Non-neutralizing antibodies elicited by recombinant Lassa-Rabies vaccine are critical for protection against Lassa fever

Lassa fever (LF), caused by Lassa virus (LASV), is a viral hemorrhagic fever for which no approved vaccine or potent antiviral treatment is available. LF is a WHO priority disease and, together with rabies, a major health burden in West Africa. Here we present the development and characterization of an inactivated recombinant LASV and rabies vaccine candidate (LASSARAB) that expresses a codon-optimized LASV glycoprotein (coGPC) and is adjuvanted by a TLR-4 agonist (GLA-SE). LASSARAB elicits lasting humoral response against LASV and RABV in both mouse and guinea pig models, and it protects both guinea pigs and mice against LF. We also demonstrate a previously unexplored role for non-neutralizing LASV GPC-specific antibodies as a major mechanism of protection by LASSARAB against LF through antibody-dependent cellular functions. Overall, these findings demonstrate an effective inactivated LF vaccine and elucidate a novel humoral correlate of protection for LF.NIH grants R01 AI105204 to M.J.S., by the Jefferson Vaccine Center, and by the Fundação para a Ciência e Tecnologia (FCT) scholarship PD/BD/105847/2014 (to T.A.-M.). This work was also funded in part through the NIAID Division of Intramural Research and the NIAID Division of Clinical Research, Battelle Memorial Institute’s prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016Iinfo:eu-repo/semantics/publishedVersio

A STEP forward in neural function and degeneration

STriatal-Enriched Phosphatase (STEP) is a brain-specific protein tyrosine phosphatase that plays a role in synaptic plasticity and has recently been implicated in neurodegenerative disease. STEP opposes the development of synaptic strengthening by dephosphorylating and inactivating key signaling proteins that include the MAP kinases ERK1/2 and p38, as well as the tyrosine kinase Fyn. STEP also dephosphorylates the GluR2 subunit of the AMPAR and the NR2B subunit of the NMDAR, which leads to internalization of the NR1/NR2B and GluR1/GluR2 receptors. STEP levels and activity are regulated through phosphorylation, local translation, ubiquitination and degradation and proteolytic cleavage. Here we review recent progress in understanding the normal regulation of STEP and how this regulation is disrupted in Alzheimer's disease, in which abnormally increased STEP levels and activity contribute to the cognitive deficits

Trypanosoma cruzi High Mobility Group B (TcHMGB) can act as an inflammatory mediator on mammalian cells

When an infection occurs, the innate immune cells recognize Pathogen Associated Molec ular Patterns (PAMPs) through their Pattern Recognition Receptors. This triggers an inflammatory response intended to kill the foreign microbe. But inflammation can also be triggered by the recognition of endogenous molecules called “Danger (or Damage) Asso ciated Molecular Patterns” (DAMPs) that are released by damaged or necrotic cells to “ring the alarm” of the immune system that repair is needed, so some of them are also known as “alarmins”. High Mobility group box 1 protein (HMGB1) is a prototypical alar min molecule released by injured cells and it is also actively secreted by cells of the innate immune system in response to invasion as well as to sterile damage. Trypanosoma cruzi, the causal agent of Chagas Disease, has its own HMGB protein that we called TcHMGB. Using in vitro and in vivo experimental systems, we demonstrated for the first time that TcHMGB is able to mediate inflammation on mammalian cells, inducing the expression of both pro-inflammatory and anti-inflammatory cytokines. Our results suggest that the parasite´s protein could have a role in the immune response and the pathogenesis of Cha gas disease, probably overlapping to some extent with the host cell DAMP molecules´ functions.Para citar este articulo: Cribb P, Perdomo V, Alonso VL, Manarin R, Barrios-Paya´n J, Marquina-Castillo B, et al. (2017) Trypanosoma cruzi High Mobility Group B (TcHMGB) can act as an inflammatory mediator on mammalian cells. PLoS Negl Trop Dis 11(2): e0005350. doi:10.1371/journal.pntd.0005350Fil: Cribb, Pamela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.Fil: Cribb, Pamela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Perdomo, Virginia Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.Fil: Perdomo, Virginia Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Alonso, Victoria Lucía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Manarin, Romina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Barrios-Payán, Jorge. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Sección de Patología Experimental; México.Fil: Marquina-Castillo, Brenda. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Sección de Patología Experimental; México.Fil: Tavernelli, Luis. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.Fil: Hernández-Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Sección de Patología Experimental; México

Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection.

The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a potentially life-threatening infection that represents a major health problem in Latin America. Several characteristics of this protozoan contribute to the lack of an effective vaccine, among them: its silent invasion mechanism, T. cruzi antigen redundancy and immunodominance without protection. Taking into account these issues, we engineered Traspain, a chimeric antigen tailored to present a multivalent display of domains from key parasitic molecules, combined with stimulation of the STING pathway by c-di-AMP as a novel prophylactic strategy. This formulation proved to be effective for the priming of functional humoral responses and pathogen-specific CD8+ and CD4+ T cells, compatible with a Th1/Th17 bias. Interestingly, vaccine effectiveness assessed across the course of infection, showed a reduction in parasite load and chronic inflammation in different proof of concept assays. In conclusion, this approach represents a promising tool against parasitic chronic infections