Understanding the Anti-Tumor Properties Mediated by the Synthetic Peptide GK-1

Cancer exhibits adaptive features typical of complex systems, like resilience and robustness to environmental challenges through the emergent co-evolution of its components. These events promote carcinogenesis through dynamic interactions among numerous components and subsystems, including the immune system. During the past decade, our research group has provided substantial evidence that the peptide GK-1 has important immunomodulatory properties. In elderly mice, GK-1 acts as a potent adjuvant of the influenza vaccine through a mechanism that involves the activation of antigen-presenting cells (APCs) and an increased production of pro-inflammatory cytokines and chemokines (IFN-γ, TNFα, CCL2). To date, there is solid evidence supporting the antitumoral properties of GK-1 in murine cancer models. First, a lower occurrence and smaller size of spontaneous bronchiolar adenomas were found in elderly GK-1-treated mice compared to paired untreated mice. In two independent studies, GK-1 treatment reduced tumor growth and increased mouse survival in a murine model of melanoma and breast tumor. In the former model, a synergy between GK-1 and anti-PD-L1 treatment was observed, while in the latter, GK-1 alone controlled the metastatic burden. The effective activation of APCs induced by GK-1, restoring the antitumor-specific immunity, may underlie some of its antineoplastic effects

Spatial Distribution of Taenia solium Porcine Cysticercosis within a Rural Area of Mexico

Cysticercosis is caused by Taenia solium, a parasitic disease that affects humans and rurally bred pigs in developing countries. The cysticercus may localize in the central nervous system of the human, causing neurocysticercosis, the most severe and frequent form of the disease. There appears to be an association between the prevalence of porcine cysticercosis and domestic pigs that wander freely and have access to human feces. In order to assess whether the risk of cysticercosis infection is clustered or widely dispersed in a limited rural area, a spatial analysis of rural porcine cysticercosis was applied to 13 villages of the Sierra de Huautla in Central Mexico. Clustering of cases in specific households would indicate tapeworm carriers in the vicinity, whereas their dispersal would suggest that the ambulatory habits of both humans and pigs contribute to the spread of cysticercosis. A total of 562 pigs were included in this study (August–December 2003). A global positioning system was employed in order to plot the geographic distribution of both cysticercotic pigs and risk factors for infection within the villages. Prevalence of pig tongue cysticercosis varied significantly in sampled villages (p = 0.003), ranging from 0% to 33.3% and averaging 13.3%. Pigs were clustered in households, but no differences in the clustering of cysticercotic and healthy pigs were found. In contrast, the presence of pigs roaming freely and drinking stagnant water correlated significantly with porcine cysticercosis (p = 0.07), as did the absence of latrines (p = 0.0008). High prevalence of porcine cysticercosis proves that transmission is still quite common in rural Mexico. The lack of significant differentiation in the geographical clustering of healthy and cysticercotic pigs weakens the argument that focal factors (e.g., household location of putative tapeworm carriers) play an important role in increasing the risk of cysticercosis transmission in pigs. Instead, it would appear that other wide-ranging biological, physical, and cultural factors determine the geographic spread of the disease. Extensive geographic dispersal of the risk of cysticercosis makes it imperative that control measures be applied indiscriminately to all pigs and humans living in this endemic area

Development of an Oral Vaccine for the Control of Cysticercosis

Parasitic diseases fecally transmitted, such taeniasis/cysticercosis Taenia solium binomial, represent a health problem whose incidence continues due to the prevalence of inadequate sanitary conditions, particularly in developing countries. When the larval stage of the parasite is established in the central nervous system causes neurocysticercosis a disease than can severely affect human health. It can also affect pigs causing cysticercosis causing economic losses. Since pigs are obligatory intermediate hosts, they have been considered as the targets for vaccination to interrupt the transmission of the parasitosis and eventually reduce the disease. Progress has been made in the development of vaccines for the prevention of porcine cysticercosis. In our research group, three peptides have been identified that, expressed synthetically (S3Pvac) or recombinantly (S3Pvac-phage), reduced the amount of cysticerci by 98.7% and 87%, respectively, in pigs exposed to natural conditions of infection. Considering that cysticercosis is orally acquired, it seems feasible to develop an edible vaccine, which could be administered by the pig farmers, simplifying the logistical difficulties of its application, reducing costs, and facilitating the implementation of vaccination programs. This chapter describes the most important advances towards the development of an oral vaccine against porcine cysticercosis

