Publications by authors named "Anca Dorhoi"

65 Publications

Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense.

Int J Mol Sci 2021 Apr 30;22(9). Epub 2021 Apr 30.

Institute of Immunology, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany.

Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by (), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of -neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with , including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis.
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http://dx.doi.org/10.3390/ijms22094801DOI Listing
April 2021

Cellular stress promotes NOD1/2-dependent inflammation via the endogenous metabolite sphingosine-1-phosphate.

EMBO J 2021 May 4:e106272. Epub 2021 May 4.

Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine-1-phosphate (S1P). Unlike peptidoglycan sensing via the leucine-rich repeats domain, cytosolic S1P directly bound to the nucleotide binding domains of NOD1/2, triggering NF-κB activation and inflammatory responses. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of the cytosolic metabolite S1P. We propose S1P, an endogenous metabolite, as a novel NOD1/2 activator and NOD1/2 as molecular hubs integrating bacterial and metabolic cues.
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http://dx.doi.org/10.15252/embj.2020106272DOI Listing
May 2021

Targeting of myeloid-derived suppressor cells by all-trans retinoic acid as host-directed therapy for human tuberculosis.

Cell Immunol 2021 Jun 8;364:104359. Epub 2021 Apr 8.

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medical and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address:

Conventional anti-tuberculosis (TB) therapies comprise lengthy antibiotic treatment regimens, exacerbated by multi-drug resistant and extensively drug resistant mycobacterial strains. We assessed the ability of all-trans retinoic acid (ATRA), as repurposed compound serving as host-directed therapy (HDT), to counteract the suppressive effects of myeloid-derived suppressor cells (MDSCs) obtained from active TB cases (untreated or during week one of treatment) on T-cell responsiveness. We show for the first time that MDSCs suppress non-specific T-cell activation and production of interleukin (IL)-2, IL-4, IL-13 and GM-CSF via contact-dependent mechanisms. ATRA treatment decreases MDSC frequency, but fails to mature MDSCs to non-suppressive, terminally differentiated myeloid cells and does not restore T-cell function or cytokine production in the presence of MDSCs. The impact of ATRA treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.
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http://dx.doi.org/10.1016/j.cellimm.2021.104359DOI Listing
June 2021

Monocyte progenitors give rise to multinucleated giant cells.

Nat Commun 2021 04 1;12(1):2027. Epub 2021 Apr 1.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. We previously found that multinucleated giant cells result from Toll-like receptor-induced DNA damage and cell autonomous cell cycle modifications. However, the giant cell progenitor identity remained unclear. Here, we show that the giant cell-forming potential is a particular trait of monocyte progenitors. Common monocyte progenitors potently produce cytokines in response to mycobacteria and their immune-active molecules. In addition, common monocyte progenitors accumulate cholesterol and lipids, which are prerequisites for giant cell transformation. Inducible monocyte progenitors are so far undescribed circulating common monocyte progenitor descendants with high giant cell-forming potential. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas. Accordingly, they exhibit important immunological functions in mycobacterial infections. Moreover, their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche.
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http://dx.doi.org/10.1038/s41467-021-22103-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016882PMC
April 2021

Comparable Long-Term Rabies Immunity in Foxes after IntraMuscular and Oral Application Using a Third-Generation Oral Rabies Virus Vaccine.

Vaccines (Basel) 2021 Jan 14;9(1). Epub 2021 Jan 14.

Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), WHO Collaborating Centre for Rabies Surveillance and Research, OIE Reference Laboratory for Rabies, 17493 Greifswald-Insel Riems, Germany.

The live genetically-engineered oral rabies virus (RABV) variant SPBN GASGAS induces long-lasting immunity in foxes and protection against challenge with an otherwise lethal dose of RABV field strains both after experimental oral and parenteral routes of administration. Induction of RABV-specific binding antibodies and immunoglobulin isotypes (IgM, total IgG, IgG1, IgG2) were comparable in orally and parenterally vaccinated foxes. Differences were only observed in the induction of virus-neutralizing (VNA) titers, which were significantly higher in the parenterally vaccinated group. The dynamics of rabies-specific antibodies pre- and post-challenge (365 days post vaccination) suggest the predominance of type-1 immunity protection of SPBN GASGAS. Independent of the route of administration, in the absence of IgG1 the immune response to SPBN GAGAS was mainly IgG2 driven. Interestingly, vaccination with SPBN GASGAS does not cause significant differences in inducible IFN-γ production in vaccinated animals, indicating a relatively weak cellular immune response during challenge. Notably, the parenteral application of SPBN GASGAS did not induce any adverse side effects in foxes, thus supporting safety studies of this oral rabies vaccine in various species.
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http://dx.doi.org/10.3390/vaccines9010049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828770PMC
January 2021

Composition and Clinical Significance of Exosomes in Tuberculosis: A Systematic Literature Review.

J Clin Med 2021 Jan 4;10(1). Epub 2021 Jan 4.

