Publications by authors named "Andreas Bergthaler"

63 Publications

The serine's call: Suppressing interferon responses.

Cell Metab 2021 May;33(5):849-850

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. Electronic address:

Cellular metabolism and immune function are closely linked. In this issue of Cell Metabolism, Shen et al. (2021) identify serine metabolism as a central integration hub of cellular metabolism, antiviral immunity, and epigenetic regulation.
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http://dx.doi.org/10.1016/j.cmet.2021.04.012DOI Listing
May 2021

Slow viral propagation during initial phase of infection leads to viral persistence in mice.

Commun Biol 2021 Apr 29;4(1):508. Epub 2021 Apr 29.

Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

Immune evasion of pathogens can modify the course of infection and impact viral persistence and pathology. Here, using different strains of the lymphocytic choriomeningitis virus (LCMV) model system, we show that slower propagation results in limited type I interferon (IFN-I) production and viral persistence. Specifically, cells infected with LCMV-Docile exhibited reduced viral replication when compared to LCMV-WE and as a consequence, infection with LCMV-Docile resulted in reduced activation of bone marrow derived dendritic cells (BMDCs) and IFN-I production in vitro in comparison with LCMV-WE. In vivo, we observed a reduction of IFN-I, T cell exhaustion and viral persistence following infection of LCMV-Docile but not LCMV-WE. Mechanistically, block of intracellular protein transport uncovered reduced propagation of LCMV-Docile when compared to LCMV-WE. This reduced propagation was critical in blunting the activation of the innate and adaptive immune system. When mice were simultaneously infected with LCMV-Docile and LCMV-WE, immune function was restored and IFN-I production, T cell effector functions as well as viral loads were similar to that of mice infected with LCMV-WE alone. Taken together, this study suggests that reduced viral propagation can result in immune evasion and viral persistence.
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http://dx.doi.org/10.1038/s42003-021-02028-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084999PMC
April 2021

Complex Interplay Between MAZR and Runx3 Regulates the Generation of Cytotoxic T Lymphocyte and Memory T Cells.

Front Immunol 2021 17;12:535039. Epub 2021 Mar 17.

Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8 T cell differentiation. In contrast to the essential role of Runx3 for CTL effector function, the deletion of MAZR had a mild effect on the generation of CTLs . However, a transcriptome analysis demonstrated that the combined deletion of MAZR and Runx3 resulted in much more widespread downregulation of CTL signature genes compared to single Runx3 deletion, indicating that MAZR partially compensates for loss of Runx3 in CTLs. Moreover, in line with the findings made , the analysis of CTL responses to LCMV infection revealed that MAZR and Runx3 cooperatively regulate the expression of CD8α, Granzyme B and perforin . Interestingly, while memory T cell differentiation is severely impaired in Runx3-deficient mice, the deletion of MAZR leads to an enlargement of the long-lived memory subset and also partially restored the differentiation defect caused by loss of Runx3. This indicates distinct functions of MAZR and Runx3 in the generation of memory T cell subsets, which is in contrast to their cooperative roles in CTLs. Together, our study demonstrates complex interplay between MAZR and Runx3 during CTL and memory T cell differentiation, and provides further insight into the molecular mechanisms underlying the establishment of CTL and memory T cell pools.
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http://dx.doi.org/10.3389/fimmu.2021.535039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010151PMC
March 2021

SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8 T cell responses.

Sci Immunol 2021 03;6(57)

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

CD8 T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8 T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8 T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8 T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8 T cell surveillance through point mutations in MHC-I-restricted viral epitopes.
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http://dx.doi.org/10.1126/sciimmunol.abg6461DOI Listing
March 2021

Dynamics of CD4 T Cell and Antibody Responses in COVID-19 Patients With Different Disease Severity.

Front Med (Lausanne) 2020 11;7:592629. Epub 2020 Nov 11.

Center for Virology, Medical University of Vienna, Vienna, Austria.

Disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from mild illness to severe respiratory disease and death. In this study, we determined the kinetics of viral loads, antibody responses (IgM, IgG, neutralization) and SARS-CoV-2-specific CD4 T cells by quantifying these parameters in 435 serial respiratory and blood samples collected from a cohort of 29 COVID-19 patients with either moderate or severe disease during the whole period of hospitalization or until death. Remarkably, there was no significant difference in the kinetics and plateau levels of neutralizing antibodies among the groups with different disease severity. In contrast, the dynamics of specific CD4 T cell responses differed considerably, but all patients with moderate or severe disease developed robust SARS-CoV-2-specific responses. Of note, none of the patients had detectable cross-reactive CD4 T cells in the first week after symptom onset, which have been described in 20-50% of unexposed individuals. Our data thus provide novel insights into the kinetics of antibody and CD4 T cell responses as well as viral loads that are key to understanding the role of adaptive immunity in combating the virus during acute infection and provide leads for the timing of immune therapies for COVID-19.
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http://dx.doi.org/10.3389/fmed.2020.592629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686651PMC
November 2020

Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import.

Nat Commun 2020 12 1;11(1):6145. Epub 2020 Dec 1.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

About a thousand genes in the human genome encode for membrane transporters. Among these, several solute carrier proteins (SLCs), representing the largest group of transporters, are still orphan and lack functional characterization. We reasoned that assessing genetic interactions among SLCs may be an efficient way to obtain functional information allowing their deorphanization. Here we describe a network of strong genetic interactions indicating a contribution to mitochondrial respiration and redox metabolism for SLC25A51/MCART1, an uncharacterized member of the SLC25 family of transporters. Through a combination of metabolomics, genomics and genetics approaches, we demonstrate a role for SLC25A51 as enabler of mitochondrial import of NAD, showcasing the potential of genetic interaction-driven functional gene deorphanization.
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http://dx.doi.org/10.1038/s41467-020-19871-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708531PMC
December 2020

Genomic epidemiology of superspreading events in Austria reveals mutational dynamics and transmission properties of SARS-CoV-2.

Sci Transl Med 2020 12 23;12(573). Epub 2020 Nov 23.

Department of Theoretical Chemistry, University of Vienna, 1090 Vienna, Austria.

Superspreading events shaped the coronavirus disease 2019 (COVID-19) pandemic, and their rapid identification and containment are essential for disease control. Here, we provide a national-scale analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) superspreading during the first wave of infections in Austria, a country that played a major role in initial virus transmissions in Europe. Capitalizing on Austria's well-developed epidemiological surveillance system, we identified major SARS-CoV-2 clusters during the first wave of infections and performed deep whole-genome sequencing of more than 500 virus samples. Phylogenetic-epidemiological analysis enabled the reconstruction of superspreading events and charts a map of tourism-related viral spread originating from Austria in spring 2020. Moreover, we exploited epidemiologically well-defined clusters to quantify SARS-CoV-2 mutational dynamics, including the observation of low-frequency mutations that progressed to fixation within the infection chain. Time-resolved virus sequencing unveiled viral mutation dynamics within individuals with COVID-19, and epidemiologically validated infector-infectee pairs enabled us to determine an average transmission bottleneck size of 10 SARS-CoV-2 particles. In conclusion, this study illustrates the power of combining epidemiological analysis with deep viral genome sequencing to unravel the spread of SARS-CoV-2 and to gain fundamental insights into mutational dynamics and transmission properties.
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http://dx.doi.org/10.1126/scitranslmed.abe2555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857414PMC
December 2020

The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages.

Nat Metab 2020 12 16;2(12):1427-1442. Epub 2020 Nov 16.

Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria.

Adipose tissue macrophages (ATMs) display tremendous heterogeneity depending on signals in their local microenvironment and contribute to the pathogenesis of obesity. The phosphoinositide 3-kinase (PI3K) signalling pathway, antagonized by the phosphatase and tensin homologue (PTEN), is important for metabolic responses to obesity. We hypothesized that fluctuations in macrophage-intrinsic PI3K activity via PTEN could alter the trajectory of metabolic disease by driving distinct ATM populations. Using mice harbouring macrophage-specific PTEN deletion or bone marrow chimeras carrying additional PTEN copies, we demonstrate that sustained PI3K activity in macrophages preserves metabolic health in obesity by preventing lipotoxicity. Myeloid PI3K signalling promotes a beneficial ATM population characterized by lipid uptake, catabolism and high expression of the scavenger macrophage receptor with collagenous structure (MARCO). Dual MARCO and myeloid PTEN deficiencies prevent the generation of lipid-buffering ATMs, reversing the beneficial actions of elevated myeloid PI3K activity in metabolic disease. Thus, macrophage-intrinsic PI3K signalling boosts metabolic health by driving ATM programmes associated with MARCO-dependent lipid uptake.
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http://dx.doi.org/10.1038/s42255-020-00311-5DOI Listing
December 2020

Human recombinant soluble ACE2 in severe COVID-19.

