umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Hultmark, Dan
Alternative names
Publications (10 of 73) Show all publications
Yang, H. & Hultmark, D. (2017). Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism. Scientific Reports, 7, Article ID 15713.
Open this publication in new window or tab >>Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15713Article in journal (Refereed) Published
Abstract [en]

We recently found that JAK/STAT signaling in skeletal muscles is important for the immune response of Drosophila larvae against wasp infection, but it was not clear how muscles could affect the immune response. Here we show that insulin signaling is required in muscles, but not in fat body or hemocytes, during larval development for an efficient encapsulation response and for the formation of lamellocytes. This effect requires TOR signaling. We show that muscle tissue affects the immune response by acting as a master regulator of carbohydrate metabolism in the infected animal, via JAK/STAT and insulin signaling in the muscles, and that there is indirect positive feedback between JAK/STAT and insulin signaling in the muscles. Specifically, stimulation of JAK/STAT signaling in the muscles can rescue the deficient immune response when insulin signaling is suppressed. Our results shed new light on the interaction between metabolism, immunity, and tissue communication.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
Keywords
Drosophila, innate immunity, hemocytes, parasitoid wasps, Jak/Stat signaling, insulin, glycogen
National Category
Immunology Cell and Molecular Biology
Research subject
Molecular Immunology
Identifiers
urn:nbn:se:umu:diva-142164 (URN)10.1038/s41598-017-15940-2 (DOI)000415282900028 ()29146985 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsAcademy of Finland
Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2018-06-09Bibliographically approved
Doublet, V., Poeschl, Y., Gogol-Doering, A., Alaux, C., Annoscia, D., Aurori, C., . . . Grozinger, C. M. (2017). Unity in defence: honeybee workers exhibit conserved molecular responses to diverse pathogens. BMC Genomics, 18, Article ID 207.
Open this publication in new window or tab >>Unity in defence: honeybee workers exhibit conserved molecular responses to diverse pathogens
Show others...
2017 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 207Article in journal (Refereed) Published
Abstract [en]

Background: Organisms typically face infection by diverse pathogens, and hosts are thought to have developed specific responses to each type of pathogen they encounter. The advent of transcriptomics now makes it possible to test this hypothesis and compare host gene expression responses to multiple pathogens at a genome-wide scale. Here, we performed a meta-analysis of multiple published and new transcriptomes using a newly developed bioinformatics approach that filters genes based on their expression profile across datasets. Thereby, we identified common and unique molecular responses of a model host species, the honey bee (Apis mellifera), to its major pathogens and parasites: the Microsporidia Nosema apis and Nosema ceranae, RNA viruses, and the ectoparasitic mite Varroa destructor, which transmits viruses.

Results: We identified a common suite of genes and conserved molecular pathways that respond to all investigated pathogens, a result that suggests a commonality in response mechanisms to diverse pathogens. We found that genes differentially expressed after infection exhibit a higher evolutionary rate than non-differentially expressed genes. Using our new bioinformatics approach, we unveiled additional pathogen-specific responses of honey bees; we found that apoptosis appeared to be an important response following microsporidian infection, while genes from the immune signalling pathways, Toll and Imd, were differentially expressed after Varroa/virus infection. Finally, we applied our bioinformatics approach and generated a gene co-expression network to identify highly connected (hub) genes that may represent important mediators and regulators of anti-pathogen responses.

Conclusions: Our meta-analysis generated a comprehensive overview of the host metabolic and other biological processes that mediate interactions between insects and their pathogens. We identified key host genes and pathways that respond to phylogenetically diverse pathogens, representing an important source for future functional studies as well as offering new routes to identify or generate pathogen resilient honey bee stocks. The statistical and bioinformatics approaches that were developed for this study are broadly applicable to synthesize information across transcriptomic datasets. These approaches will likely have utility in addressing a variety of biological questions.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keywords
Apis mellifera, Nosema, Varroa destructor, DWV, IAPV, RNA virus, Meta-analysis, Transcriptomics, Co-expression network, Immunity
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-133518 (URN)10.1186/s12864-017-3597-6 (DOI)000395589000001 ()28249569 (PubMedID)
Note

