Differential Release and Phagocytosis of Tegument Glycoconjugates in Neurocysticercosis: Implications for Immune Evasion Strategies

Neurocysticercosis (NCC) is an infection of the central nervous system (CNS) by the metacestode of the helminth Taenia solium. The severity of the symptoms is associated with the intensity of the immune response. First, there is a long asymptomatic period where host immunity seems incapable of resolving the infection, followed by a chronic hypersensitivity reaction. Since little is known about the initial response to this infection, a murine model using the cestode Mesocestoides corti (syn. Mesocestoides vogae) was employed to analyze morphological changes in the parasite early in the infection. It was found that M. corti material is released from the tegument making close contact with the nervous tissue. These results were confirmed by infecting murine CNS with ex vivo–labeled parasites. Because more than 95% of NCC patients exhibit humoral responses against carbohydrate-based antigens, and the tegument is known to be rich in glycoconjugates (GCs), the expression of these types of molecules was analyzed in human, porcine, and murine NCC specimens. To determine the GCs present in the tegument, fluorochrome-labeled hydrazides as well as fluorochrome-labeled lectins with specificity to different carbohydrates were used. All the lectins utilized labeled the tegument. GCs bound by isolectinB4 were shed in the first days of infection and not resynthesized by the parasite, whereas GCs bound by wheat germ agglutinin and concavalinA were continuously released throughout the infectious process. GCs bound by these three lectins were taken up by host cells. Peanut lectin-binding GCs, in contrast, remained on the parasite and were not detected in host cells. The parasitic origin of the lectin-binding GCs found in host cells was confirmed using antibodies against T. solium and M. corti. We propose that both the rapid and persistent release of tegumental GCs plays a key role in the well-known immunomodulatory effects of helminths, including immune evasion and life-long inflammatory sequelae seen in many NCC patients

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Leishmaniasis represents a major international health problem, has a high morbidity and mortality rate, and is classified as an emerging and uncontrolled disease by the World Health Organization. The migration of population from endemic to nonendemic areas, and tourist activities in endemic regions are spreading the disease to new areas. Unfortunately, treatment of leishmaniasis is far from satisfactory, with only a few drugs available that show significant side-effects. Here, we show in vitro and in vivo evidence for the antileishmanial activity of the ether phospholipid edelfosine, being effective against a wide number of Leishmania spp. causing cutaneous, mucocutaneous and visceral leishmaniasis. Our experimental mouse and hamster models demonstrated not only a significant antileishmanial activity of edelfosine oral administration against different wild-type Leishmania spp., but also against parasites resistant to pentavalent antimonials, which constitute the first line of treatment worldwide. In addition, edelfosine exerted a higher antileishmanial activity and a lower proneness to generate drug resistance than miltefosine, the first drug against leishmaniasis that can be administered orally. These data, together with our previous findings, showing an anti-inflammatory action and a very low toxicity profile, suggest that edelfosine is a promising orally administered drug for leishmaniasis, thus warranting clinical evaluation

Transcriptome analysis of the ependymal barrier during murine neurocysticercosis

<p>Abstract</p> <p>Background</p> <p>Central nervous system (CNS) barriers play a pivotal role in the protection and homeostasis of the CNS by enabling the exchange of metabolites while restricting the entry of xenobiotics, blood cells and blood-borne macromolecules. While the blood–brain barrier and blood-cerebrospinal fluid barrier (CSF) control the interface between the blood and CNS, the ependyma acts as a barrier between the CSF and parenchyma, and regulates hydrocephalic pressure and metabolic toxicity. Neurocysticercosis (NCC) is an infection of the CNS caused by the metacestode (larva) of <it>Taenia solium</it> and a major cause of acquired epilepsy worldwide. The common clinical manifestations of NCC are seizures, hydrocephalus and symptoms due to increased intracranial pressure. The majority of the associated pathogenesis is attributed to the immune response against the parasite. The properties of the CNS barriers, including the ependyma, are affected during infection, resulting in disrupted homeostasis and infiltration of leukocytes, which correlates with the pathology and disease symptoms of NCC patients.</p> <p>Results</p> <p>In order to characterize the role of the ependymal barrier in the immunopathogenesis of NCC, we isolated ependymal cells using laser capture microdissection from mice infected or mock-infected with the closely related parasite <it>Mesocestoides corti</it>, and analyzed the genes that were differentially expressed using microarray analysis. The expression of 382 genes was altered. Immune response-related genes were verified by real-time RT-PCR. Ingenuity Pathway Analysis (IPA) software was used to analyze the biological significance of the differentially expressed genes, and revealed that genes known to participate in innate immune responses, antigen presentation and leukocyte infiltration were affected along with the genes involved in carbohydrate, lipid and small molecule biochemistry. Further, MHC class II molecules and chemokines, including CCL12, were found to be upregulated at the protein level using immunofluorescence microcopy. This is important, because these molecules are members of the most significant pathways by IPA analyses.</p> <p>Conclusion</p> <p>Thus, our study indicates that ependymal cells actively express immune mediators and likely contribute to the observed immunopathogenesis during infection. Of particular interest is the major upregulation of antigen presentation pathway-related genes and chemokines/cytokines. This could explain how the ependyma is a prominent source of leukocyte infiltration into ventricles through the disrupted ependymal lining by way of pial vessels present in the internal leptomeninges in murine NCC.</p