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  • 1.
    Arefin, Badrul
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kucerova, Lucie
    Dobes, Pavel
    Márkus, Róbert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Strnad, Hynek
    Wang, Zhi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hyrsl, Pavel
    Zurovec, Michal
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Genome-Wide Transcriptional Analysis of Drosophila Larvae Infected by Entomopathogenic Nematodes Shows Involvement of Complement, Recognition and Extracellular Matrix Proteins2014In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 6, no 2, p. 192-204Article in journal (Refereed)
    Abstract [en]

    Heterorhabditis bacteriophora is an entomopathogenic nematode (EPN) which infects its host by accessing the hemolymph where it releases endosymbiotic bacteria of the species Photorhabdus luminescens. We performed a genome-wide transcriptional analysis of the Drosophila response to EPN infection at the time point at which the nematodes reached the hemolymph either via the cuticle or the gut and the bacteria had started to multiply. Many of the most strongly induced genes have been implicated in immune responses in other infection models. Mapping of the complete set of differentially regulated genes showed the hallmarks of a wound response, but also identified a large fraction of EPN-specific transcripts. Several genes identified by transcriptome profiling or their homologues play protective roles during nematode infections. Genes that positively contribute to controlling nematobacterial infections encode: a homolog of thioester-containing complement protein 3, a basement membrane component (glutactin), a recognition protein (GNBP-like 3) and possibly several small peptides. Of note is that several of these genes have not previously been implicated in immune responses.

  • 2.
    Arefin, Badrul
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kucerova, Lucie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Krautz, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kranenburg, Holger
    Parvin, Farjana
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Apoptosis in Hemocytes Induces a Shift in Effector Mechanisms in the Drosophila Immune System and Leads to a Pro-Inflammatory State2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, article id e0136593Article in journal (Refereed)
    Abstract [en]

    Apart from their role in cellular immunity via phagocytosis and encapsulation, Drosophila hemocytes release soluble factors such as antimicrobial peptides, and cytokines to induce humoral responses. In addition, they participate in coagulation and wounding, and in development. To assess their role during infection with entomopathogenic nematodes, we depleted plasmatocytes and crystal cells, the two classes of hemocytes present in naive larvae by expressing proapoptotic proteins in order to produce hemocyte-free (Hml-apo, originally called Hemo(less)) larvae. Surprisingly, we found that Hml-apo larvae are still resistant to nematode infections. When further elucidating the immune status of Hml-apo larvae, we observe a shift in immune effector pathways including massive lamellocyte differentiation and induction of Toll-as well as repression of imd signaling. This leads to a pro-inflammatory state, characterized by the appearance of melanotic nodules in the hemolymph and to strong developmental defects including pupal lethality and leg defects in escapers. Further analysis suggests that most of the phenotypes we observe in Hml-apo larvae are alleviated by administration of antibiotics and by changing the food source indicating that they are mediated through the microbiota. Biochemical evidence identifies nitric oxide as a key phylogenetically conserved regulator in this process. Finally we show that the nitric oxide donor L-arginine similarly modifies the response against an early stage of tumor development in fly larvae.

  • 3.
    Arefin, Badrul
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kunc, Martin
    Krautz, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Drosophila models for different grades of leukemia2016Manuscript (preprint) (Other academic)
  • 4.
    Arefin, Badrul
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kunc, Martin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Institute of Experimental Biology, Czech Republic.
    Krautz, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Immune Phenotype of Three Drosophila Leukemia Models2017In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 7, no 7, p. 2139-2149Article in journal (Refereed)
    Abstract [en]

    Many leukemia patients suffer from dysregulation of their immune system, making them more susceptible to infections and leading to general weakening (cachexia). Both adaptive and innate immunity are affected. The fruit fly Drosophila melanogaster has an innate immune system, including cells of the myeloid lineage (hemocytes). To study Drosophila immunity and physiology during leukemia, we established three models by driving expression of a dominant-active version of the Ras oncogene (Ras(V12)) alone or combined with knockdowns of tumor suppressors in Drosophila hemocytes. Our results show that phagocytosis, hemocyte migration to wound sites, wound sealing, and survival upon bacterial infection of leukemic lines are similar to wild type. We find that in all leukemic models the two major immune pathways (Toll and Imd) are dysregulated. Toll-dependent signaling is activated to comparable extents as after wounding wild-type larvae, leading to a proinflammatory status. In contrast, Imd signaling is suppressed. Finally, we notice that adult tissue formation is blocked and degradation of cell masses during metamorphosis of leukemic lines, which is akin to the state of cancer-dependent cachexia. To further analyze the immune competence of leukemic lines, we used a natural infection model that involves insect-pathogenic nematodes. We identified two leukemic lines that were sensitive to nematode infections. Further characterization demonstrates that despite the absence of behavioral abnormalities at the larval stage, leukemic larvae show reduced locomotion in the presence of nematodes. Taken together, this work establishes new Drosophila models to study the physiological, immunological, and behavioral consequences of various forms of leukemia.