Errata BMC Genomics 2017 18:256 https://doi.org/10.1186/s12864-017-3624-7

Available from: 2017-05-20 Created: 2017-05-20 Last updated: 2018-06-09Bibliographically approved
Ekström, J.-O. & Hultmark, D. (2016). A Novel Strategy for Live Detection of Viral Infection in Drosophila melanogaster. Scientific Reports, 6, Article ID 26250.
Open this publication in new window or tab >>A Novel Strategy for Live Detection of Viral Infection in Drosophila melanogaster
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 26250Article in journal (Refereed) Published
Abstract [en]

We have created a transgenic reporter for virus infection, and used it to study Nora virus infection in Drosophila melanogaster. The transgenic construct, Munin, expresses the yeast transcription factor Gal4, tethered to a transmembrane anchor via a linker that can be cleaved by a viral protease. In infected cells, liberated Gal4 will then transcribe any gene that is linked to a promoter with a UAS motif, the target for Gal4 transcription. For instance, infected cells will glow red in the offspring of a cross between the Munin stock and flies with a UAS-RFPnls transgene (expressing a red fluorescent protein). In such flies we show that after natural infection, via the faecal-oral route, 5-15% of the midgut cells are infected, but there is little if any infection elsewhere. By contrast, we can detect infection in many other tissues after injection of virus into the body cavity. The same principle could be applied for other viruses and it could also be used to express or suppress any gene of interest in infected cells.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-123371 (URN)10.1038/srep26250 (DOI)000375996600001 ()27189868 (PubMedID)
Available from: 2016-07-04 Created: 2016-07-01 Last updated: 2018-06-07Bibliographically approved
Schmid, M. R., Anderl, I., Vo, H. T. M., Valanne, S., Yang, H., Kronhamn, J., . . . Hultmark, D. (2016). Genetic Screen in Drosophila Larvae Links ird1 Function to Toll Signaling in the Fat Body and Hemocyte Motility. PLoS ONE, 11(7), Article ID e0159473.
Open this publication in new window or tab >>Genetic Screen in Drosophila Larvae Links ird1 Function to Toll Signaling in the Fat Body and Hemocyte Motility
Show others...
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159473Article in journal (Refereed) Published
Abstract [en]

To understand how Toll signaling controls the activation of a cellular immune response in Drosophila blood cells (hemocytes), we carried out a genetic modifier screen, looking for deletions that suppress or enhance the mobilization of sessile hemocytes by the gain-of-function mutation Toll(10b) (Tl-10b). Here we describe the results from chromosome arm 3R, where five regions strongly suppressed this phenotype. We identified the specific genes immune response deficient 1 (ird1), headcase (hdc) and possibly Rab23 as suppressors, and we studied the role of ird1 in more detail. An ird1 null mutant and a mutant that truncates the N-terminal kinase domain of the encoded Ird1 protein affected the Tl-10b phenotype, unlike mutations that affect the C-terminal part of the protein. The ird1 null mutant suppressed mobilization of sessile hemocytes, but enhanced other Tl-10b hemocyte phenotypes, like the formation of melanotic nodules and the increased number of circulating hemocytes. ird1 mutants also had blood cell phenotypes on their own. They lacked crystal cells and showed aberrant formation of lamellocytes. ird1 mutant plasmatocytes had a reduced ability to spread on an artificial substrate by forming protrusions, which may explain why they did not go into circulation in response to Toll signaling. The effect of the ird1 mutation depended mainly on ird1 expression in hemocytes, but ird1-dependent effects in other tissues may contribute. Specifically, the Toll receptor was translocated from the cell membrane to intracellular vesicles in the fat body of the ird1 mutant, and Toll signaling was activated in that tissue, partially explaining the Tl-10b-like phenotype. As ird1 is otherwise known to control vesicular transport, we conclude that the vesicular transport system may be of particular importance during an immune response.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-126336 (URN)10.1371/journal.pone.0159473 (DOI)000381516100034 ()27467079 (PubMedID)
Available from: 2016-10-25 Created: 2016-10-03 Last updated: 2018-06-09Bibliographically approved
Yang, H. & Hultmark, D. (2016). Tissue communication in a systemic immune response of Drosophila.. Fly, 10(3), 115-122
Open this publication in new window or tab >>Tissue communication in a systemic immune response of Drosophila.
2016 (English)In: Fly, ISSN 1933-6942, Vol. 10, no 3, p. 115-122Article in journal (Refereed) Published
Abstract [en]