Institute of Clinical Immunology, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.

Tuberculosis (TB) remains a major health issue worldwide. In order to contain TB infections, improved vaccines as well as accurate and reliable diagnostic tools are desirable. Exosomes are employed for the diagnosis of various diseases. At present, research on exosomes in TB is still at the preliminary stage. Recent studies have described isolation and characterization of () derived exosomes in vivo and in vitro. -derived exosomes (exo) may be critical for TB pathogenesis by delivering mycobacterial-derived components to the recipient cells. Proteomic and transcriptomic analysis of exo have revealed a variety of proteins and miRNA, which are utilized by the TB bacteria for pathogenesis. Exosomes has been isolated in body fluids, are amenable for fast detection, and could contribute as diagnostic or prognostic biomarker to disease control. Extraction of exosomes from biological fluids is essential for the exosome research and requires careful standardization for TB. In this review, we summarized the different studies on exo molecules, including protein and miRNA and the method used to detect exosomes in biological fluids and cell culture supernatants. Thus, the detection of exo molecules in biological fluids may have a potential to expedite the diagnosis of TB infection. Moreover, the analysis of exo may generate new aspects in vaccine development.
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http://dx.doi.org/10.3390/jcm10010145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795701PMC
January 2021

Isolation of Bovine Neutrophils by Fluorescence- and Magnetic-Activated Cell Sorting.

Methods Mol Biol 2021 ;2236:203-217

INRAE, Univ Tours, ISP, Nouzilly, France.

Flow cytometry and magnetic bead technology enable the separation of cell populations with the highest degree of purity. Here, we describe protocols to sort bovine neutrophils from blood, the labeling and sorting, including gating strategies. We also provide advice to preserve neutrophil viability and detail a protocol to measure phagocytosis and oxidative species production.
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http://dx.doi.org/10.1007/978-1-0716-1060-2_16DOI Listing
March 2021

Susceptibility of Raccoon Dogs for Experimental SARS-CoV-2 Infection.

Emerg Infect Dis 2020 12 22;26(12):2982-2985. Epub 2020 Oct 22.

Raccoon dogs might have been intermediate hosts for severe acute respiratory syndrome-associated coronavirus in 2002-2004. We demonstrated susceptibility of raccoon dogs to severe acute respiratory syndrome coronavirus 2 infection and transmission to in-contact animals. Infected animals had no signs of illness. Virus replication and tissue lesions occurred in the nasal conchae.
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http://dx.doi.org/10.3201/eid2612.203733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706974PMC
December 2020

Platelets Restrict the Oxidative Burst in Phagocytes and Facilitate Primary Progressive Tuberculosis.

Am J Respir Crit Care Med 2020 09;202(5):730-744

Immunology Department and.

Platelets are generated in the capillaries of the lung, control hemostasis, and display immunological functions. Tuberculosis primarily affects the lung, and patients show platelet changes and hemoptysis. A role of platelets in immunopathology of pulmonary tuberculosis requires careful assessment. To identify the dynamics and interaction partners of platelets in the respiratory tissue and establish their impact on the outcome of pulmonary tuberculosis. Investigations were primarily performed in murine models of primary progressive pulmonary tuberculosis, by analysis of mouse strains with variable susceptibility to infection using platelet depletion and delivery of antiplatelet drugs. Platelets were present at the site of infection and formed aggregates with different myeloid subsets during experimental tuberculosis. Such aggregates were also detected in patients with tuberculosis. Platelets were detrimental during the early phase of infection, and this effect was uncoupled from their canonical activation. Platelets left lung cell dynamics and patterns of antimycobacterial T-cell responses unchanged but hampered antimicrobial defense by restricting production of reactive oxygen species in lung-residing myeloid cells. Platelets are detrimental in primary progressive pulmonary tuberculosis, orchestrate lung immunity by modulating innate immune responsiveness, and may be amenable to new interventions for this deadly disease.
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http://dx.doi.org/10.1164/rccm.201910-2063OCDOI Listing
September 2020

Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus.

J Clin Invest 2020 06;130(6):2789-2799

Centre for Tuberculosis Research, South African Medical Research Council, Cape Town, South Africa.

The critical role of suppressive myeloid cells in immune regulation has come to the forefront in cancer research, with myeloid-derived suppressor cells (MDSCs) as a main oncology immunotherapeutic target. Recent improvement and standardization of criteria classifying tumor-induced MDSCs have led to unified descriptions and also promoted MDSC research in tuberculosis (TB) and AIDS. Despite convincing evidence on the induction of MDSCs by pathogen-derived molecules and inflammatory mediators in TB and AIDS, very little attention has been given to their therapeutic modulation or roles in vaccination in these diseases. Clinical manifestations in TB are consequences of complex host-pathogen interactions and are substantially affected by HIV infection. Here we summarize the current understanding and knowledge gaps regarding the role of MDSCs in HIV and Mycobacterium tuberculosis (co)infections. We discuss key scientific priorities to enable application of this knowledge to the development of novel strategies to improve vaccine efficacy and/or implementation of enhanced treatment approaches. Building on recent findings and potential for cross-fertilization between oncology and infection biology, we highlight current challenges and untapped opportunities for translating new advances in MDSC research into clinical applications for TB and AIDS.
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http://dx.doi.org/10.1172/JCI136288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260010PMC
June 2020

Early dynamics of innate immunity during pulmonary tuberculosis.

