Functions of O-fucosyltransferase in Notch trafficking and signaling: towards the end of a controversy?

The precise role of the O-fucosyltransferase Ofut1 in Notch-receptor trafficking has remained controversial. A recent study sheds new light on the non-catalytic activity of Ofut1 and provides further evidence that Ofut1 acts as a chaperone in the endoplasmic reticulum

Prevalence of Local Immune Response against Oral Infection in a Drosophila/Pseudomonas Infection Model

Pathogens have developed multiple strategies that allow them to exploit host resources and resist the immune response. To study how Drosophila flies deal with infectious diseases in a natural context, we investigated the interactions between Drosophila and a newly identified entomopathogen, Pseudomonas entomophila. Flies orally infected with P. entomophila rapidly succumb despite the induction of both local and systemic immune responses, indicating that this bacterium has developed specific strategies to escape the fly immune response. Using a combined genetic approach on both host and pathogen, we showed that P. entomophila virulence is multi-factorial with a clear differentiation between factors that trigger the immune response and those that promote pathogenicity. We demonstrate that AprA, an abundant secreted metalloprotease produced by P. entomophila, is an important virulence factor. Inactivation of aprA attenuated both the capacity to persist in the host and pathogenicity. Interestingly, aprA mutants were able to survive to wild-type levels in immune-deficient Relish flies, indicating that the protease plays an important role in protection against the Drosophila immune response. Our study also reveals that the major contribution to the fly defense against P. entomophila is provided by the local, rather than the systemic immune response. More precisely, our data points to an important role for the antimicrobial peptide Diptericin against orally infectious Gram-negative bacteria, emphasizing the critical role of local antimicrobial peptide expression against food-borne pathogens

Poisoning by Anticoagulant Rodenticides in Humans and Animals: Causes and Consequences

Anticoagulant rodenticides (ARs) are a keystone of the management of rodent populations in the world. The widespread use of these molecules raises questions on exposure and intoxication risks, which define the safety of these products. Exposures and intoxications can affect humans, domestic animals and wildlife. Consequences are different for each group, from the simple issue of intoxication in humans to public health concern if farm animals are exposed. After a rapid presentation of the mechanism of action and the use of anticoagulant rodenticides, this chapter assesses the prominence of poisoning by anticoagulant rodenticides in humans, domestic animals and wildlife

New insights into control of arbovirus replication and spread by insect RNA interference pathways

Arthropod-borne (arbo) viruses are transmitted by vectors, such as mosquitoes, to susceptible vertebrates. Recent research has shown that arbovirus replication and spread in mosquitoes is not passively tolerated but induces host responses to control these pathogens. Small RNA-mediated host responses are key players among these antiviral immune strategies. Studies into one such small RNA-mediated antiviral response, the exogenous RNA interference (RNAi) pathway, have generated a wealth of information on the functions of this mechanism and the enzymes which mediate antiviral activities. However, other small RNA-mediated host responses may also be involved in modulating antiviral activity. The aim of this review is to summarize recent research into the nature of small RNA-mediated antiviral responses in mosquitoes and to discuss future directions for this relatively new area of research

0307 : QSOX1 has a protective role in the myocardium face to acute stress

IntroductionQSOX1 was identified as a plasma biomarker of acute heart failure (AHF). QSOX1 being a sulfhydryl oxidase, our aim was to decipher the role of QSOX1 in the heart face to an AHF event.MethodsAHF was provoked by IP injections of Isoproterenol (ISO, 300mg/kg/12h) for 2 days in mice (C57Bl/6 J) whereas control (C) received NaCl 9‰. Mice were killed at day 3, after echocardiography. QSOX1 KO (C57Bl/6 J) mice were generated using a QSOX1tm1a embryonic stem cell clone (KOMP). The KO construct contains a promoter-less lacZ gene under the control of the QSOX1 regulatory sequences. The mRNA levels were analyzed by RT-qPCR. The cellular level of oxidative stress was detected by using DHE. Fibrosis was analysed by Sirius red and collagen mRNA.ResultsAt baseline QSOX1-/- adult mice did not display any cardiac or vascular phenotype. After ISO, lacZ expression dramatically increased in QSOX1+/- hearts with the strongest β-galactosidase staining in the atria. In mice receiving ISO, a pulmonary congestion, BNP (x2 p<0.001) and CD68 (x3, p<0.001) increases were observed only in QSOX1-/-, whereas Galectin 3 increased in both groups. After ISO, the severe cardiac dysfunction in QSOX1-/- mice was associated with signs of enhanced oxidative stress (DHE staining p<0.0001). An early fibrosis was observed by Sirius red analysis and associated with an increase of collagen 1 and 3 mRNAs without difference between WT and QSOX1-/- mice.ConclusionWe provided evidence that the absence of QSOX1 leads to a more serious cardiac dysfunction in response to acute cardiac stress by ISO than in WT counterparts. Hence, our data indicated that QSOX1 protects the heart in response to acute stress

Small RNA analysis in Sindbis virus infected human HEK293 cells

In contrast to the defence mechanism of RNA interference (RNAi) in plants and invertebrates, its role in the innate response to virus infection of mammals is a matter of debate. Since RNAi has a well-established role in controlling infection of the alphavirus Sindbis virus (SINV) in insects, we have used this virus to investigate the role of RNAi in SINV infection of human cells

Roles for Drosophila melanogaster myosin IB in maintenance of enterocyte brush-border structure and resistance to the bacterial pathogen Pseudomonas entomophila

Author Posting. © American Society for Cell Biology, 2007. This article is posted here by permission of American Society for Cell Biology for personal use, not for redistribution. The definitive version was published in Molecular Biology of the Cell 18 (2007): 4625-4636, doi:10.1091/mbc.E07-02-0191.Drosophila myosin IB (Myo1B) is one of two class I myosins in the Drosophila genome. In the larval and adult midgut enterocyte, Myo1B is present within the microvillus (MV) of the apical brush border (BB) where it forms lateral tethers between the MV membrane and underlying actin filament core. Expression of green fluorescent protein-Myo1B tail domain in the larval gut showed that the tail domain is sufficient for localization of Myo1B to the BB. A Myo1B deletion mutation exhibited normal larval gut physiology with respect to food uptake, clearance, and pH regulation. However, there is a threefold increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive enterocyte nuclei in the Myo1B mutant. Ultrastructural analysis of mutant midgut revealed many perturbations in the BB, including membrane tethering defects, MV vesiculation, and membrane shedding. The apical localization of both singed (fascin) and Dmoesin is impaired. BBs isolated from mutant and control midgut revealed that the loss of Myo1B causes the BB membrane and underlying cytoskeleton to become destabilized. Myo1B mutant larvae also exhibit enhanced sensitivity to oral infection by the bacterial pathogen Pseudomonas entomophila, and severe cytoskeletal defects are observed in the BB of proximal midgut epithelial cells soon after infection. Resistance to P. entomophila infection is restored in Myo1B mutant larvae expressing a Myo1B transgene. These results indicate that Myo1B may play a role in the local midgut response pathway of the Imd innate immune response to Gram-negative bacterial infection.This work was supported by National Institutes of Health grants DK-25387 (to M.S.M.), DK-55389 (to Jon Morrow, Yale School of Medicine), and GM-52857 (to L.G.T.) and a research grant from the Crohns and Colitis Foundation of America (to M.S.M.)