Several signaling pathways, including the JAK/STAT and Toll pathways, are known to activate blood cells (hemocytes) in Drosophila melanogaster larvae. They are believed to regulate the immune response against infections by parasitoid wasps, such as Leptopilina boulardi, but how these pathways control the hemocytes is not well understood. Here, we discuss the recent discovery that both muscles and fat body take an active part in this response. Parasitoid wasp infection induces Upd2 and Upd3 secretion from hemocytes, leading to JAK/STAT activation mainly in hemocytes and in skeletal muscles. JAK/STAT activation in muscles, but not in hemocytes, is required for an efficient encapsulation of wasp eggs. This suggests that Upd2 and Upd3 are important cytokines, coordinating different tissues for the cellular immune response in Drosophila. In the fat body, Toll signaling initiates a systemic response in which hemocytes are mobilized and activated hemocytes (lamellocytes) are generated. However, the contribution of Toll signaling to the defense against wasps is limited, probably because the wasps inject inhibitors that prevent the activation of the Toll pathway. In conclusion, parasite infection induces a systemic response in Drosophila larvae involving major organ systems and probably the physiology of the entire organism.

Place, publisher, year, edition, pages
Philadelphia: Taylor & Francis, 2016
Keywords
Drosophila, fat body, JAK, STAT, muscles, tissue communication, Toll
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-125879 (URN)10.1080/19336934.2016.1182269 (DOI)000381307600003 ()27116253 (PubMedID)
Available from: 2016-09-21 Created: 2016-09-21 Last updated: 2018-06-07Bibliographically approved
Anderl, I., Vesala, L., Ihalainen, T. O., Vanha-aho, L.-M., Andó, I., Rämet, M. & Hultmark, D. (2016). Transdifferentiation and Proliferation in Two Distinct Hemocyte Lineages in Drosophila melanogaster Larvae after Wasp Infection. PLoS Pathogens, 12(7), Article ID e1005746.
Open this publication in new window or tab >>Transdifferentiation and Proliferation in Two Distinct Hemocyte Lineages in Drosophila melanogaster Larvae after Wasp Infection
Show others...
2016 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 12, no 7, article id e1005746Article in journal (Refereed) Published
Abstract [en]

Cellular immune responses require the generation and recruitment of diverse blood cell types that recognize and kill pathogens. In Drosophila melanogaster larvae, immune-inducible lamellocytes participate in recognizing and killing parasitoid wasp eggs. However, the sequence of events required for lamellocyte generation remains controversial. To study the cellular immune system, we developed a flow cytometry approach using in vivo reporters for lamellocytes as well as for plasmatocytes, the main hemocyte type in healthy larvae. We found that two different blood cell lineages, the plasmatocyte and lamellocyte lineages, contribute to the generation of lamellocytes in a demand-adapted hematopoietic process. Plasmatocytes transdifferentiate into lamellocyte-like cells in situ directly on the wasp egg. In parallel, a novel population of infection-induced cells, which we named lamelloblasts, appears in the circulation. Lamelloblasts proliferate vigorously and develop into the major class of circulating lamellocytes. Our data indicate that lamellocyte differentiation upon wasp parasitism is a plastic and dynamic process. Flow cytometry with in vivo hemocyte reporters can be used to study this phenomenon in detail.

Place, publisher, year, edition, pages
Public library science, 2016
National Category
Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-126760 (URN)10.1371/journal.ppat.1005746 (DOI)000383366400030 ()
Available from: 2016-10-18 Created: 2016-10-13 Last updated: 2018-06-09Bibliographically approved
Sadanandan, S. A., Ekström, J.-O., Jonna, V. R., Hofer, A. & Hultmark, D. (2016). VP3 is crucial for the stability of Nora virus virions. Virus Research, 223, 20-27
Open this publication in new window or tab >>VP3 is crucial for the stability of Nora virus virions
Show others...
2016 (English)In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 223, p. 20-27Article in journal (Refereed) Published
Abstract [en]

