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David S Schneider

Publications and source records attributed to David S Schneider.

10 recordsLinked to original sources
PubMed2007

Psidin is required in Drosophila blood cells for both phagocytic degradation and immune activation of the fat body.

Phagocytic blood cells are critical to innate immune defense: They internalize and destroy microbial invaders and produce signals that trigger other immune responses. Despite this central role, the in vivo contributions of phagocytosis to systemic immune activation are not well understood. Drosophila has proven a fruitful model for the investigation of evolutionarily conserved innate immune mechanisms, including NF-kappaB-dependent transcriptional induction, RNAi in antiviral responses, and phagocytosis. The phagocytes of Drosophila encounter bacterial invaders early in infection and contribute to survival of infection. Phagocytosis in flies and mammals is highly homologous: Both rely on scavenger receptors, opsonins, and actin rearrangements for engulfment; have phagosomal cysteine proteases active at low pH; and can be subverted by similar intracellular pathogens. Although the role of Drosophila phagocytes in the activation of other immune tissues has not been clear, we show that induction of the antibacterial-peptide gene Defensin in the fat body during infection requires blood-cell contributions. We identify a gene, psidin, that encodes a lysosomal protein required in the blood cells for both degradation of engulfed bacteria and activation of fat-body Defensin. These data establish a role for the phagocytic blood cells of Drosophila in detection of infection and activation of the humoral immune response.

Animals↗
PubMed2006

Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila.

BACKGROUND: Studies in Drosophila have taught us a great deal about how animals regulate the immediate innate immune response, but we still know little about how infections cause pathology. Here, we examine the pathogenesis associated with Mycobacterium marinum infection in the fly. M. marinum is closely related to M. tuberculosis, which causes tuberculosis in people. RESULTS: A microarray analysis showed that metabolism is profoundly affected in M. marinum-infected flies. A genetic screen identified foxo mutants as slower-dying after infection than wild-type flies. FOXO activity is inhibited by the insulin effector kinase Akt; we show that Akt activation is systemically reduced as a result of M. marinum infection. Finally, we show that flies infected with Mycobacterium marinum undergo a process like wasting: They progressively lose metabolic stores, in the form of fat and glycogen. They also become hyperglycemic. In contrast, foxo mutants exhibit less wasting. CONCLUSIONS: In people, many infections--including tuberculosis--can cause wasting, much as we see in Drosophila. Our study is the first examination of the metabolic consequences of infection in a genetically tractable invertebrate and gives insight into the metabolic consequences of mycobacterial infection, implicating impaired insulin signaling as a key mediator of these events. These results suggest that the fly can be used to study more than the immediate innate immune response to infection; it can also be used to understand the physiological consequences of infection and the immune response.

Animals↗
PubMed2006

Genomic dissection of microbial pathogenesis in cultured Drosophila cells.

Recent RNA interference screens that were performed at a genome-wide level have identified host factors that are important for the growth of Listeria monocytogenes in cultured cells from the fruit fly Drosophila melanogaster. The screens identified genes that are involved in phagocytosis but did not detect genes known to be involved in immune signaling pathways. These studies provide a foundation for the identification of host factors and virulence mechanisms.

Animals↗
PubMed2005

WntD is a feedback inhibitor of Dorsal/NF-kappaB in Drosophila development and immunity.

Regulating the nuclear factor-kappaB (NF-kappaB) family of transcription factors is of critical importance to animals, with consequences of misregulation that include cancer, chronic inflammatory diseases and developmental defects. Studies in Drosophila melanogaster have proved fruitful in determining the signals used to control NF-kappaB proteins, beginning with the discovery that the Toll/NF-kappaB pathway, in addition to patterning the dorsal-ventral axis of the fly embryo, defines a major component of the innate immune response in both Drosophila and mammals. Here, we characterize the Drosophila wntD (Wnt inhibitor of Dorsal) gene. We show that WntD acts as a feedback inhibitor of the NF-kappaB homologue Dorsal during both embryonic patterning and the innate immune response to infection. wntD expression is under the control of Toll/Dorsal signalling, and increased levels of WntD block Dorsal nuclear accumulation, even in the absence of the IkappaB homologue Cactus. The WntD signal is independent of the common Wnt signalling component Armadillo (beta-catenin). By engineering a gene knockout, we show that wntD loss-of-function mutants have immune defects and exhibit increased levels of Toll/Dorsal signalling. Furthermore, the wntD mutant phenotype is suppressed by loss of zygotic dorsal. These results describe the first secreted feedback antagonist of Toll signalling, and demonstrate a novel Wnt activity in the fly.