  • 5. Beck, Markus
    et al.
    Reineke, Annette
    Lorenz, Heidrun
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Schmidt, Otto
    Two distinct reproductive strategies are correlated with an ovarian phenotype in co-existing parthenogenetic strains of a parasitic wasp.2001In: Journal of Insect Physiology, Vol. 47, p. 1189-1195Article in journal (Refereed)
  • 6. Bidla, G
    et al.
    Lindgren, M
    Theopold, U
    Stockholm University.
    Dushay, M
    Hemolymph coagulation and phenoloxidase in Drosophila larvae2005In: Developmental & Comparative Immunology, Vol. 29, p. 669-679Article in journal (Refereed)
  • 7.
    Bidla, Gawa
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hauling, Thomas
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Dushay, Mitchell S.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Activation of Insect Phenoloxidase after Injury: Endogenous versus Foreign Elicitors2009In: Journal of Innate Immunity, ISSN 1662-811X, Vol. 1, no 4, p. 301-308Article in journal (Refereed)
    Abstract [en]

    The enzyme phenoloxidase (PO) is one of the first immune molecules that was identified in invertebrates. Recently, the immune function of PO has been challenged. We tested how PO is activated following injury in 2 insects, i.e. the fruit fly Drosophila melanogaster and the wax moth Galleria mellonella. Rapid PO activation in Drosophila was limited to discrete areas of the hemolymph clot which forms after injury. Surprisingly, unlike systemic PO activation during bacterial sepsis, clot melanization was not sensitive to microbial elicitors in our assay. Instead, Drosophila clot melanization was activated by endogenous signals such as apoptotic cells and was superinduced by phosphatidylserine, a negatively charged phospholipid normally found on the inner surface of the plasma membrane and exposed during apoptosis. In contrast, melanization in G. mellonella hemolymph was stronger and more uniform and was sensitive to peptidoglycan. This shows that both exogenous and endogenous signals can trigger the same immune mechanism in species and context-dependent ways. Our findings have implications for the evolutionary dynamics of immune mechanisms and are in agreement with recent comparisons of insect immune transcriptomes.

  • 8. Dobes, Pavel
    et al.
    Wang, Zhi
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Markus, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hyrsl, Pavel
    An improved method for nematode infection assays in Drosophila larvae2012In: Fly, ISSN 1933-6934, Vol. 6, no 2, p. 75-79Article in journal (Refereed)
    Abstract [en]

    The infective juveniles (IJs) of entomopathogenic nematodes (EPNs) seek out host insects and release their symbiotic bacteria into their body cavity causing septicaemia, which eventually leads to host death. The interaction between EPNs and their hosts are only partially understood, in particular the host immune responses appears to involve pathways other than phagocytosis and the canonical transcriptional induction pathways. These pathways are genetically tractable and include for example clotting factors and lipid mediators. The aim of this study was to optimize the nematode infections in

    Drosophila melanogaster larvae, a well-studied and genetically tractable model organism. Here we show that two nematode species namely Steinernema feltiae and Heterorhabditis bacteriophora display different infectivity towards Drosophila larvae with the latter being less pathogenic. The effects of supporting media and IJ dosage on the mortality of the hosts were assessed and optimized. Using optimum conditions, a faster and efficient setup for nematode infections was developed. This newly established infection model in Drosophila larvae will be applicable in large scale screens aimed at identifying novel genes/pathways involved in innate immune responses.

  • 9.
    Engström, Y
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Loseva, O
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Proteomics of the Drosophila immune response2004In: Trends in Biotechnology, Vol. 22, no 11, p. 600-605Article in journal (Refereed)
  • 10.
    Fors, Lisa
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Markus, Robert
    Ericson, Lars
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Geographic variation in parasitoid virulence and parasitoid host race formationManuscript (preprint) (Other academic)
  • 11.
    Fors, Lisa
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Markus, Robert
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ericson, Lars
    Hambäck, Peter A.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Geographic variation and trade-offs in parasitoid virulence2016In: Journal of Animal Ecology, ISSN 0021-8790, E-ISSN 1365-2656, Vol. 85, no 6, p. 1595-1604Article in journal (Refereed)
    Abstract [en]

    1. Host-parasitoid systems are characterized by a continuous development of new defence strategies in hosts and counter-defence mechanisms in parasitoids. This co-evolutionary arms race makes host-parasitoid systems excellent for understanding trade-offs in host use caused by evolutionary changes in host immune responses and parasitoid virulence. However, knowledge obtained from natural host-parasitoid systems on such trade-offs is still limited.

    2. In this study, the aim was to examine trade-offs in parasitoid virulence in Asecodes parviclava (Hymenoptera: Eulophidae) when attacking three closely related beetles: Galerucella pusilla, Galerucella calmariensis and Galerucella tenella (Coleoptera: Chrysomelidae). A second aim was to examine whether geographic variation in parasitoid infectivity or host immune response could explain differences in parasitism rate between northern and southern sites.

