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  • 1.
    Chotiwan, Nunya
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Willekens, Stefanie M. A.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Schexnaydre, Erin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hahn, Max
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mihai, Ionut Sebastian
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Zhang, Jianguo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ebel, Gregory D.
    Department of Microbiology, Immunology and Pathology, Colorado State University, CO, Fort Collins, United States.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Type I interferon shapes brain distribution and tropism of tick-borne flavivirus2023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 2007Article in journal (Refereed)
    Abstract [en]

    Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.

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  • 2.
    Dernstedt, Andy
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Leidig, Jana
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Holm, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Kerkman, Priscilla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mjösberg, Jenny
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 599647Article in journal (Refereed)
    Abstract [en]

    Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAF(lo) B cells. Consistent with this, a majority of light and dark zone GC B cells were DAF(lo) and susceptible to complement-dependent phagocytosis, as compared with DAF(hi) GC B cells. We could also show that the DAF(hi) GC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis.

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  • 3.
    Filcek, Kimberly
    et al.
    University of Maryland, Department of Microbial Pathogenesis.
    Vielfort, Katarina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Muraleedharan, Samada
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Valdivia, Raphael
    Duke University, Department of Molecular Genetics and Microbiology.
    Bavoil, Patrik
    University of Maryland, Department of Microbial Pathogenesis.
    Sixt, Barbara Susanne
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America.
    Insertional mutagenesis in the zoonotic pathogen Chlamydia caviae2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 11, article id e0224324Article in journal (Refereed)
    Abstract [en]

    The ability to introduce targeted genetic modifications in microbial genomes has revolutionized our ability to study the role and mode of action of individual bacterial virulence factors. Although the fastidious lifestyle of obligate intracellular bacterial pathogens poses a technical challenge to such manipulations, the last decade has produced significant advances in our ability to conduct molecular genetic analysis in Chlamydia trachomatis, a major bacterial agent of infertility and blindness. Similar approaches have not been established for the closely related veterinary Chlamydia spp., which cause significant economic damage, as well as rare but potentially life-threatening infections in humans. Here we demonstrate the feasibility of conducting site-specific mutagenesis for disrupting virulence genes in Ccaviae, an agent of guinea pig inclusion conjunctivitis that was recently identified as a zoonotic agent in cases of severe community-acquired pneumonia. Using this approach, we generated Ccaviae mutants deficient for the secreted effector proteins IncA and SinC. We demonstrate that Ccaviae IncA plays a role in mediating fusion of the bacteria-containing vacuoles inhabited by Ccaviae. Moreover, using a chicken embryo infection model, we provide first evidence for a role of SinC in Ccaviae virulence in vivo.

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  • 4. Haim-Vilmovsky, Liora
    et al.
    Henriksson, Johan
    EMBL-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
    Walker, Jennifer A.
    Miao, Zhichao
    Natan, Eviatar
    Kar, Gozde
    Clare, Simon
    Barlow, Jillian L.
    Charidemou, Evelina
    Mamanova, Lira
    Chen, Xi
    Proserpio, Valentina
    Pramanik, Jhuma
    Woodhouse, Steven
    Protasio, Anna V.
    Efremova, Mirjana
    Griffin, Julian L.
    Berriman, Matt
    Dougan, Gordon
    Fisher, Jasmin
    Marioni, John C.
    McKenzie, Andrew N. J.
    Teichmann, Sarah A.
    Mapping Rora expression in resting and activated CD4+ T cells2021In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 5, article id e0251233Article in journal (Refereed)
    Abstract [en]

    The transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells in general, but with an emphasis on Th2 cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4 + T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment. Copyright: © 2021 Haim-Vilmovsky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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  • 5.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    CRISPR screening in single cells2019In: Single cell method: sequencing and proteomics / [ed] Valentina Proserpio, Humana Press, 2019, , p. 12p. 395-406Chapter in book (Refereed)
    Abstract [en]

    The combination of single-cell RNA-seq and CRISPR allows for efficient interrogation of possibly any number of genes, only limited by the sequencing capability. Here we describe the current protocols for CRISPR screening in single cells, from cloning and virus production to generating sequencing data.