Lancet Respir Med 2020 11 24;8(11):1154-1158. Epub 2020 Sep 24.

Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada; Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.

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http://dx.doi.org/10.1016/S2213-2600(20)30418-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515587PMC
November 2020

Hepatocyte-intrinsic type I interferon signaling reprograms metabolism and reveals a novel compensatory mechanism of the tryptophan-kynurenine pathway in viral hepatitis.

PLoS Pathog 2020 10 12;16(10):e1008973. Epub 2020 Oct 12.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria.

The liver is a central regulator of metabolic homeostasis and serum metabolite levels. Hepatocytes are the functional units of the liver parenchyma and not only responsible for turnover of biomolecules but also act as central immune signaling platforms. Hepatotropic viruses infect liver tissue, resulting in inflammatory responses, tissue damage and hepatitis. Combining well-established in vitro and in vivo model systems with transcriptomic analyses, we show that type I interferon signaling initiates a robust antiviral immune response in hepatocytes. Strikingly, we also identify IFN-I as both, sufficient and necessary, to induce wide-spread metabolic reprogramming in hepatocytes. IFN-I specifically rewired tryptophan metabolism and induced hepatic tryptophan oxidation to kynurenine via Tdo2, correlating with altered concentrations of serum metabolites upon viral infection. Infected Tdo2-deficient animals displayed elevated serum levels of tryptophan and, unexpectedly, also vast increases in the downstream immune-suppressive metabolite kynurenine. Thus, Tdo2-deficiency did not result in altered serum homeostasis of the tryptophan to kynurenine ratio during infection, which seemed to be independent of hepatocyte-intrinsic compensation via the IDO-axis. These data highlight that inflammation-induced reprogramming of systemic tryptophan metabolism is tightly regulated in viral hepatitis.
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http://dx.doi.org/10.1371/journal.ppat.1008973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580883PMC
October 2020

Severe COVID-19 is associated with elevated serum IgA and antiphospholipid IgA-antibodies.

Clin Infect Dis 2020 Sep 30. Epub 2020 Sep 30.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Background: Severe coronavirus disease 2019 (COVID-19) frequently entails complications that bear similarities to autoimmune diseases. To date, there is little data on possible IgA-mediated autoimmune responses. Here, we aim to determine whether COVID-19 is associated with a vigorous total IgA response and if IgA antibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome (APS), our approach focused on antiphospholipid antibodies (aPL).

Methods: In this retrospective cohort study clinical data and aPL from 64 patients with COVID-19 were compared from three independent tertiary hospitals (one in Liechtenstein, two in Switzerland). Samples were collected from April 9 th to May 1 st, 2020.

Results: Clinical records of 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID) (41%), a discovery cohort with severe illness (sdCOVID) (22%) and a confirmation cohort with severe illness (scCOVID) (38%). Total IgA, IgG and aPL were measured with clinical diagnostic kits. Severe illness was significantly associated with increased total IgA (sdCOVID, P=0.01; scCOVID, p-value<0.001), but not total IgG. Among aPL, both cohorts with severe illness significantly correlated with elevated anti-Cardiolipin IgA (sdCOVID and scCOVID, p-value<0.001), anti-Cardiolipin IgM (sdCOVID, P=0.003; scCOVID, P<0.001), and anti-Beta2 Glycoprotein-1 IgA (sdCOVID and scCOVID, P<0.001). Systemic lupus erythematosus was excluded from all patients as a potential confounder.

Conclusions: Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response, possibly triggered in the bronchial mucosa, induces systemic autoimmunity.
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http://dx.doi.org/10.1093/cid/ciaa1496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543315PMC
September 2020

Systemic Immunometabolism: Challenges and Opportunities.

