Animal modelling for inherited central vision loss.

Disease-causing variants of a large number of genes trigger inherited retinal degeneration leading to photoreceptor loss. Because cones are essential for daylight and central vision such as reading, mobility, and face recognition, this review focuses on a variety of animal models for cone diseases. The pertinence of using these models to reveal genotype/phenotype correlations and to evaluate new therapeutic strategies is discussed. Interestingly, several large animal models recapitulate human diseases and can serve as a strong base from which to study the biology of disease and to assess the scale-up of new therapies. Examples of innovative approaches will be presented such as lentiviral-based transgenesis in pigs and adeno-associated virus (AAV)-gene transfer into the monkey eye to investigate the neural circuitry plasticity of the visual system. The models reported herein permit the exploration of common mechanisms that exist between different species and the identification and highlighting of pathways that may be specific to primates, including humans

Immune Response to Lactobacillus plantarum Expressing Borrelia burgdorferi OspA Is Modulated by the Lipid Modification of the Antigen

Over the past decade there has been increasing interest in the use of lactic acid bacteria as mucosal delivery vehicles for vaccine antigens, microbicides and therapeutics. We investigated the mechanism by which a mucosal vaccine based in recombinant lactic acid bacteria breaks the immunological tolerance of the gut in order to elicit a protective immune response.We analyzed how the lipid modification of OspA affects the localization of the antigen in our delivery vehicle using a number of biochemistry techniques. Furthermore, we examined how OspA-expressing L. plantarum breaks the oral tolerance of the gut by stimulating human intestinal epithelial cells, peripheral blood mononuclear cells and monocyte derived dendritic cells and measuring cytokine production. We show that the leader peptide of OspA targets the protein to the cell envelope of L. plantarum, and it is responsible for protein export across the membrane. Mutation of the lipidation site in OspA redirects protein localization within the cell envelope. Further, we show that lipidated-OspA-expressing L. plantarum does not induce secretion of the pro-inflammatory cytokine IL-8 by intestinal epithelial cells. In addition, it breaks oral tolerance of the gut via Th1/Th2 cell mediated immunity, as shown by the production of pro- and anti-inflammatory cytokines by human dendritic cells, and by the production of IgG2a and IgG1 antibodies, respectively.Lipid modification of OspA expressed in L. plantarum modulates the immune response to this antigen through a Th1/Th2 immune response

HIV Infection and Gut Mucosal Immune Function: Updates on Pathogenesis with Implications for Management and Intervention

HIV is primarily a sexually transmitted infection. However, given that the gastrointestinal tract (GIT) houses most of the body’s lymphocytes, including activated memory CD4+ T cells that are preferential targets for HIV, recent research has focused on the role of the GIT in transmission and pathogenesis. In health, the GIT maintains a balance between immune tolerance and rapid responsiveness. A complex network of innate and adaptive responses maintains this balance, which is severely perturbed in HIV infection. Recent studies have focused on mechanisms of GIT CD4+ T-cell depletion and epithelial disruption in HIV infection, the role of inflammation in accelerating viral dissemination, the kinetics of the adaptive response following transmission, and the extent of T-cell reconstitution following antiretroviral therapy. This review summarizes the results of recent investigations that may have important implications for the development of vaccines, microbicides, and therapeutic interventions for HIV and other mucosal pathogens

Do Neutrophils Play a Role in Establishing Liver Abscesses and Distant Metastases Caused by Klebsiella pneumoniae?

Serotype K1 Klebsiella pneumoniae is a major cause of liver abscesses and endophthalmitis. This study was designed to identify the role of neutrophils in the development of distant metastatic complications that were caused by serotype K1 K. pneumoniae. An in vitro cellular model was used to assess serum resistance and neutrophil-mediated killing. BALB/c mice were injected with neutrophils containing phagocytosed K. pneumoniae. Serotype K1 K. pneumoniae was significantly more resistant to serum killing, neutrophil-mediated phagocytosis and intra-cellular killing than non-K1 isolates (p<0.01). Electron microscopic examination had similar findings as in the bioassay findings. Intraperitoneal injection of neutrophils containing phagocytosed serotype K1 K. pneumoniae led to abscess formation in multiple sites including the subcutaneous tissue, lung, and liver, whereas no abscess formation was observed in mice injected with non-K1 isolates. The resistance of serotype K1 K. pneumoniae to complement- and neutrophil-mediated intracellular killing results in the dissemination of K. pneumoniae via the bloodstream. Escape from neutrophil intracellular killing may contribute to the dissemination and establishment of distant metastases. Thus, neutrophils play a role as a vehicle for helping K. pneumoniae and contributing to the establishment of liver abscess and distant metastatic complications

Low-dose oral immunization with lyophilized tissue of herbicide-resistant lettuce expressing hepatitis B surface antigen for prototype plant-derived vaccine tablet formulation

Efficient immunization against hepatitis B virus (HBV) and other pathogens with plant-based oral vaccines requires appropriate plant expressors and the optimization of vaccine compositions and administration protocols. Previous immunization studies were mainly based on a combination of the injection of a small surface antigen of HBV (S-HBsAg) and the feeding with raw tissue containing the antigen, supplemented with an adjuvant, and coming from plants conferring resistance to kanamycin. The objective of this study was to develop a prototype oral vaccine formula suitable for human immunization. Herbicide-resistant lettuce was engineered, stably expressing through progeny generation micrograms of S-HBsAg per g of fresh weight and formed into virus-like particles (VLPs). Lyophilized tissue containing a relatively low, 100-ng VLP-assembled antigen dose, administered only orally to mice with a long, 60-day interval between prime and boost immunizations and without exogenous adjuvant, elicited mucosal and systemic humoral anti-HBs responses at the nominally protective level. Lyophilized tissue was converted into tablets, which preserved S-HBsAg content for at least one year of room temperature storage. The results of the study provide indications on immunization methodology using a durable, efficacious, and convenient plant-derived prototype oral vaccine against hepatitis B

Maternal Risk of Breeding Failure Remained Low throughout the Demographic Transitions in Fertility and Age at First Reproduction in Finland

Radical declines in fertility and postponement of first reproduction during the recent human demographic transitions have posed a challenge to interpreting human behaviour in evolutionary terms. This challenge has stemmed from insufficient evolutionary insight into individual reproductive decision-making and the rarity of datasets recording individual long-term reproductive success throughout the transitions. We use such data from about 2,000 Finnish mothers (first births: 1880s to 1970s) to show that changes in the maternal risk of breeding failure (no offspring raised to adulthood) underlay shifts in both fertility and first reproduction. With steady improvements in offspring survival, the expected fertility required to satisfy a low risk of breeding failure became lower and observed maternal fertility subsequently declined through an earlier age at last reproduction. Postponement of the age at first reproduction began when this risk approximated zero–even for mothers starting reproduction late. Interestingly, despite vastly differing fertility rates at different stages of the transitions, the number of offspring successfully raised to breeding per mother remained relatively constant over the period. Our results stress the importance of assessing the long-term success of reproductive strategies by including measures of offspring quality and suggest that avoidance of breeding failure may explain several key features of recent life-history shifts in industrialized societies

Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism

Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases