathology control. Hence, novel strategies capable of blocking MIF and/or promoting IL-10 receptor signaling pathways, could potentially be used as therapy to counteract immunopathology development during African trypanosome infection, as well as during other infectious conditions. Together, this review aims at summarizing the current knowledge on the opposite immunopathological molecular \"Yin-Yang\" switch roles of MIF and IL-10 in the modulation of the host immune microenvironment during infection, and more particularly during African trypanosomiasis as a paradigm.

Profiling a propolis sample from Papua New Guinea (PNG) using high-resolution mass spectrometry indicated that it contained several triterpenoids. Further fractionation by column chromatography and medium-pressure liquid chromatography (MPLC) followed by nuclear magnetic resonance spectroscopy (NMR) identified 12 triterpenoids. Five of these were obtained pure and the others as mixtures of two or three compounds. The compounds identified were: mangiferonic acid, ambonic acid, isomangiferolic acid, ambolic acid, 27-hydroxyisomangiferolic acid, cycloartenol, cycloeucalenol, 24-methylenecycloartenol, 20-hydroxybetulin, betulin, betulinic acid and madecassic acid. The fractions from the propolis and the purified compounds were tested in vitro against Crithidia fasciculata, Trypanosoma congolense, drug-resistant Trypanosoma congolense, Trypanosoma b. brucei and multidrug-resistant Trypanosoma b. brucei (B48). They were also assayed for their toxicity against U947 cells. The compounds and fractions displayed moderate to high activity against parasitic protozoa but only low cytotoxicity against the mammalian cells. The most active isolated compound, 20-hydroxybetulin, was found to be trypanostatic when different concentrations were tested against T. b. brucei growth.

A series of fourteen 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-phenyl-C-aryl imines with thionicotinic acid, two difficult substrates. The reactions were operationally simple, did not require specialized equipment or anhydrous solvents, could be performed as either two or three component reactions, and gave moderate-good yields as high as 63%. This provides ready access to N-phenyl compounds in this family, which have been generally difficult to prepare. As part of the study, the first crystal structure of neutral thionicotinic acid is also reported, and showed the molecule to be in the form of the thione tautomer. Additionally, the synthesized compounds were tested against T. brucei, the causative agent of Human African Sleeping Sickness. Screening at 50 µM concentration showed that five of the compounds strongly inhibited growth and killed parasites.

The recently developed ultrastructure expansion microscopy (U-ExM) technique allows us to increase the spatial resolution within a cell or tissue for microscopic imaging through the physical expansion of the sample. In this study, we validate the use of U-ExM in Trypanosoma brucei measuring the expansion factors of several different compartments/organelles and thus verify the isotropic expansion of the cell. We furthermore demonstrate the use of this sample preparation protocol for future studies by visualizing the nucleus and kDNA, as well as proteins of the cytoskeleton, the basal body, the mitochondrion and the endoplasmic reticulum. Lastly, we discuss the challenges and opportunities of U-ExM.