  • 6.
    Hildebrandt, Franziska
    et al.
    Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden.
    Mohammed, Mubasher
    Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden.
    Dziedziech, Alexis
    Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden; Department of Global Health, Institut Pasteur, Paris, France; Department of Global Health, Institut Pasteur, Paris, France; Department of Cell and Molecular Biology, Biomedical Center (BMC), Uppsala University, Uppsala, Sweden.
    Bhandage, Amol K.
    Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden; Department of Global Health, Institut Pasteur, Paris, France; Department of Cell and Molecular Biology, Biomedical Center (BMC), Uppsala University, Uppsala, Sweden.
    Divne, Anna-Maria
    Microbial Single Cell Genomics Facility, SciLifeLab, Biomedical Center (BMC) Uppsala University, Uppsala, Sweden.
    Barrenäs, Fredrik
    Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden.
    Barragan, Antonio
    Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ankarklev, Johan
    Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden; Microbial Single Cell Genomics Facility, SciLifeLab, Biomedical Center (BMC) Uppsala University, Uppsala, Sweden.
    scDual-Seq of Toxoplasma gondii-infected mouse BMDCs reveals heterogeneity and differential infection dynamics2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1224591Article in journal (Refereed)
    Abstract [en]

    Dendritic cells and macrophages are integral parts of the innate immune system and gatekeepers against infection. The protozoan pathogen, Toxoplasma gondii, is known to hijack host immune cells and modulate their immune response, making it a compelling model to study host-pathogen interactions. Here we utilize single cell Dual RNA-seq to parse out heterogeneous transcription of mouse bone marrow-derived dendritic cells (BMDCs) infected with two distinct genotypes of T. gondii parasites, over multiple time points post infection. We show that the BMDCs elicit differential responses towards T. gondii infection and that the two parasite lineages distinctly manipulate subpopulations of infected BMDCs. Co-expression networks define host and parasite genes, with implications for modulation of host immunity. Integrative analysis validates previously established immune pathways and additionally, suggests novel candidate genes involved in host-pathogen interactions. Altogether, this study provides a comprehensive resource for characterizing host-pathogen interplay at high-resolution.

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  • 7.
    Jafari, Shadi
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Yan, Hua
    Department of Biology, University of Florida, FL, Gainesville, United States.
    Alenius, Mattias
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Stress and odorant receptor feedback during a critical period after hatching regulates olfactory sensory neuron differentiation in Drosophila2021In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 19, no 4, article id e3001101Article in journal (Refereed)
    Abstract [en]

    Here, we reveal that the regulation of Drosophila odorant receptor (OR) expression during the pupal stage is permissive and imprecise. We found that directly after hatching an OR feedback mechanism both directs and refines OR expression. We demonstrate that, as in mice, dLsd1 and Su(var)3-9 balance heterochromatin formation to direct OR expression. We show that the expressed OR induces dLsd1 and Su(var)3-9 expression, linking OR level and possibly function to OR expression. OR expression refinement shows a restricted duration, suggesting that a gene regulatory critical period brings olfactory sensory neuron differentiation to an end. Consistent with a change in differentiation, stress during the critical period represses dLsd1 and Su(var)3-9 expression and makes the early permissive OR expression permanent. This induced permissive gene regulatory state makes OR expression resilient to stress later in life. Hence, during a critical period OR feedback, similar to in mouse OR selection, defines adult OR expression in Drosophila.

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  • 8.
    Lu, Qiongxuan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Vladareanu, Ioana
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Zhao, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Chen, Changchun
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    IL-17 undermines longevity and stress tolerance by inhibiting a protective transcriptional networkManuscript (preprint) (Other academic)
  • 9.
    Mihai, Ionut Sebastian
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Chafle, Sarang
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Representing and extracting knowledge from single-cell data2023In: Biophysical Reviews, ISSN 1867-2450Article, review/survey (Refereed)
    Abstract [en]

    Single-cell analysis is currently one of the most high-resolution techniques to study biology. The large complex datasets that have been generated have spurred numerous developments in computational biology, in particular the use of advanced statistics and machine learning. This review attempts to explain the deeper theoretical concepts that underpin current state-of-the-art analysis methods. Single-cell analysis is covered from cell, through instruments, to current and upcoming models. The aim of this review is to spread concepts which are not yet in common use, especially from topology and generative processes, and how new statistical models can be developed to capture more of biology. This opens epistemological questions regarding our ontology and models, and some pointers will be given to how natural language processing (NLP) may help overcome our cognitive limitations for understanding single-cell data.

