A mucin-like peptide from Fasciola hepatica instructs dendritic cells with parasite specific Th1-polarizing activity

Fasciolosis is a trematode zoonosis of interest in public health and cattle production. We report here the immunostimulatory effect of a 66 mer mucin-like peptide from Fasciola hepatica (Fhmuc), which synergizes with lipopolysaccharide (LPS) to promote dendritic cell (DC) maturation, endowing these cells with Th1-polarizing capacity. Exposure of DCs to Fhmuc in presence of LPS induced enhanced secretion of pro-inflammatory cytokines and expression of co-stimulatory molecules by DCs, promoting their T cell stimulatory capacity and selectively augmenting IFN- secretion by allogeneic T cells. Furthermore, exposure of DCs to Fhmuc augmented LPS-induced Toll-like receptor (TLR) 4 expression on the cell surface. Finally, Fhmuc-conditioned DCs induced parasite specific-adaptive immunity with increased levels of IFN-gamma secreted by splenocytes from vaccinated animals, and higher parasite-specific IgG antibodies. However, DC-treated Fhmuc conferred modest protection against F. hepatica infection highlighting the potent immuno-regulatory capacity of the parasite. In summary, this work highlights the capacity of a mucin-derived peptide from F. hepatica to enhance LPS-maturation of DCs and induce parasite-specific immune responses with potential implications in vaccination and therapeutic strategies.Fil: Noya, Verónica. Universidad de la República; UruguayFil: Brossard, Natalie. Universidad de la República; UruguayFil: Rodríguez, Ernesto. Universidad de la República; UruguayFil: Dergan Dylon, Leonardo Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Carmona, Carlos. Universidad de la República; UruguayFil: Rabinovich, Gabriel Adrián. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Freire, Teresa. Universidad de la República; Urugua

Glycans from Fasciola hepatica modulate the host immune response and TLR-Induced maturation of dendritic cells

Helminths express various carbohydrate-containing glycoconjugates on their surface, and they release glycan-rich excretion/secretion products that can be very important in their life cycles, infection and pathology. Recent evidence suggests that parasite glycoconjugates could play a role in the evasion of the immune response, leading to a modified Th2-polarized immune response that favors parasite survival in the host. Nevertheless, there is limited information about the nature or function of glycans produced by the trematode Fasciola hepatica, the causative agent of fasciolosis. In this paper, we investigate whether glycosylated molecules from F. hepatica participate in the modulation of host immunity. We also focus on dendritic cells, since they are an important target of immune-modulation by helminths, affecting their activity or function. Our results indicate that glycans from F. hepatica promote the production of IL-4 and IL-10, suppressing IFNγ production. During infection, this parasite is able to induce a semi-mature phenotype of DCs expressing low levels of MHCII and secrete IL-10. Furthermore, we show that parasite glycoconjugates mediate the modulation of LPS-induced maturation of DCs since their oxidation restores the capacity of LPS-treated DCs to secrete high levels of the pro-inflammatory cytokines IL-6 and IL-12/23p40 and low levels of the anti-inflammatory cytokine IL-10. Inhibition assays using carbohydrates suggest that the immune-modulation is mediated, at least in part, by the recognition of a mannose specific-CLR that signals by recruiting the phosphatase Php2. The results presented here contribute to the understanding of the role of parasite glycosylated molecules in the modulation of the host immunity and might be useful in the design of vaccines against fasciolosis.Fil: Rodriguez, Ernesto. Universidad de la República; UruguayFil: Noya, Verónica. Universidad de la República; UruguayFil: Cervi, Laura Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Chiribao, Maria Laura. Universidad de la República; UruguayFil: Brossard, Natalie. Universidad de la República; UruguayFil: Chiale, Carolina. Universidad de la República; UruguayFil: Carmona, Carlos. Universidad de la República; UruguayFil: Giacomini, Cecilia. Universidad de la República; UruguayFil: Freire, Teresa. Universidad de la República; Urugua

Modulation of Dendritic Cell Maturation by Fasciola hepatica: Implications of Glycans and Mucins for Vaccine Development