    3. More specifically, we wanted to examine whether the capacity to infect host larvae differed depending on the previous host species of the parasitoids and if such differences were connected to differences in the induction of host immune systems. This was achieved by combining controlled parasitism experiments with cytological studies of infected larvae.

    4. Our results reveal that parasitism success in A. parviclava differs both depending on previous and current host species, with a higher virulence when attacking larvae of the same species as the previous host. Virulence was in general high for parasitoids from G. pusilla and low for parasitoids from G. calmariensis. At the same time, G. pusilla larvae had the strongest immune response and G. calmariensis the weakest. These observations were linked to changes in the larval hemocyte composition, showing changes in cell types important for the encapsulation process in individuals infected by more or less virulent parasitoids.

    5. These findings suggest ongoing evolution in parasitoid virulence and host immune response, making the system a strong candidate for further studies on host race formation and speciation.

  • 12.
    Fors, Lisa
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Markus, Robert
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hambäck, Peter A.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Differences in Cellular Immune Competence Explain Parasitoid Resistance for Two Coleopteran Species2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e108795Article in journal (Refereed)
    Abstract [en]

    The immune defence of an organism is evolving continuously, causing counteradaptations in interacting species, which in turn affect other ecological and evolutionary processes. Until recently comparative studies of species interactions and immunity, combining information from both ecological and immunological fields, have been rare. The cellular immune defense in insects, mainly mediated by circulating hemocytes, has been studied primarily in Lepidoptera and Diptera, whereas corresponding information about coleopteran species is still scarce. In the study presented here, we used two closely related chrysomelids, Galerucella pusilla and G. calmariensis (Coleoptera), both attacked by the same parasitoid, Asecodes parviclava (Hymenoptera). In order to investigate the structure of the immune system in Galerucella and to detect possible differences between the two species, we combined ecological studies with controlled parasitism experiments, followed by an investigation of the cell composition in the larval hemolymph. We found a striking difference in parasitism rate between the species, as well as in the level of successful immune response (i.e. encapsulation and melanisation of parasitoid eggs), with G. pusilla showing a much more potent immune defense than G. calmariensis. These differences were linked to differences in the larval cell composition, where hemocyte subsets in both naive and parasitised individuals differed significantly between the species. In particular, the hemocytes shown to be active in the encapsulation process; phagocytes, lamellocytes and granulocytes, differ between the species, indicating that the cell composition reflects the ability to defend against the parasitoid.

  • 13. Glatz, R
    et al.
    Roberts, H L S
    Li, D
    Sarjan, M
    Theopold, U H
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Asgari, S
    Schmidt, O
    Lectin-induced haemocyte inactivation in insects2004In: Journal of Insect Physiology, Vol. 50, p. 955-963Article in journal (Refereed)
  • 14.
    Hauling, Thomas
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Krautz, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Markus, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Volkenhoff, Anne
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kucerova, Lucie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    A Drosophila immune response against Ras-induced overgrowth2014In: Biology Open, ISSN 2046-6390, Vol. 3, no 4, p. 250-260Article in journal (Refereed)
    Abstract [en]

    Our goal is to characterize the innate immune response against the early stage of tumor development. For this, animal models where genetic changes in specific cells and tissues can be performed in a controlled way have become increasingly important, including the fruitfly Drosophila melanogaster. Many tumor mutants in Drosophila affect the germline and, as a consequence, also the immune system itself, making it difficult to ascribe their phenotype to a specific tissue. Only during the past decade, mutations have been induced systematically in somatic cells to study the control of tumorous growth by neighboring cells and by immune cells. Here we show that upon ectopic expression of a dominant-active form of the Ras oncogene (Ras(V12)), both imaginal discs and salivary glands are affected. Particularly, the glands increase in size, express metalloproteinases and display apoptotic markers. This leads to a strong cellular response, which has many hallmarks of the granuloma-like encapsulation reaction, usually mounted by the insect against larger foreign objects. RNA sequencing of the fat body reveals a characteristic humoral immune response. In addition we also identify genes that are specifically induced upon expression of Ras(V12). As a proof-of-principle, we show that one of the induced genes (santa-maria), which encodes a scavenger receptor, modulates damage to the salivary glands. The list of genes we have identified provides a rich source for further functional characterization. Our hope is that this will lead to a better understanding of the earliest stage of innate immune responses against tumors with implications for mammalian immunity.

  • 15.
    Hauptmann, Giselbert
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Söll, Iris
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Krautz, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Multi-target Chromogenic Whole-mount In Situ Hybridization for Comparing Gene Expression Domains in Drosophila Embryos2016In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 107, article id e53830Article in journal (Refereed)
    Abstract [en]

    To analyze gene regulatory networks active during embryonic development and organogenesis it is essential to precisely define how the different genes are expressed in spatial relation to each other in situ. Multi-target chromogenic whole-mount in situ hybridization (MC-WISH) greatly facilitates the instant comparison of gene expression patterns, as it allows distinctive visualization of different mRNA species in contrasting colors in the same sample specimen. This provides the possibility to relate gene expression domains topographically to each other with high accuracy and to define unique and overlapping expression sites. In the presented protocol, we describe a MC-WISH procedure for comparing mRNA expression patterns of different genes in Drosophila embryos. Up to three RNA probes, each specific for another gene and labeled by a different hapten, are simultaneously hybridized to the embryo samples and subsequently detected by alkaline phosphatase-based colorimetric immunohistochemistry. The described procedure is detailed here for Drosophila, but works equally well with zebrafish embryos.