Immunity 2020 09;53(3):496-509

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria. Electronic address:

Over the past 10 years, the field of immunometabolism made great strides to unveil the crucial role of intracellular metabolism in regulating immune cell function. Emerging insights into how systemic inflammation and metabolism influence each other provide a critical additional dimension on the organismal level. Here, we discuss the concept of systemic immunometabolism and review the current understanding of the communication circuits that underlie the reciprocal impact of systemic inflammation and metabolism across organs in inflammatory and infectious diseases, as well as how these mechanisms apply to homeostasis. We present current challenges of systemic immunometabolic research, and in this context, highlight opportunities and put forward ideas to effectively explore organismal physiological complexity in both health and disease.
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http://dx.doi.org/10.1016/j.immuni.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491485PMC
September 2020

A crucial role for Jagunal homolog 1 in humoral immunity and antibody glycosylation in mice and humans.

J Exp Med 2021 Jan;218(1)

Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.

Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.
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http://dx.doi.org/10.1084/jem.20200559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953624PMC
January 2021

Emergence of coronavirus disease 2019 (COVID-19) in Austria.

Wien Klin Wochenschr 2020 Nov 20;132(21-22):645-652. Epub 2020 Aug 20.

Österreichische Agentur für Gesundheit und Ernährungssicherheit (AGES), Spargelfeldstr. 191, 1220, Vienna, Austria.

This is a report on the first identified cases of coronavirus disease 2019 (COVID-19) in Austria. The first documented case was a person who stayed in Kühtai, Tyrol, from 24 to 26 January 2020, and had been infected by a Chinese instructor in Starnberg (Germany) between 20 and 22 January. This counts as a German case since her diagnosis was eventually made in Munich (Germany) on 28 January. On 25 February, two cases imported from Italy were diagnosed in Innsbruck but again no secondary cases were identified in Austria. The first three infections of Austrian inhabitants were detected on 27 February in Vienna. The two resulting clusters finally included 6 (source of initial infection unknown) and 61 cases. Most likely, Italy was the source of the latter cluster. On 12 March the first fatal case of COVID-19 in Austria was reported, a 69-year-old Viennese who died in a Vienna hospital after returning from a cruise ship tour in Italy. On 6 March three autochthonously acquired cases were reported in the Tyrol, all related to the ski resort Ischgl. Of the first 14 Islandic COVID-19 cases infected in Ischgl, 11 had already returned to Iceland on 29 February. We consider that the incriminated barkeeper, who tested PCR positive on 7 March, was neither the primary case nor a superspreader. In our opinion, undetected transmission of SARS-CoV‑2 had been ongoing in Ischgl prior to the first laboratory confirmed cases. Our data also underline that the introduction of SARS-CoV‑2 into Austria was not one single event.
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http://dx.doi.org/10.1007/s00508-020-01723-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439636PMC
November 2020

Repression of the B cell identity factor Pax5 is not required for plasma cell development.

J Exp Med 2020 11;217(11)

Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.

B cell and plasma cell fates are controlled by different transcriptional networks, as exemplified by the mutually exclusive expression and cross-antagonism of the B cell identity factor Pax5 and the plasma cell regulator Blimp1. It has been postulated that repression of Pax5 by Blimp1 is essential for plasma cell development. Here, we challenged this hypothesis by analyzing the IghPax5/+ mouse, which expressed a Pax5 minigene from the immunoglobulin heavy-chain locus. Despite high Pax5 expression, plasma cells efficiently developed in young IghPax5/+ mice at steady state and upon immunization, while their number moderately declined in older mice. Although Pax5 significantly deregulated the plasma cell expression program, key plasma cell regulators were normally expressed in IghPax5/+ plasma cells. While IgM and IgA secretion by IghPax5/+ plasma cells was normal, IgG secretion was modestly decreased. Hence, Pax5 repression is not essential for robust plasma cell development and antibody secretion, although it is required for optimal IgG production and accumulation of long-lived plasma cells.
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http://dx.doi.org/10.1084/jem.20200147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596824PMC
November 2020

Immunometabolism pathways as the basis for innovative anti-viral strategies (INITIATE): A Marie Sklodowska-Curie innovative training network.

Virus Res 2020 10 28;287:198094. Epub 2020 Jul 28.

