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Molecular characterization of the Drosophila responses towards nematodes
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholm University. (Ulrich Theopold)ORCID-id: 0000-0003-1117-9125
2016 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

A sophisticated evolutionary conserved innate immune system has evolved in insects to fight pathogens and to restrict damage in harmful (danger) situations including cancer. A significant amount of knowledge about different infection models in Drosophila has been generated in past decades, which revealed functional resemblances and implications for vertebrate systems. However, how Drosophila responds towards multicellular parasitic nematodes and in danger situations is still little understood. Therefore, the aim of the thesis was to characterize multiple aspects of the host defense in the two important contexts mentioned above.

We analyzed the transcriptome profiles of nematode-infected Drosophila larvae with uninfected samples. For this we employed the entomopathogenic nematode Heterorhabditis bacteriophora with its symbiont Photorhabdus luminescence to infect Drosophila larvae. We found 642 genes were differentially regulated upon infection. Among them a significant portion belonged to immune categories. Further functional analysis identified a thioester containing protein TEP3, a recognition protein GNBP-like 3, the basement membrane component protein Glutactin and several other small peptides. Upon loss or reduced expression of these genes hosts showed mortality during nematode infections. This study uncovers a novel function for several of the genes in immunity.

Furthermore, we investigated the cellular response towards nematodes. When we eliminated hemocytes genetically (referred to as hml-apo) in Drosophila, we found hml-apo larvae are resistant to nematodes. Subsequent characterization of hml-apo larvae showed massive lamellocyte differentiation (another blood cell type which is rare in naïve larvae), emergence of melanotic masses, up- and down-regulation of Toll and Imd signaling respectively suggesting a pro-inflammatory response. Moreover, a striking defective leg phenotype in adult escapers from pupal lethality was observed. We identified nitric oxide (NO) as a key regulator of these processes. We also showed that imaginal disc growth factors 3 (IDGF3): (a) protects hosts against nematodes, (b) is a clotting component and (c) negatively regulates Wnt and JAK/STAT signaling. To follow larval behavior in the presence or absence of nematodes we monitored Drosophila larval locomotion behaviors using FIMtrack (a recently devised automated method) to elucidate evasive strategies of hosts. Finally, we characterized host defenses in three Drosophila leukemia models with and without nematode infection. Taken together, these studies shed light on host responses in two crucial circumstances, nematode infections and danger situations.

sted, utgiver, år, opplag, sider
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2016. , s. 65
Emneord [en]
Drosophila, nematodes, infection, danger situations, immune response, coagulation, apoptosis, nitric oxide, leukemia
HSV kategori
Forskningsprogram
molekylärbiologi
Identifikatorer
URN: urn:nbn:se:su:diva-134346ISBN: 978-91-7649-535-3 (tryckt)ISBN: 978-91-7649-536-0 (tryckt)OAI: oai:DiVA.org:su-134346DiVA, id: diva2:1032982
Disputas
2016-11-24, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 3: Manuscript.

Tilgjengelig fra: 2016-11-01 Laget: 2016-10-05 Sist oppdatert: 2017-05-04bibliografisk kontrollert
Delarbeid
1. Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvae
Åpne denne publikasjonen i ny fane eller vindu >>Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvae
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Forskningsprogram
molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-134344 (URN)
Tilgjengelig fra: 2016-10-05 Laget: 2016-10-05 Sist oppdatert: 2016-10-06bibliografisk kontrollert
2. The Drosophila Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing
Åpne denne publikasjonen i ny fane eller vindu >>The Drosophila Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing
Vise andre…
2016 (engelsk)Inngår i: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 8, nr 2, s. 199-210Artikkel i tidsskrift (Fagfellevurdert) Published
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.

Emneord
Chitinase-like proteins, Imaginal disc growth factor, Hemolymph clot, Wound healing, Nematode infection, Insect immunity
HSV kategori
Forskningsprogram
molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-129978 (URN)10.1159/000442351 (DOI)000372510800009 ()26694862 (PubMedID)
Tilgjengelig fra: 2016-05-09 Laget: 2016-05-09 Sist oppdatert: 2017-11-30bibliografisk kontrollert
3. Drosophila models for different grades of leukemia
Åpne denne publikasjonen i ny fane eller vindu >>Drosophila models for different grades of leukemia
2016 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Forskningsprogram
molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-134331 (URN)978-91-7649-536-0 (ISBN)
Tilgjengelig fra: 2016-10-05 Laget: 2016-10-04 Sist oppdatert: 2016-10-06bibliografisk kontrollert
4. Apoptosis in Hemocytes Induces a Shift in Effector Mechanisms in the Drosophila Immune System and Leads to a Pro-Inflammatory State
Åpne denne publikasjonen i ny fane eller vindu >>Apoptosis in Hemocytes Induces a Shift in Effector Mechanisms in the Drosophila Immune System and Leads to a Pro-Inflammatory State
Vise andre…
2015 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 8, artikkel-id e0136593Artikkel i tidsskrift (Fagfellevurdert) Published
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.

HSV kategori
Forskningsprogram
molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-121511 (URN)10.1371/journal.pone.0136593 (DOI)000360435500023 ()
Tilgjengelig fra: 2015-10-09 Laget: 2015-10-05 Sist oppdatert: 2017-12-01bibliografisk kontrollert
5. Genome-Wide Transcriptional Analysis of Drosophila Larvae Infected by Entomopathogenic Nematodes Shows Involvement of Complement, Recognition and Extracellular Matrix Proteins
Åpne denne publikasjonen i ny fane eller vindu >>Genome-Wide Transcriptional Analysis of Drosophila Larvae Infected by Entomopathogenic Nematodes Shows Involvement of Complement, Recognition and Extracellular Matrix Proteins
Vise andre…
2014 (engelsk)Inngår i: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 6, nr 2, s. 192-204Artikkel i tidsskrift (Fagfellevurdert) Published
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.

Emneord
Basement membrane, Coagulation, Hemocyte, Insect immunity, Nematodes, Recognition molecule, Thioester-containing proteins
HSV kategori
Forskningsprogram
molekylärbiologi
Identifikatorer
urn:nbn:se:su:diva-102305 (URN)10.1159/000353734 (DOI)000331774900009 ()
Merknad

AuthorCount:9;

Tilgjengelig fra: 2014-04-03 Laget: 2014-03-31 Sist oppdatert: 2017-12-05bibliografisk kontrollert

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