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  • 10.
    Mihai, Ionut Sebastian
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Das, Debojyoti
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Maršalkaite, Gabija
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meta-analysis of gene popularity: Less than half of gene citations stem from gene regulatory networks2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 2, p. 1-13, article id 319Article in journal (Refereed)
    Abstract [en]

    The reasons for selecting a gene for further study might vary from historical momentum to funding availability, thus leading to unequal attention distribution among all genes. However, certain biological features tend to be overlooked in evaluating a gene’s popularity. Here we present a meta-analysis of the reasons why different genes have been studied and to what extent, with a focus on the gene-specific biological features. From unbiased datasets we can define biological properties of genes that reasonably may affect their perceived importance. We make use of both linear and nonlinear computational approaches for estimating gene popularity to then compare their relative importance. We find that roughly 25% of the studies are the result of a historical positive feedback, which we may think of as social reinforcement. Of the remaining features, gene family membership is the most indicative followed by disease relevance and finally regulatory pathway association. Disease relevance has been an important driver until the 1990s, after which the focus shifted to exploring every single gene. We also present a resource that allows one to study the impact of reinforcement, which may guide our research toward genes that have not yet received proportional attention.

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  • 11.
    Mohammed, Mubasher
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Dziedziech, Alexis
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Sekar, Vaishnovi
    Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Ernest, Medard
    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Rockville, United States.
    Alves E Silva, Thiago Luiz
    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Rockville, United States.
    Balan, Balu
    Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, VIC, Melbourne, Australia; Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, VIC, Parkville, Australia.
    Emami, S. Noushin
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Biryukova, Inna
    Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Friedländer, Marc R.
    Science for Life Laboratory, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Jex, Aaron
    Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, VIC, Melbourne, Australia; Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, VIC, Parkville, Australia.
    Jacobs-Lorena, Marcelo
    Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, MD, Baltimore, United States.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vega-Rodriguez, Joel
    Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Rockville, United States.
    Ankarklev, Johan
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Microbial Single Cell Genomics, Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Single-cell transcriptomics to define Plasmodium falciparum stage transition in the mosquito midgut2023In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 11, no 2Article in journal (Refereed)
    Abstract [en]

    Malaria inflicts the highest rate of morbidity and mortality among the vector-borne diseases. The dramatic bottleneck of parasite numbers that occurs in the gut of the obligatory mosquito vector provides a promising target for novel control strategies. Using single-cell transcriptomics, we analyzed Plasmodium falciparum development in the mosquito gut, from unfertilized female gametes through the first 20 h after blood feeding, including the zygote and ookinete stages. This study revealed the temporal gene expression of the ApiAP2 family of transcription factors and of parasite stress genes in response to the harsh environment of the mosquito midgut. Further, employing structural protein prediction analyses, we found several upregulated genes predicted to encode intrinsically disordered proteins (IDPs), a category of proteins known for their importance in regulation of transcription, translation, and protein-protein interactions. IDPs are known for their antigenic properties and may serve as suitable targets for antibody- or peptide-based transmission suppression strategies. In total, this study uncovers the P. falciparum transcriptome from early to late parasite development in the mosquito midgut, inside its natural vector, which provides an important resource for future malaria transmission-blocking initiatives. IMPORTANCE The malaria parasite Plasmodium falciparum causes more than half a million deaths per year. The current treatment regimen targets the symptom-causing blood stage inside the human host. However, recent incentives in the field call for novel interventions to block parasite transmission from humans to the mosquito vector. Therefore, we need to better understand the parasite biology during its development inside the mosquito, including a deeper understanding of the expression of genes controlling parasite progression during these stages. Here, we have generated single-cell transcriptome data, covering P. falciparum’s development, from gamete to ookinete inside the mosquito midgut, uncovering previously untapped parasite biology, including a repertoire of novel biomarkers to be explored in future transmission-blocking efforts. We anticipate that our study provides an important resource, which can be further explored to improve our understanding of the parasite biology as well as aid in guiding future malaria intervention strategies.

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  • 12.
    Pu, Longjun
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Wang, Jing
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lu, Qiongxuan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nilsson, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Philbrook, Alison
    Department of Biology, Brandeis University, Waltham, USA.
    Pandey, Anjali
    Department of Biology, Brandeis University, Waltham, USA.
    Zhao, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    van Schendel, Robin
    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    Koh, Alan
    MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
    Peres, Tanara V.
    MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
    Hashi, Weheliye H.
    MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
    Myint, Si Lhyam
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Brown, Andre
    MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
    Tijsterman, Marcel
    Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    Sengupta, Piali
    Department of Biology, Brandeis University, Waltham, USA.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Chen, Changchun
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in  C. elegans2023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, article id 8410Article in journal (Refereed)
    Abstract [en]

    G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.