  • 16. Herwald, Heiko
    et al.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hemostasis in Invertebrates and Vertebrates: An Evolutionary Excursion2011In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 3, no 1, p. 1-2Article in journal (Refereed)
  • 17.
    Hyrsl, Pavel
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Dobes, Pavel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Wang, Zhi
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hauling, Thomas
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Wilhelmsson, Christine
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Clotting Factors and Eicosanoids Protect against Nematode Infections2011In: Journal of Innate Immunity, ISSN 1662-811X, Vol. 3, no 1, p. 65-70Article in journal (Refereed)
    Abstract [en]

    We show that hemolymph clotting protects Drosophila melanogaster against infections with an entomopathogenic nematode and its symbiotic bacterium. We also provide biochemical and genetic evidence for an involvement of eicosanoids in the same infection model. Taken together, our results confirm the conserved nature of the immune function of clot formation.

  • 18.
    Karlsson, C
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Korayem, A M
    Scherfer, C
    Loseva, O
    Dushay, M S
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Proteomic Analysis of the Drosophila Larval Hemolymph Clot2004In: The Journal of Biological Chemistry, Vol. 279, no 50, p. 52033-52041Article in journal (Refereed)
  • 19.
    Keehnen, Naomi L. P.
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Rolff, Jens
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wheat, Christopher W.
    Stockholm University, Faculty of Science, Department of Zoology.
    Insect Antimicrobial Defences: A Brief History, Recent Findings, Biases, and a Way Forward in Evolutionary Studies2017In: Advances in Insect Physiology, ISSN 0065-2806, E-ISSN 2213-6800, Vol. 52, p. 1-33Article in journal (Refereed)
    Abstract [en]

    We propose that an evolutionary and phenotype-driven approach, harnessing current technological developments, has much to offer for our understanding of insect immunity. After briefly reviewing the history of the discovery of canonical immune system, the current understanding of its components is reviewed and then we argue that the current paradigm of research may be biassed due to (a) its limited taxonomic perspective, (b) the evolutionary time scale being studied, and (c) a focus primarily if not exclusively, upon the canonical, humoural gene set. For the rest of the review, we then discuss the importance of a phenotype down approach as an understudied perspective, exemplified by the need for understanding the basis of cellular responses and wounding as a source of selection on immunity in the wild. We propose that research on those topics almost certainly will provide new insights into the evolution of the insect immune system.

  • 20. Korayem, A M
    et al.
    Fabbri, M
    Takahashi, K
    Scherfer, C
    Lindgren, M
    Schmidt, O
    Ueda, R
    Dushay, M S
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A Drosophila salivary glad mucin is also expressed in immune tissues: evidence for a function in coagulation and the entrapment of bacteria2004In: Insect Biochemistry and Molecular Biology, Vol. 34, p. 1297-1304Article in journal (Refereed)
  • 21.
    Krautz, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Arefin, Badrul
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Damage signals in the insect immune response2014In: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 5, article id 342Article, review/survey (Refereed)
    Abstract [en]

    Insects and mammals share an ancient innate immune system comprising both humoral and cellular responses. The insect immune system consists of the fat body, which secretes effector molecules into the hemolymph and several classes of hemocytes, which reside in the hemolymph and of protective border epithelia. Key features of wound- and immune responses are shared between insect and mammalian immune systems including the mode of activation by commonly shared microbial (non-self) patterns and the recognition of these patterns by dedicated receptors. It is unclear how metazoan parasites in insects, which lack these shared motifs, are recognized. Research in recent years has demonstrated that during entry into the insect host, many eukaryotic pathogens leave traces that alert potential hosts of the damage they have afflicted. In accordance with terminology used in the mammalian immune systems, these signals have been dubbed danger- or damage-associated signals. Damage signals are necessary byproducts generated during entering hosts either by mechanical or proteolytic damage. Here, we briefly review the current stage of knowledge on how wound closure and wound healing during mechanical damage is regulated and how damage-related signals contribute to these processes. We also discuss how sensors of proteolytic activity induce insect innate immune responses. Strikingly damage-associated signals are also released from cells that have aberrant growth, including tumor cells. These signals may induce apoptosis in the damaged cells, the recruitment of immune cells to the aberrant tissue and even activate humoral responses. Thus, this ensures the removal of aberrant cells and compensatory proliferation to replace lost tissue. Several of these pathways may have been co-opted from wound healing and developmental processes.