Nora virus is an enteric virus that causes persistent, non-pathological infection in Drosophila melanogaster. It replicates in the fly gut and is transmitted via the fecal-oral route. Nora virus has a single-stranded positive-sense RNA genome, which is translated in four open reading frames. Reading frame three encodes the VP3 protein, the structure and function of which we have investigated in this work. We have shown that VP3 is a trimer that has an α-helical secondary structure, with a functionally important coiled-coil domain. In order to identify the role of VP3 in the Nora virus life cycle, we constructed VP3-mutants using the cDNA clone of the virus. Our results show that VP3 does not have a role in the actual assembly of the virus particles, but virions that lack VP3 or harbor VP3 with a disrupted coiled coil domain are incapable of transmission via the fecal-oral route. Removing the region downstream of the putative coiled coil appears to have an effect on the fitness of the virus but does not hamper its replication or transmission. We also found that the VP3 protein and particularly the coiled coil domain are crucial for the stability of Nora virus virions when exposed to heat or proteases. Hence, we propose that VP3 is imperative to Nora virus virions as it confers stability to the viral capsid.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
RNA viruses, Nora virus, Capsid stability, Virus biology
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-124102 (URN)10.1016/j.virusres.2016.06.011 (DOI)000383826600003 ()27329665 (PubMedID)
Available from: 2016-07-17 Created: 2016-07-17 Last updated: 2018-06-07Bibliographically approved
Vanha-aho, L.-M., Anderl, I., Vesala, L., Hultmark, D., Valanne, S. & Rämet, M. (2015). Edin expression in the fat body is required in the defense against parasitic wasps in Drosophila melanogaster. PLoS Pathogens, 11(5), Article ID e1004895.
Open this publication in new window or tab >>Edin expression in the fat body is required in the defense against parasitic wasps in Drosophila melanogaster
Show others...
2015 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 5, article id e1004895Article in journal (Refereed) Published
Abstract [en]

The cellular immune response against parasitoid wasps in Drosophila involves the activation, mobilization, proliferation and differentiation of different blood cell types. Here, we have assessed the role of Edin (elevated during infection) in the immune response against the parasitoid wasp Leptopilina boulardi in Drosophila melanogaster larvae. The expression of edin was induced within hours after a wasp infection in larval fat bodies. Using tissue-specific RNAi, we show that Edin is an important determinant of the encapsulation response. Although edin expression in the fat body was required for the larvae to mount a normal encapsulation response, it was dispensable in hemocytes. Edin expression in the fat body was not required for lamellocyte differentiation, but it was needed for the increase in plasmatocyte numbers and for the release of sessile hemocytes into the hemolymph. We conclude that edin expression in the fat body affects the outcome of a wasp infection by regulating the increase of plasmatocyte numbers and the mobilization of sessile hemocytes in Drosophila larvae.

Place, publisher, year, edition, pages
Public library science, 2015
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-105266 (URN)10.1371/journal.ppat.1004895 (DOI)000355269300039 ()25965263 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2018-06-07Bibliographically approved
Yang, H., Kronhamn, J., Ekstrom, J.-O., Korkut, G. G. & Hultmark, D. (2015). JAK/STAT signaling in Drosophila muscles controls the cellular immune response against parasitoid infection. EMBO Reports, 16(12), 1664-1672
Open this publication in new window or tab >>JAK/STAT signaling in Drosophila muscles controls the cellular immune response against parasitoid infection
Show others...
2015 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 16, no 12, p. 1664-1672Article in journal (Refereed) Published
Abstract [en]

The role of JAK/STAT signaling in the cellular immune response of Drosophila is not well understood. Here, we show that parasitoid wasp infection activates JAK/STAT signaling in somatic muscles of the Drosophila larva, triggered by secretion of the cytokines Upd2 and Upd3 from circulating hemocytes. Deletion of upd2 or upd3, but not the related os (upd1) gene, reduced the cellular immune response, and suppression of the JAK/STAT pathway in muscle cells reduced the encapsulation of wasp eggs and the number of circulating lamellocyte effector cells. These results suggest that JAK/STAT signaling in muscles participates in a systemic immune defense against wasp infection.

Keywords
Drosophila, innate immunity, JAK/STAT signaling, muscles
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-116103 (URN)10.15252/embr.201540277 (DOI)000368237100012 ()26412855 (PubMedID)
Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2018-06-07Bibliographically approved
Anderl, I. & Hultmark, D. (2015). New ways to make a blood cell. eLIFE, 4, Article ID e06877.
Open this publication in new window or tab >>New ways to make a blood cell
2015 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e06877Article in journal, Editorial material (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-102220 (URN)10.7554/eLife.06877 (DOI)000351865000003 ()
Available from: 2015-05-10 Created: 2015-04-22 Last updated: 2018-06-07Bibliographically approved
Organisations

Search in DiVA

Show all publications