Fasciola hepatica is a worldwide distributed helminth pathogen that causes great economic losses in sheep andcattle. This parasite is able to regulate the host immune response, producing high levels of IL-5 and low levels ofIFNγ, as well as modulating the function of dendritic cells (DCs), mast cells or macrophages, among others.Moreover, TLR-mediated maturation of DCs can be suppressed by F. hepatica derived components. Here, weinvestigated the role of glycans in the modulation of LPS-induced maturation of DCs, as well as in the production ofIL-5 and IFNγ by splenocytes from infected mice. We show that F. hepatica induces the recruitment to theperitoneum of semi-matured DCs, as judged by a down-regulation of MHC class II molecule expression and anincrease of CD80 and CD86 expression of DCs in the peritoneum of infected animals. Furthermore, we provideevidence indicating that glycan structures from F. hepatica are responsible, at least in part, for inhibiting LPS-induced DC maturation and production of IFNγ by splenocytes from infected animals. On the other hand, we showthat a mucin-like non-glycosylated peptide highly expressed in NEJ (Fhmuc) is able to synergize with LPS ininducing DC-maturation, and that it induces a T cell response specific for F. hepatica, both alone or in combinationwith DCs. Our data highlight the role of F. hepatica glycans in modulating the host immune response and mightcontribute to the design of vaccines against fasciolosis.Fil: Noya, Veronica. Universidad de la República; UruguayFil: Rodriguez, Ernesto. Universidad de la República; UruguayFil: Cervi, Laura Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Giacomini, Cecilia. Universidad de la República; UruguayFil: Brossard, Natalie. Universidad de la República; UruguayFil: Chiale, Carolina. Universidad de la República; UruguayFil: Carmona, Carlos. Universidad de la República; UruguayFil: Freire, Teresa. Universidad de la República; Urugua

A mucin-like peptide from Fasciola hepatica instructs dendritic cells with parasite specific Th1-polarizing activity

Fasciolosis is a trematode zoonosis of interest in public health and cattle production. We report here the immunostimulatory effect of a 66 mer mucin-like peptide from Fasciola hepatica (Fhmuc), which synergizes with lipopolysaccharide (LPS) to promote dendritic cell (DC) maturation, endowing these cells with Th1-polarizing capacity. Exposure of DCs to Fhmuc in presence of LPS induced enhanced secretion of pro-inflammatory cytokines and expression of co-stimulatory molecules by DCs, promoting their T cell stimulatory capacity and selectively augmenting IFN-3 secretion by allogeneic T cells. Furthermore, exposure of DCs to Fhmuc augmented LPS-induced Toll-like receptor (TLR) 4 expression on the cell surface. Finally, Fhmuc-conditioned DCs induced parasite specific-adaptive immunity with increased levels of IFN-3 secreted by splenocytes from vaccinated animals, and higher parasite-specific IgG antibodies. However, Fhmuc-treated DC conferred modest protection against F. hepatica infection highlighting the potent immuno-regulatory capacity of the parasite. In summary, this work highlights the capacity of a mucin-derived peptide from F. hepatica to enhance LPS-maturation of DCs and induce parasite-specific immune responses with potential implications in vaccination and therapeutic strategies

NAION in a Healthy 37-Year Old: Supporting the Association with PDE5 Inhibitors

Non-arteritic anterior ischemic optic neuropathy (NAION) has been previously associated with use of phosphodiesterase type 5 (PDE5) inhibitors. The proposed mechanism is that vasodilation reduces perfusion of the optic nerve with subsequent ischemia. However, evidence of causality is inconclusive. We describe a case of NAION occurring after recreational use of sildenafil in a young, healthy patient without microvascular risk factors or optic disc drusen. We review the published literature on sildenafil associated NAION

When a Line Makes all the Difference

Canser associated retinopathy (CAR) is a rare paraneoplastic disorder where antibodies are produced against tumor proteins homologous to specific retinal proteins, most commonly against recoverin, a retinal photoreceptor protein involved in light and dark adaptation

A Nod to the Nodule

A 67-year-old man presented to emergency department in March'21 with 6hours h/o fever, headache, confusion, right- sided weakness and urinary incontinence. He had h/o hypertension, rheumatoid arthritis, spinal stenosis and was taking etanercept/leflunomide/sulfasalazine. Non-contrasted CT showed left frontoparietal lesion with surrounding edema, thought to be either mass lesion or subacute stroke.1 Atzeni, F. et al. Central nervous system involvement in rheumatoid arthritis patients and the potential implications; of using biological agents. Best Practice and Research: Clinical Rheumatology vol. 32 (2018).; 2. Bathon, J. M., Moreland, L. W. & DiBartolomeo, A. G. Inflammatory central nervous system involvement in; rheumatoid arthritis. Seminars in Arthritis and Rheumatism 18, 258-266 (1989).; 3. Nesbitt, C., Willshire, L., Quan, D., Shaw, C. & Batchelor, P. Leptomeningeal rheumatoid nodules: diagnosis and; failed therapeutics. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 22, 425-428; (2015).; 4. Takahashi, M. et al. Multiple intracranial nodules associated with rheumatoid arthritis: case report. Neurologia; medico-chirurgica 54, 317-320 (2014).; 5. Kim, R. C. & Collins, G. H. The neuropathology of rheumatoid disease. Human Pathology 12, (1981)