  • 22.
    Krautz, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Khalili, Dilan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hauling, Thomas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Söll, Iris
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hauptmann, Giselbert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    An innate immune response against dysplasia in a secretory organManuscript (preprint) (Other academic)
  • 23.
    Krautz, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Khalili, Dilan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Söll, Iris
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hauptmann, Giselbert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Drosophila larval fat body preparations to reveal regionalized gene expression​Manuscript (preprint) (Other academic)
  • 24.
    Kubrak, Olga I.
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Kucerova, Lucie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nylin, Sören
    Stockholm University, Faculty of Science, Department of Zoology.
    Nässel, Dick R.
    Stockholm University, Faculty of Science, Department of Zoology.
    Characterization of Reproductive Dormancy in Male Drosophila melanogaster2016In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, article id 572Article in journal (Refereed)
    Abstract [en]

    Insects are known to respond to seasonal and adverse environmental changes by entering dormancy, also known as diapause. In some insect species, including Drosophila melanogaster, dormancy occurs in the adult organism and postpones reproduction. This adult dormancy has been studied in female flies where it is characterized by arrested development of ovaries, altered nutrient stores, lowered metabolism, increased stress and immune resistance and drastically extended lifespan. Male dormancy, however, has not been investigated in D. melanogaster, and its physiology is poorly known in most insects. Here we show that unmated 3-6 h old male flies placed at low temperature (11 degrees C) and short photoperiod (10 Light:14 Dark) enter a state of dormancy with arrested spermatogenesis and development of testes and male accessory glands. Over 3 weeks of diapause we see a dynamic increase in stored carbohydrates and an initial increase and then a decrease in lipids. We also note an up-regulated expression of genes involved in metabolism, stress responses and innate immunity. Interestingly, we found that male flies that entered reproductive dormancy do not attempt to mate females kept under non-diapause conditions (25 degrees C, 1 2L:1 2D), and conversely non-diapausing males do not mate females in dormancy. In summary, our study shows that male D. melanogaster can enter reproductive dormancy. However, our data suggest that dormant male flies deplete stored nutrients faster than females, studied earlier, and that males take longer to recover reproductive capacity after reintroduction to non-diapause conditions.

  • 25.
    Kubrak, Olga I.
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Kucerova, Lucie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nässel, Dick R.
    Stockholm University, Faculty of Science, Department of Zoology.
    The Sleeping Beauty: How Reproductive Diapause Affects Hormone Signaling, Metabolism, Immune Response and Somatic Maintenance in Drosophila melanogaster2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, article id e113051Article in journal (Refereed)
    Abstract [en]

    Some organisms can adapt to seasonal and other environmental challenges by entering a state of dormancy, diapause. Thus, insects exposed to decreased temperature and short photoperiod enter a state of arrested development, lowered metabolism, and increased stress resistance. Drosophila melanogaster females can enter a shallow reproductive diapause in the adult stage, which drastically reduces organismal senescence, but little is known about the physiology and endocrinology associated with this dormancy, and the genes involved in its regulation. We induced diapause in D. melanogaster and monitored effects over 12 weeks on dynamics of ovary development, carbohydrate and lipid metabolism, as well as expression of genes involved in endocrine signaling, metabolism and innate immunity. During diapause food intake diminishes drastically, but circulating and stored carbohydrates and lipids are elevated. Gene transcripts of glucagonand insulin-like peptides increase, and expression of several target genes of these peptides also change. Four key genes in innate immunity can be induced by infection in diapausing flies, and two of these, drosomycin and cecropin A1, are upregulated by diapause independently of infection. Diapausing flies display very low mortality, extended lifespan and decreased aging of the intestinal epithelium. Many phenotypes induced by diapause are reversed after one week of recovery from diapause conditions. Furthermore, mutant flies lacking specific insulin-like peptides (dilp5 and dilp2-3) display increased diapause incidence. Our study provides a first comprehensive characterization of reproductive diapause in D. melanogaster, and evidence that glucagon- and insulin-like signaling are among the key regulators of the altered physiology during this dormancy.

  • 26.
    Kucerova, Lucie
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of South Bohemia, Czech Republic.
    Broz, Vaclav
    Arefin, Badrul
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Maaroufi, Houda Ouns
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hurychova, Jana
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Masaryk University, Czech Republic.
    Strnad, Hynek
    Zurovec, Michal
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Drosophila Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing2016In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 8, no 2, p. 199-210Article in journal (Refereed)
    Abstract [en]

    Chitinase-like proteins (CLPs) of the 18 glycosyl hydrolase family retain structural similarity to chitinases but lack enzymatic activity. Although CLPs are upregulated in several human disorders that affect regenerative and inflammatory processes, very little is known about their normal physiological function. We show that an insect CLP (Drosophila imaginal disc growth factor 3, IDGF3) plays an immune-protective role during entomopathogenic nematode (EPN) infections. During these infections, nematodes force their entry into the host via border tissues, thus creating wounds. Whole-genome transcriptional analysis of nematode-infected wildtype and Idgf3 mutant larvae have shown that, in addition to the regulation of genes related to immunity and wound closure, IDGF3 represses Jak/STAT and Wingless signaling. Further experiments have confirmed that IDGF3 has multiple roles in innate immunity. It serves as an essential component required for the formation of hemolymph clots that seal wounds, and Idgf3 mutants display an extended developmental delay during wound healing. Altogether, our findings indicate that vertebrate and invertebrate CLP proteins function in analogous settings and have a broad impact on inflammatory reactions and infections. This opens the way to further genetic analysis of Drosophila IDGF3 and will help to elucidate the exact molecular context of CLP function.