Istituto Pasteur Italia Cenci Bolognetti Foundation, 00161, Rome, Italy. Electronic address:

The past century has witnessed major advances in the control of many infectious diseases, yet outbreaks and epidemics caused by (re-) emerging RNA viruses continue to pose a global threat to human health. As illustrated by the global COVID19 pandemic, high healthcare costs, economic disruption and loss of productivity reinforce the unmet medical need to develop new antiviral strategies to combat not only the current pandemic but also future viral outbreaks. Pivotal for effective anti-viral defense is the innate immune system, a first line host response that senses and responds to virus infection. While molecular details of the innate immune response are well characterized, this research field is now being revolutionized with the recognition that cell metabolism has a major impact on the antiviral and inflammatory responses to virus infections. A detailed understanding of the role of metabolic regulation with respect to antiviral and inflammatory responses, together with knowledge of the strategies used by viruses to exploit immunometabolic pathways, will ultimately change our understanding and treatment of pathogenic viral diseases. INITIATE is a Marie Sklodowska-Curie Actions Innovative Training Network (MSCA-ITN), with the goal to train 15 early stage PhD researchers (ESRs) to become experts in antiviral immunometabolism (https://initiate-itn.eu/). To this end, INITIATE brings together a highly complementary international team of academic and corporate leaders from 7 European countries, with outstanding track records in the historically distinct research fields of virology, immunology and metabolism. The ESRs of INITIATE are trained in these interdisciplinary research fields through individual investigator-driven research projects, specialized scientific training events, workshops on academia-industry interactions, outreach & communication. INITIATE will deliver a new generation of creative and entrepreneurial researchers who will be able to face the inevitable future challenges in combating viral diseases.
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http://dx.doi.org/10.1016/j.virusres.2020.198094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384980PMC
October 2020

Structural cells are key regulators of organ-specific immune responses.

Nature 2020 07 1;583(7815):296-302. Epub 2020 Jul 1.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens. Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity. However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence. To advance our understanding of immunology outside the haematopoietic system, here we systematically investigate the regulation of immune genes in the three major types of structural cells: epithelium, endothelium and fibroblasts. We characterize these cell types across twelve organs in mice, using cellular phenotyping, transcriptome sequencing, chromatin accessibility profiling and epigenome mapping. This comprehensive dataset revealed complex immune gene activity and regulation in structural cells. The observed patterns were highly organ-specific and seem to modulate the extensive interactions between structural cells and haematopoietic immune cells. Moreover, we identified an epigenetically encoded immune potential in structural cells under tissue homeostasis, which was triggered in response to systemic viral infection. This study highlights the prevalence and organ-specific complexity of immune gene activity in non-haematopoietic structural cells, and it provides a high-resolution, multi-omics atlas of the epigenetic and transcriptional networks that regulate structural cells in the mouse.
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http://dx.doi.org/10.1038/s41586-020-2424-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610345PMC
July 2020

Selective Mediator dependence of cell-type-specifying transcription.

Nat Genet 2020 07 1;52(7):719-727. Epub 2020 Jun 1.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

The Mediator complex directs signals from DNA-binding transcription factors to RNA polymerase II (Pol II). Despite this pivotal position, mechanistic understanding of Mediator in human cells remains incomplete. Here we quantified Mediator-controlled Pol II kinetics by coupling rapid subunit degradation with orthogonal experimental readouts. In agreement with a model of condensate-driven transcription initiation, large clusters of hypophosphorylated Pol II rapidly disassembled upon Mediator degradation. This was accompanied by a selective and pronounced disruption of cell-type-specifying transcriptional circuits, whose constituent genes featured exceptionally high rates of Pol II turnover. Notably, the transcriptional output of most other genes was largely unaffected by acute Mediator ablation. Maintenance of transcriptional activity at these genes was linked to an unexpected CDK9-dependent compensatory feedback loop that elevated Pol II pause release rates across the genome. Collectively, our work positions human Mediator as a globally acting coactivator that selectively safeguards the functionality of cell-type-specifying transcriptional networks.
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http://dx.doi.org/10.1038/s41588-020-0635-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610447PMC
July 2020

Inverse Data-Driven Modeling and Multiomics Analysis Reveals Phgdh as a Metabolic Checkpoint of Macrophage Polarization and Proliferation.