Identification of Loci Controlling Restriction of Parasite Growth in Experimental Taenia crassiceps Cysticercosis

Human neurocysticercosis (NC) caused by Taenia solium is a parasitic disease of the central nervous system that is endemic in many developing countries. In this study, a genetic approach using the murine intraperitoneal cysticercosis caused by the related cestode Taenia crassiceps was employed to identify host factors that regulate the establishment and proliferation of the parasite. A/J mice are permissive to T. crassiceps infection while C57BL/6J mice (B6) are comparatively restrictive, with a 10-fold difference in numbers of peritoneal cysticerci recovered 30 days after infection. The genetic basis of this inter-strain difference was explored using 34 AcB/BcA recombinant congenic strains derived from A/J and B6 progenitors, that were phenotyped for T. crassiceps replication. In agreement with their genetic background, most AcB strains (A/J-derived) were found to be permissive to infection while most BcA strains (B6-derived) were restrictive with the exception of a few discordant strains, together suggesting a possible simple genetic control. Initial haplotype association mapping using >1200 informative SNPs pointed to linkages on chromosomes 2 (proximal) and 6 as controlling parasite replication in the AcB/BcA panel. Additional linkage analysis by genome scan in informative [AcB55xDBA/2]F1 and F2 mice (derived from the discordant AcB55 strain), confirmed the effect of chromosome 2 on parasite replication, and further delineated a major locus (LOD = 4.76, p<0.01; peak marker D2Mit295, 29.7 Mb) that we designate Tccr1 (T. crassiceps cysticercosis restrictive locus 1). Resistance alleles at Tccr1 are derived from AcB55 and are inherited in a dominant fashion. Scrutiny of the minimal genetic interval reveals overlap of Tccr1 with other host resistance loci mapped to this region, most notably the defective Hc/C5 allele which segregates both in the AcB/BcA set and in the AcB55xDBA/2 cross. These results strongly suggest that the complement component 5 (C5) plays a critical role in early protective inflammatory response to infection with T. crassiceps

Characterization of S3Pvac Anti-Cysticercosis Vaccine Components: Implications for the Development of an Anti-Cestodiasis Vaccine

Background: Cysticercosis and hydatidosis seriously affect human health and are responsible for considerable economic loss in animal husbandry in non-developed and developed countries. S3Pvac and EG95 are the only field trial-tested vaccine candidates against cysticercosis and hydatidosis, respectively. S3Pvac is composed of three peptides (KETc1, GK1 and KETc12), originally identified in a Taenia crassiceps cDNA library. S3Pvac synthetically and recombinantly expressed is effective against experimentally and naturally acquired cysticercosis.Methodology/ Principal Findings: In this study, the homologous sequences of two of the S3Pvac peptides, GK1 and KETc1, were identified and further characterized in Taenia crassiceps WFU, Taenia solium, Taenia saginata, Echinococcus granulosus and Echinococcus multilocularis. Comparisons of the nucleotide and amino acid sequences coding for KETc1 and GK1 revealed significant homologies in these species. The predicted secondary structure of GK1 is almost identical between the species, while some differences were observed in the C terminal region of KETc1 according to 3D modeling. A KETc1 variant with a deletion of three C-terminal amino acids protected to the same extent against experimental murine cysticercosis as the entire peptide. on the contrary, immunization with the truncated GK1 failed to induce protection. Immunolocalization studies revealed the non stage-specificity of the two S3Pvac epitopes and their persistence in the larval tegument of all species and in Taenia adult tapeworms.Conclusions/ Significance: These results indicate that GK1 and KETc1 may be considered candidates to be included in the formulation of a multivalent and multistage vaccine against these cestodiases because of their enhancing effects on other available vaccine candidates