  • 27.
    Kucerova, Lucie
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kubrak, Olga I.
    Stockholm University, Faculty of Science, Department of Zoology.
    Bengtsson, Jonas M.
    Stockholm University, Faculty of Science, Department of Zoology.
    Strnad, Hynek
    Nylin, Sören
    Stockholm University, Faculty of Science, Department of Zoology.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nässel, Dick R.
    Stockholm University, Faculty of Science, Department of Zoology.
    Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster2016In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, article id 50Article in journal (Refereed)
    Abstract [en]

    Background: In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. Results: A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin-IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll-dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. Conclusions: We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan.

  • 28.
    Kunc, Martin
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Masaryk University, Czech Republic.
    Arefin, Badrul
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hyrsl, Pavel
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvae2017In: fly, ISSN 1933-6934, Vol. 11, no 3, p. 208-217Article in journal (Refereed)
    Abstract [en]

    One of the key factors that determine the interaction between hosts and their parasites is the frequency of their interactions, which depends on the locomotory behavior of both parts. To address host behavior we used natural infections involving insect pathogenic nematodes and Drosophila melanogaster larvae as hosts. Using a modified version of a recently described method (FIMTrack) to assess several parameters in larger sets of animals, we initially detected specific differences in larval food searching when comparing Drosophila strains. These differences were further influenced by the presence of nematodes. Given a choice, Drosophila larvae clearly avoided nematodes irrespective of their genetic background. Our newly developed methods will be useful to test candidate genes and pathways involved in host/pathogen interactions in general and to assess specific parameters of their interaction.

  • 29. Kunc, Martin
    et al.
    Arefin, Badrul
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hyrsl, Pavel
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvaeManuscript (preprint) (Other academic)
  • 30.
    Lesch, Christine
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Goto, Akira
    Lindgren, Malin
    Bidla, Gawa
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Dushay, Mitchell S.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A role for Hemolectin in coagulation and immunity in Drosophila melanogaster2007In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 31, no 12, p. 1255-1263Article in journal (Refereed)
    Abstract [en]

    Hemolectin has been identified as a candidate clotting factor in Drosophila. We reassessed the domain structure of Hemolectin (Hml) and propose that instead of C-type lectin domains, the two discoidin domains are most likely responsible for the protein's lectin activity. We also tested Hml's role in coagulation and immunity in Drosophila. Here we describe the isolation of a new hml allele in a forward screen for coagulation mutants, and our characterization of this and two other hml alleles, one of which is a functional null. While loss of Hml had strong effects on larval hemolymph coagulation ex vivo, mutant larvae survived wounding. Drosophila thus possesses redundant hemostatic mechanisms. We also found that loss of Hml in immune-handicapped adults rendered them more sensitive to Gram(−) bacterial infection. This demonstrates an immunological role of this clotting protein and reinforces the importance of the clot in insect immunity.

  • 31. Lesch, Christine
    et al.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Methods to study hemolymph clotting in insects2008In: Insect Immunology, Academic Press , 2008Chapter in book (Other academic)
  • 32. Li, D
    et al.
    Korayem, A M
    Zhao, Z
    Schmidt, O
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Scherfer, C
    Insect hemolymph clotting: evidence for interaction between the coagulation system and the prophenoxidase activating cascade2002In: Insect Biochemistry & Molecular Biology, Vol. 32, p. 919-928Article in journal (Refereed)
  • 33. Li, D
    et al.
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Schmidt, O
    Posstible function of two insect phospholipid-hydroperoxide glutathione peroxidases2003In: Journal of insect Physiology, Vol. 49, p. 1-9Article in journal (Refereed)
  • 34. Lindgren, Malin
    et al.
    Riazi, Raha
    Lesch, Christine
    Wilhelmsson, Christine
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Dushay, Mitchell S
    Fondue and transglutaminase in the Drosophila larval clot2008In: Journal of insect physiology, ISSN 0022-1910, E-ISSN 1879-1611, Vol. 54, p. 586-592Article in journal (Refereed)
  • 35. Lööf, Torsten G.
    et al.
    Morgelin, Matthias
    Johansson, Linda
    Oehmcke, Sonja
    Olin, Anders I.
    Dickneite, Gerhard
    Norrby-Teglund, Anna
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Herwald, Heiko
    Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 9, p. 2589-2598Article in journal (Refereed)
    Abstract [en]