Cell Rep 2020 02;30(5):1542-1552.e7

Department of Ecogenomics and Systems Biology, University of Vienna, Vienna 1090, Austria; Vienna Metabolomics Center (VIME), University of Vienna, Vienna 1090, Austria. Electronic address:

Mechanistic or mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of effector functions, proliferation, and cellular metabolism in macrophages. The biochemical processes that are controlled by mTORC1 are still being defined. Here, we demonstrate that integrative multiomics in conjunction with a data-driven inverse modeling approach, termed COVRECON, identifies a biochemical node that influences overall metabolic profiles and reactions of mTORC1-dependent macrophage metabolism. Using a combined approach of metabolomics, proteomics, mRNA expression analysis, and enzymatic activity measurements, we demonstrate that Tsc2, a negative regulator of mTORC1 signaling, critically influences the cellular activity of macrophages by regulating the enzyme phosphoglycerate dehydrogenase (Phgdh) in an mTORC1-dependent manner. More generally, while lipopolysaccharide (LPS)-stimulated macrophages repress Phgdh activity, IL-4-stimulated macrophages increase the activity of the enzyme required for the expression of key anti-inflammatory molecules and macrophage proliferation. Thus, we identify Phgdh as a metabolic checkpoint of M2 macrophages.
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http://dx.doi.org/10.1016/j.celrep.2020.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003064PMC
February 2020

Environmental arginine controls multinuclear giant cell metabolism and formation.

Nat Commun 2020 01 22;11(1):431. Epub 2020 Jan 22.

Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, 1090, Vienna, Austria.

Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.
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http://dx.doi.org/10.1038/s41467-020-14285-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976629PMC
January 2020

Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function.

Immunity 2019 12 26;51(6):1074-1087.e9. Epub 2019 Nov 26.

CeMM Research Center for Molecular Medicine or the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria. Electronic address:

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8 T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.immuni.2019.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926485PMC
December 2019

Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis.

JCI Insight 2019 10 17;4(20). Epub 2019 Oct 17.

Center of Pathobiochemistry and Genetics, Institute of Medical Genetics.

The mechanistic target of rapamycin complex 2 (mTORC2) is a potentially novel and promising anticancer target due to its critical roles in proliferation, apoptosis, and metabolic reprogramming of cancer cells. However, the activity and function of mTORC2 in distinct cells within malignant tissue in vivo is insufficiently explored. Surprisingly, in primary human and mouse colorectal cancer (CRC) samples, mTORC2 signaling could not be detected in tumor cells. In contrast, only macrophages in tumor-adjacent areas showed mTORC2 activity, which was downregulated in stromal macrophages residing within human and mouse tumor tissues. Functionally, inhibition of mTORC2 by specific deletion of Rictor in macrophages stimulated tumorigenesis in a colitis-associated CRC mouse model. This phenotype was driven by a proinflammatory reprogramming of mTORC2-deficient macrophages that promoted colitis via the cytokine SPP1/osteopontin to stimulate tumor growth. In human CRC patients, high SPP1 levels and low mTORC2 activity in tumor-associated macrophages correlated with a worsened clinical prognosis. Treatment of mice with a second-generation mTOR inhibitor that inhibits mTORC2 and mTORC1 exacerbated experimental colorectal tumorigenesis in vivo. In conclusion, mTORC2 activity is confined to macrophages in CRC and limits tumorigenesis. These results suggest activation but not inhibition of mTORC2 as a therapeutic strategy for colitis-associated CRC.
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http://dx.doi.org/10.1172/jci.insight.124164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824305PMC
October 2019

MicroRNA-155 Controls T Helper Cell Activation During Viral Infection.

Front Immunol 2019 13;10:1367. Epub 2019 Jun 13.

Department of Rheumatology, Medical University Vienna, Vienna, Austria.