Animals↗
PubMed2004

Secreted Bacterial Effectors and Host-Produced Eiger/TNF Drive Death in aSalmonella-Infected Fruit Fly.

Death by infection is often as much due to the host's reaction as it is to the direct result of microbial action. Here we identify genes in both the host and microbe that are involved in the pathogenesis of infection and disease in Drosophila melanogaster challenged with Salmonella enterica serovartyphimurium (S. typhimurium). We demonstrate that wild-typeS. typhimurium causes a lethal systemic infection when injected into the hemocoel of D. melanogaster. Deletion of the gene encoding the secreted bacterial effect or Salmonella leucine-rich (PslrP)changes an acute and lethal infection to one that is persistent and less deadly. We propose a model in which Salmonella secreted effectors stimulate the fly and thus cause an immune response that is damaging both to the bacteria and, subsequently, to the host. In support of this model, we show that mutations in the fly gene eiger, a TNF homolog, delay the lethality of Salmonella infection. These results suggest that S. typhimurium-infected flies die from a condition that resembles TNF-induced metabolic collapse in vertebrates. This idea provides us with a new model to study shock-like biology in a genetically manipulable host. In addition, it allows us to study the difference in pathways followed by a microbe when producing an acute or persistent infection.

Animals↗
PubMed2003

Exploration of host-pathogen interactions using Listeria monocytogenes and Drosophila melanogaster.

The facultative intracellular bacterial pathogen Listeria monocytogenes is capable of replicating within a broad range of host cell types and host species. We report here the establishment of the fruit fly Drosophila melanogaster as a new model host for the exploration of L. monocytogenes pathogenesis and host response to infection. Listeria monocytogenes was capable of establishing lethal infections in adult fruit flies and larvae with extensive bacterial replication occurring before host death. Bacteria were found in the cytosol of insect phagocytic cells, and were capable of directing host cell actin polymerization. Bacterial gene products necessary for intracellular replication and cell-to-cell spread within mammalian cells were similarly found to be required within insect cells, and although previous work has suggested that L. monocytogenes virulence gene expression requires temperatures above 30 degrees C, bacteria within insect cells were found to express virulence determinants at 25 degrees C. Mutant strains of Drosophila that were compromised for innate immune responses demonstrated increased susceptibility to L. monocytogenes infection. These data indicate L. monocytogenes infection of fruit flies shares numerous features of mammalian infection, and thus that Drosophila has the potential to serve as a genetically tractable host system that will facilitate the analysis of host cellular responses to L. monocytogenes infection.

Actins↗
PubMed2003

Drosophila melanogaster is a genetically tractable model host for Mycobacterium marinum.

Mycobacterium marinum is a pathogenic mycobacterial species that is closely related to Mycobacterium tuberculosis and causes tuberculosis-like disease in fish and frogs. We infected the fruit fly Drosophila melanogaster with M. marinum. This bacterium caused a lethal infection in the fly, with a 50% lethal dose (LD(50)) of 5 CFU. Death was accompanied by widespread tissue damage. M. marinum initially proliferated inside the phagocytes of the fly; later in infection, bacteria were found both inside and outside host cells. Intracellular M. marinum blocked vacuolar acidification and failed to colocalize with dead Escherichia coli, similar to infections of mouse macrophages. M. marinum lacking the mag24 gene were less virulent, as determined both by LD(50) and by death kinetics. Finally, in contrast to all other bacteria examined, mycobacteria failed to elicit the production of antimicrobial peptides in Drosophila.We believe that this system should be a useful genetically tractable model for mycobacterial infection.

Animals↗
PubMed2002

Plant immunity and film Noir: what gumshoe detectives can teach us about plant-pathogen interactions.

Plant cells practice constant vigilance using resistance (R) proteins to monitor pathogenic processes. Three papers published recently in Cell and one in Science provide support for a model in which plant cells set up surveillance of signal transduction pathways, preparing to destroy the cell if any untoward fiddling with cellular physiology is detected. The demonstration of three separate examples of such a system suggests that it is broadly used and should provoke a reexamination of microbial pathogenesis in animal cells to look for similar mechanisms.

Bacteria↗
PubMed2002

Screening the fruitfly immune system.

The anti-microbial defense system of Drosophila shows functional similarities with the vertebrate innate immune system. Two recent gene-expression profiling studies of fruitflies challenged with infectious agents have identified key molecular players in the fruitfly's response to bacterial and fungal infection, as well as a large number of immune-regulated genes with unknown immunological function.

Animals↗