    Phylogenetically conserved serine protease cascades play an important role in invertebrate and vertebrate immunity. The mammalian coagulation system can be traced back some 400 million years and shares homology with ancestral serine proteinase cascades that are involved in, for example, Toll receptor signaling in insects and release of antimicrobial peptides during hemolymph clotting. In the present study, we show that the induction of coagulation by bacteria leads to immobilization and killing of Streptococcus pyogenes bacteria inside the clot. The entrapment is mediated via cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII (fXIII), an evolutionarily conserved transglutaminase. In a streptococcal skin infection model, fXIII(-/-) mice developed severe signs of patho-logic inflammation at the local site of infection, and fXIII treatment of wild-type animals dampened bacterial dissemination during early infection. Bacterial killing and cross-linking to fibrin networks was also detected in tissue biopsies from patients with streptococcal necrotizing fasciitis, supporting the concept that coagulation is part of the early innate immune system.

  • 36. Lööf, Torsten G.
    et al.
    Schmidt, Otto
    Herwald, Heiko
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Coagulation Systems of Invertebrates and Vertebrates and Their Roles in Innate Immunity: The Same Side of Two Coins?2011In: Journal of Innate Immunity, ISSN 1662-811X, Vol. 3, no 1, p. 34-40Article, review/survey (Refereed)
    Abstract [en]

    Bacterial infections represent a serious health care problem, and all multicellular organisms have developed defense mechanisms to eliminate pathogens that enter the host via different paths including wounds. Many invertebrates have an open circulatory system, and effective coagulation systems are in place to ensure fast and efficient closure of wounds. It was proposed early on that coagulation systems in invertebrates play a major role not only in sealing wounds but also in preventing systemic infections. More recent evidence suggests that vertebrates, too, rely on clotting as an immune effector mechanism. Here we discuss the evolution of clotting systems against the background of their versatile function in innate immunity. Copyright (C) 2010 S. Karger AG, Basel

  • 37. Scherfer, C
    et al.
    Qazi, M R
    Takahashi, K
    Ueda, R
    Dushay, M S
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lemaitre, B
    The Toll immune-regulated Drosophila protein Fondue is involved in hemoplymph clotting and puparium formation2006In: Developmental Biology, Vol. 295, p. 156-163Article in journal (Refereed)
  • 38. Scherfer, C.
    et al.
    Wilhelmsson, C.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Loseva, O.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bidla, G.
    Goto, A.
    Havemann, J.
    Dushay, M. S.
    Theopold, U.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Isolation and Characterization of Hemolymph Clotting Factors in Drosophila melanogaster by a Pullout Method2004In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 14, p. 625-629Article in journal (Refereed)
  • 39. Schmidt, O
    et al.
    Rahman, M M
    Ma, G
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Sun, Y
    Sarjan, M
    Fabbri, M
    Roberts, H
    Mode of action of antimicrobial proteins, pore-forming toxins and biologically active peptides (hypothesis)2005In: Inv. Survival Journal, ISSN 90, Vol. 2, p. 82-Article in journal (Other academic)
  • 40. Schmidt, O
    et al.
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    An extracellular driving force of cell-sharpe changes2004In: BioEssays, Vol. 26, p. 1344-1350Article in journal (Refereed)
  • 41. Schmidt, Otto
    et al.
    Söderhäll, Kenneth
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Faye, Ingrid
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The Role of Adhesion in Arthropod Immune Recognition2010In: Annual review of entomology, ISSN 1545-2948, Vol. 55, p. 485-504Article in journal (Refereed)
    Abstract [en]

    The recognition and inactivation of toxins and pathogens are mediated by a combination of cell-free and cellular mechanisms. A number of soluble and membrane-bound pattern recognition molecules interact with elicitors to become involved in both cell-free inactivation as well as cellular uptake reactions. Here we describe the possible recognition and effector function of key arthropod immune proteins, such as peroxinectin, hemolin, and hemomucin, as an outcome of changes in adhesiveness, which drive self-assembly reactions leading to cell-free coagulation and cellular uptake reactions. The fact that some of these proteins are essential for immune and developmental functions in some species, but not found in closely related species, may point to the existence of multiprotein assemblies, which are conserved at the mechanistic level and can function with more than one combination of protein constituents. Expected final online publication date for the Annual Review of Entomology Volume 55 is December 03, 2009. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

  • 42. Schmidt, Otto
    et al.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Beckage, Nancy E
    Insect and Vertebrate Immunity: Key Similarities versus Differences2008In: Insect Immunology, Elsevier Inc , 2008Chapter in book (Other (popular science, discussion, etc.))
  • 43.
    Theopold, U
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Schmidt, O
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Söderhäll, K
    Dushay, M S
    Coagulation in arthropods: defence, wound closure and healing2004In: Trends in Immunology, Vol. 25, no 6, p. 289-294Article in journal (Refereed)
  • 44.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A bad boy comes good2009In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 461, p. 486-487Article, review/survey (Other (popular science, discussion, etc.))
  • 45.
    Theopold, Ulrich
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Dorian, Camilla
    Schmidt, Otto
    Changes in glycosylation during Drosophila development.: The influence of ecdysone on hemomucin isoforms2001In: Insect Biochemistry and Molecular Biology, Vol. 31, p. 189-197Article in journal (Refereed)
  • 46.
    Theopold, Ulrich
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Dushay, Mitchell S
    Mechanisms of Drosophila Immunity: An Innate Immune System at Work2008In: Current Immunology Rewiews, ISSN 1573-3955, Vol. 3, no 4, p. 276-288Article, review/survey (Refereed)
    Abstract [en]