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  • 13.
    Rosendal, Ebba
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindqvist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Chotiwan, Nunya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Transcriptional response to flavivirus infection in neurons, astrocytes and microglia in vivo and in vitroManuscript (preprint) (Other academic)
  • 14.
    Rosendal, Ebba
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Mihai, Ionut Sebastian
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). National Clinical Research School in Chronic Inflammatory Diseases (NCRSCID), Karolinska Institutet, Solna, Sweden.
    Becker, Miriam
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between The Medical School Hannover, The Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Das, Debojyoti
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Persson, B. David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Swedish National Veterinary Institute (SVA), Uppsala, Sweden.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
    Gröning, Remigius
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Corporate Research, Umeå, Sweden.
    Forsell, Mattias
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ankarklev, Johan
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Microbial Single Cell Genomics Facility, SciLifeLab, Biomedical Center (BMC) Uppsala University, Uppsala, Sweden.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections2022In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 3, article id e00892-22Article in journal (Refereed)
    Abstract [en]

    The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19.

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  • 15.
    Schoutrop, Esther
    et al.
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Poiret, Thomas
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    El-Serafi, Ibrahim
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Basic Medical Sciences Department, College of Medicine, Ajman University, Ajman, United Arab Emirates; Department of Biochemistry, Faculty of Medicine, Port-Said University, Egypt.
    Zhao, Ying
    Experimental Cancer Medicine, Division of Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Clinical Research Center and Center of Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    He, Rui
    Experimental Cancer Medicine, Division of Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Clinical Research Center and Center of Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Moter, Alina
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hassan, Moustapha
    Experimental Cancer Medicine, Division of Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Clinical Research Center and Center of Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Magalhaes, Isabelle
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Mattsson, Jonas
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Gloria and Seymour Epstein Chair in Cell Therapy and Transplantation, Princess Margaret Cancer Centre and University of Toronto, Princess Margaret Cancer Centre, University Health Network, ON, Toronto, Canada.
    Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models2023In: Journal for ImmunoTherapy of Cancer, E-ISSN 2051-1426, Vol. 11, no 2, article id e005691Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Limited persistence of functional CAR T cells in the immunosuppressive solid tumor microenvironment remains a major hurdle in the successful translation of CAR T cell therapy to treat solid tumors. Fine-tuning of CAR T cell activation by mutating CD3ζ chain immunoreceptor tyrosine-based activation motifs (ITAMs) in CD19-CAR T cells (containing the CD28 costimulatory domain) has proven to extend functional CAR T cell persistence in preclinical models of B cell malignancies.

    METHODS: In this study, two conventional second-generation MSLN-CAR T cell constructs encoding for either a CD28 co-stimulatory (M28z) or 4-1BB costimulatory (MBBz) domain and a novel mesothelin (MSLN)-directed CAR T cell construct encoding for the CD28 costimulatory domain and CD3ζ chain containing a single ITAM (M1xx) were evaluated using in vitro and in vivo preclinical models of ovarian cancer. Two ovarian cancer cell lines and two orthotopic models of ovarian cancer in NSG mice were used: SKOV-3 cells inoculated through microsurgery in the ovary and to mimic a disseminated model of advanced ovarian cancer, OVCAR-4 cells injected intraperitoneally. MSLN-CAR T cell treatment efficacy was evaluated by survival analysis and the characterization and quantification of the different MSLN-CAR T cells were performed by flow cytometry, quantitative PCR and gene expression analysis.

    RESULTS: M1xx CAR T cells elicited superior antitumor potency and persistence, as compared with the conventional second generation M28z and MBBz CAR T cells. Ex vivo M28z and MBBz CAR T cells displayed a more exhausted phenotype than M1xx CAR T cells as determined by co-expression of PD-1, LAG-3 and TIM-3. Furthermore, M1xx CAR T cells showed superior ex vivo IFNy, TNF and GzB production and were characterized by a self-renewal gene signature.

    CONCLUSIONS: Altogether, our study demonstrates the enhanced therapeutic potential of MSLN-CAR T cells expressing a mutated CD3ζ chain containing a single ITAM for the treatment of ovarian cancer. CAR T cells armored with calibrated activation potential may improve the clinical responses in solid tumors.

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