MicroRNA (miR) 155 has been implicated in the regulation of innate and adaptive immunity as well as autoimmune processes. Importantly, it has been shown to regulate several antiviral responses, but its contribution to the immune response against cytopathic viruses such as vesicular stomatitis virus (VSV) infections is not known. Using transgenic/recombinant VSV expressing ovalbumin, we show that miR-155 is crucially involved in regulating the T helper cell response against this virus. Our experiments indicate that miR-155 in CD4 T cells controls their activation, proliferation, and cytokine production and upon immunization with OVA as well as during VSV viral infection. Using intravital multiphoton microscopy we analyzed the interaction of antigen presenting cells (APCs) and T cells after OVA immunization and found impaired complex formation when using miR-155 deficient CD4 T cells compared to wildtype CD4 T cells . In contrast, miR-155 was dispensable for the maturation of myeloid APCs and for their T cell stimulatory capacity. Our data provide the first evidence that miR-155 is required for efficient CD4 T cell activation during anti-viral defense by allowing robust APC-T cell interaction required for activation and cytokine production of virus specific T cells.
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http://dx.doi.org/10.3389/fimmu.2019.01367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593301PMC
October 2020

AIF-regulated oxidative phosphorylation supports lung cancer development.

Cell Res 2019 07 27;29(7):579-591. Epub 2019 May 27.

Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a Kras-driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of Kras-driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout Kras mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.
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http://dx.doi.org/10.1038/s41422-019-0181-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796841PMC
July 2019

CD8 T cells induce cachexia during chronic viral infection.

Nat Immunol 2019 06 20;20(6):701-710. Epub 2019 May 20.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8 T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8 T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8 T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8 T cells in IAC.
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http://dx.doi.org/10.1038/s41590-019-0397-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531346PMC
June 2019

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.

Cancer Cell 2019 01;35(1):125-139.e9

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Electronic address:

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.ccell.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335503PMC
January 2019

Human tripartite motif protein 52 is required for cell context-dependent proliferation.

Oncotarget 2018 Mar 5;9(17):13565-13581. Epub 2018 Feb 5.

Department of Microbiology, Immunobiology, and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter, Vienna 1030, Austria.

Tripartite motif (TRIM) proteins have been shown to play important roles in cancer development and progression by modulating cell proliferation or resistance from cell death during non-homeostatic stress conditions found in tumor micro-environments. In this study, we set out to investigate the importance for cellular fitness of the virtually uncharacterized family member TRIM52. The human gene has arisen recently in evolution, making it unlikely that TRIM52 is required for basic cellular functions in normal cells. However, a recent genome-wide ablation screening study has suggested that TRIM52 may be essential for optimal proliferation or survival in certain genetic cancer backgrounds. Identifying genes which fit this concept of genetic context-dependent fitness in cancer cells is of interest as they are promising targets for tumor-specific therapy. We report here that ablation significantly diminished the proliferation of specific glioblastoma cell lines in cell culture and mouse xenografts by compromising their cell cycle progression in a p53-dependent manner. Together, our findings point to a non-redundant TRIM52 function that is required for optimal proliferation.
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http://dx.doi.org/10.18632/oncotarget.24422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862599PMC
March 2018

Characterization of host proteins interacting with the lymphocytic choriomeningitis virus L protein.

PLoS Pathog 2017 Dec 20;13(12):e1006758. Epub 2017 Dec 20.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse, Vienna, Austria.

RNA-dependent RNA polymerases (RdRps) play a key role in the life cycle of RNA viruses and impact their immunobiology. The arenavirus lymphocytic choriomeningitis virus (LCMV) strain Clone 13 provides a benchmark model for studying chronic infection. A major genetic determinant for its ability to persist maps to a single amino acid exchange in the viral L protein, which exhibits RdRp activity, yet its functional consequences remain elusive. To unravel the L protein interactions with the host proteome, we engineered infectious L protein-tagged LCMV virions by reverse genetics. A subsequent mass-spectrometric analysis of L protein pulldowns from infected human cells revealed a comprehensive network of interacting host proteins. The obtained LCMV L protein interactome was bioinformatically integrated with known host protein interactors of RdRps from other RNA viruses, emphasizing interconnected modules of human proteins. Functional characterization of selected interactors highlighted proviral (DDX3X) as well as antiviral (NKRF, TRIM21) host factors. To corroborate these findings, we infected Trim21-/- mice with LCMV and found impaired virus control in chronic infection. These results provide insights into the complex interactions of the arenavirus LCMV and other viral RdRps with the host proteome and contribute to a better molecular understanding of how chronic viruses interact with their host.
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http://dx.doi.org/10.1371/journal.ppat.1006758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738113PMC
December 2017