    Insect immune systems which lack the type of adaptive immunity known in vertebrates rely on several mechanisms including solid barriers against the environment, rapid coagulation of hemolymph after wounding, the formation of aggregates that immobilize and kill foreign invaders, phagocytosis, and the production of antimicrobial peptides. The mode of action and the regulation of the expression of antimicrobial peptides have been studied intensively for more than three decades and are now increasingly well understood. In addition, the characterization of several key molecules involved in other branches of insect immunity has led to a deeper and much more comprehensive understanding of innate immunity in insects. Here we focus on the current status of our view of immunity in the vinegar fly Drosophila melanogaster, the best characterized insect model. We also discuss how evolutionary and ecological forces may have shaped immune responses in Drosophila as compared to other insect species. Finally, several infection models reveal finely-tuned and pathogen-dependent interactions between Drosophila immunity and fly physiology.

  • 47.
    Theopold, Ulrich
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Krautz, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dushay, Mitchell S.
    The Drosophila clotting system and its messages for mammals2014In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 42, no 1, p. 42-46Article in journal (Refereed)
    Abstract [en]

    Drosophila has been increasingly used as a model to study hemolymph clotting. Proteomics and bioinformatics identified candidate clotting-factors, several of which were tested using genetics. Mutants and lines with reduced expression of clotting-factors show subtle effects after wounding, indicating that sealing wounds may rely on redundant mechanisms. More striking effects are observed after infection, in particular when a natural infection model involving entomopathogenic nematodes is used. When translated into mammalian models these results reveal that mammalian blood clots serve a similar immune function, thus providing a new example of the usefulness of studying invertebrate models.

  • 48.
    Theopold, Ulrich
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Schneider, David
    Stanford, California.
    The Tinkerer at Work2009In: Journal of Innate Immunity, Vol. 1, p. 281-Article, book review (Other academic)
  • 49.
    Wang, Zhi
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Bidla, Gawa
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Markus, Robert
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Crystal cell activation through ruptureManuscript (preprint) (Other academic)
    Abstract [en]

    Cell lysis is increasingly recognized as a mode of immune cell activation. We studied secretion by cell rupture using crystal cells, a specialized type of immune cell from the model insect

    Drosophila melanogaster. Crystal cells contain a multifunctional enzyme in a proform within crystalline inclusions, which are released during rupture and dissolve within minutes. Using targeted screens we identified cytoskeletal components and regulators as mediators of cell rupture. We also find evidence for an involvement of the endocytic pathway and for caspases. In addition we find no evidence for a release of nuclear DNA. Taken together our results set crystal cell activation apart from other activation processes that involve cell lysis such as the release of neutrophil traps.

  • 50.
    Wang, Zhi
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Wilhelmsson, Christine
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hyrsl, Pavel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Loof, Torsten G.
    Dobes, Pavel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Klupp, Martina
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Loseva, Olga
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Moergelin, Matthias
    Ikle, Jennifer
    Cripps, Richard M.
    Herwald, Heiko
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Pathogen Entrapment by Transglutaminase - A Conserved Early Innate Immune Mechanism2010In: PLOS pathogens, ISSN 1553-7366, Vol. 6, no 2, p. e1000763-Article in journal (Refereed)
    Abstract [en]

    Clotting systems are required in almost all animals to prevent loss of body fluids after injury. Here, we show that despite the risks associated with its systemic activation, clotting is a hitherto little appreciated branch of the immune system. We compared clotting of human blood and insect hemolymph to study the best-conserved component of clotting systems, namely the Drosophila enzyme transglutaminase and its vertebrate homologue Factor XIIIa. Using labelled artificial substrates we observe that transglutaminase activity from both Drosophila hemolymph and human blood accumulates on microbial surfaces, leading to their sequestration into the clot. Using both a human and a natural insect pathogen we provide functional proof for an immune function for transglutaminase (TG). Drosophila larvae with reduced TG levels show increased mortality after septic injury. The same larvae are also more susceptible to a natural infection involving entomopathogenic nematodes and their symbiotic bacteria while neither phagocytosis, phenoloxidase or-as previously shown-the Toll or imd pathway contribute to immunity. These results firmly establish the hemolymph/blood clot as an important effector of early innate immunity, which helps to prevent septic infections. These findings will help to guide further strategies to reduce the damaging effects of clotting and enhance its beneficial contribution to immune reactions.

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