Immunoprofiles associated with controlled human malaria infection and naturally acquired immunity identify a shared IgA pre-erythrocytic immunoproteome

Knowledge of the Plasmodium falciparum antigens that comprise the human liver stage immunoproteome is important for pre-erythrocytic vaccine development, but, compared with the erythrocytic stage immunoproteome, more challenging to classify. Previous studies of P. falciparum antibody responses report IgG and rarely IgA responses. We assessed IgG and IgA antibody responses in adult sera collected during two controlled human malaria infection (CHMI) studies in malaria-naïve volunteers and in 1- to 6-year-old malaria-exposed Malian children on a 251 P. falciparum antigen protein microarray. IgG profiles in the two CHMI groups were equivalent and differed from Malian children. IgA profiles were robust in the CHMI groups and a subset of Malian children. We describe immunoproteome differences in naïve vs. exposed individuals and report pre-erythrocytic proteins recognized by the immune system. IgA responses detected in this study expand the list of pre-erythrocytic antigens for further characterization as potential vaccine candidates.

NUB1 and FAT10 Proteins as Potential Novel Biomarkers in Cancer: A Translational Perspective

Cancer increases the global disease burden substantially, but it remains a challenge to manage it. The search for novel biomarkers is essential for risk assessment, diagnosis, prognosis, prediction of treatment response, and cancer monitoring. This paper examined NEDD8 ultimate buster-1 (NUB1) and F-adjacent transcript 10 (FAT10) proteins as novel biomarkers in cancer. This literature review is based on the search of the electronic database, PubMed. NUB1 is an interferon-inducible protein that mediates apoptotic and anti-proliferative actions in cancer, while FAT10 is a ubiquitin-like modifier that promotes cancer. The upregulated expression of both NUB1 and FAT10 has been observed in various cancers. NUB1 protein binds to FAT10 non-covalently to promote FAT10 degradation. An overexpressed FAT10 stimulates nuclear factor-kappa β, activates the inflammatory pathways, and induces the proliferation of cancer. The FAT10 protein interacts with the mitotic arrest deficient 2 protein, causing chromosomal instability and breast tumourigenesis. FAT10 binds to the proliferating cell nuclear antigen protein and inhibits the DNA damage repair response. In addition, FAT10 involves epithelial–mesenchymal transition, invasion, apoptosis, and multiplication in hepatocellular carcinoma. Our knowledge about them is still limited. There is a need to further develop NUB1 and FAT10 as novel biomarkers.

Assessment of a New Antigen Detection Test for the Diagnosis of Canine Visceral Leishmaniasis

Canine visceral leishmaniasis (CVL) is a serious zoonotic disease in Brazil and Southern Europe. CVL is primarily caused by Leishmania infantum and its diagnosis relies primarily on detection of parasites in bone marrow or lymph node aspirates by microscopic observation of the parasites in stained smears, parasite culture, or polymerase chain reaction (PCR). Serological tests exist but they do not distinguish active disease from simple exposure to parasite antigens. Here, we have assessed the utility of a new monoclonal antibody––based antigen (protein) detection test for the diagnosis of CVL. The test was positive in 70% of beagle dogs experimentally infected with L. infantum. In contrast, culture of the parasites from bone marrow aspirates was positive in only 40% of the infected animals. These preliminary results suggest that this antigen detection test, which we have recently described for the diagnosis of human VL, has the potential to be a useful diagnostic tool for CVL.

Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR

Background Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). Methods In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure–activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. Results It was found that several new derivatives, including compounds 6a–6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a–6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. Conclusion The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeted on SjTGR

Background: Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Since the increasing drug-resistant to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as a potential anti-schistosomiasis reagent targeted to thioredoxin glutathione reductase (TGR). Methods: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild type Schistosoma japonicum TGR (wtSjTGR) to develop new leading compound for schistosomiasis. Thirty nine novel derivatives were prepared to test their activity to both two enzymes. The docking method was used to detect the bind sites between active molecule and SjTGR; The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. Results: It was founded that several new derivatives such as compounds 6a-6d, 9ab, 9bd, 9be have a better activity to rSjTGR-Sec or SWAP containing wtSjTGR than furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity to both two enzymes. In particular, compound 6d with trifluoromethyl on pyridine ring has been found to have much higher inhibition to both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method revealed the matching sites between 6d and Schistosoma japonicumi TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. Conclusion: The data obtained herein showed preliminarily that 6d with trifluoromethyl on pyridine ring could be a valuable leading compound for further study.

Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design

HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions—such as the epitopes of broadly neutralizing antibodies (bNAbs)—and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.