Immunol Lett 2020 05 21;221:56-60. Epub 2020 Feb 21.

Institute of Immunology, Friedrich-Loeffler-Institute, Greifswald - Insel Riems, Germany; Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany. Electronic address:

Tuberculosis (TB) most frequently affects the lung, with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, promptly gaining access to lung-resident myeloid cells, notably alveolar macrophages. Historical observational case-contact surveys and recent epidemiological studies report on resistors. These individuals are likely protected against infection by defence mechanisms occurring promptly after bacterial exposure. The early events proceeding within the Mtb-infected lung are critical for the outcome of the infection. Despite the heightened relevance of the first contact between Mtb and the host, the current understanding of precise immune events occurring shortly after Mtb exposure is still limited. More recently, new information has emerged and we here summarize cellular and molecular events of innate immunity, considering the lung compartments and cellular communication over time. We discuss new concepts emerging from experimental models of pulmonary TB, highlight recent advances and summarize requirements for accurate mapping of early events in TB. A better understanding of disease pathogenesis at incipient stages will facilitate the development of novel therapeutics and more effective prophylactic measures for TB.
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http://dx.doi.org/10.1016/j.imlet.2020.02.010DOI Listing
May 2020

Host monitoring of quorum sensing during infection.

Science 2019 12;366(6472)

Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.

rapidly adapts to altered conditions by quorum sensing (QS), a communication system that it uses to collectively modify its behavior through the production, release, and detection of signaling molecules. QS molecules can also be sensed by hosts, although the respective receptors and signaling pathways are poorly understood. We describe a pattern of regulation in the host by the aryl hydrocarbon receptor (AhR) that is critically dependent on qualitative and quantitative sensing of quorum. QS molecules bind to AhR and distinctly modulate its activity. This is mirrored upon infection with collected from diverse growth stages and with QS mutants. We propose that by spying on bacterial quorum, AhR acts as a major sensor of infection dynamics, capable of orchestrating host defense according to the status quo of infection.
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http://dx.doi.org/10.1126/science.aaw1629DOI Listing
December 2019

Corrigendum: The Emerging Role of Myeloid-Derived Suppressor Cells in Tuberculosis.

Front Immunol 2019;10:1528. Epub 2019 Jul 2.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, South African MRC Centre for Tuberculosis Research, DST and NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Stellenbosch, South Africa.

[This corrects the article DOI: 10.3389/fimmu.2019.00917.].
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http://dx.doi.org/10.3389/fimmu.2019.01528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614722PMC
July 2019

Porcine Invariant Natural Killer T Cells: Functional Profiling and Dynamics in Steady State and Viral Infections.

Front Immunol 2019 18;10:1380. Epub 2019 Jun 18.

Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.

Pigs are important livestock and comprehensive understanding of their immune responses in infections is critical to improve vaccines and therapies. Moreover, similarities between human and swine physiology suggest that pigs are a superior animal model for immunological studies. However, paucity of experimental tools for a systematic analysis of the immune responses in pigs represent a major disadvantage. To evaluate the pig as a biomedical model and additionally expand the knowledge of rare immune cell populations in swine, we established a multicolor flow cytometry analysis platform of surface marker expression and cellular responses for porcine invariant Natural Killer T cells (iNKT). In humans, iNKT cells are among the first line defenders in various tissues, respond to CD1d-restricted antigens and become rapidly activated. Naïve porcine iNKT cells were CD3/CD4/CD8 or CD3/CD4/CD8 and displayed an effector- or memory-like phenotype (CD25/ICOS/CD5/CD45RA/CCR7 /CD27). Based on their expression of the transcription factors T bet and the iNKT cell-specific promyelocytic leukemia zinc finger protein (PLZF), porcine iNKT cells were differentiated into functional subsets. Analogous to human iNKT cells, stimulation of porcine leukocytes with the CD1d ligand α-galactosylceramide resulted in rapid iNKT cell proliferation, evidenced by an increase in frequency and Ki-67 expression. Moreover, this approach revealed CD25, CD5, ICOS, and the major histocompatibility complex class II (MHC II) as activation markers on porcine iNKT cells. Activated iNKT cells also expressed interferon-γ, upregulated perforin expression, and displayed degranulation. In steady state, iNKT cell frequency was highest in newborn piglets and decreased with age. Upon infection with two viruses of high relevance to swine and humans, iNKT cells expanded. Animals infected with African swine fever virus displayed an increase of iNKT cell frequency in peripheral blood, regional lymph nodes, and lungs. During Influenza A virus infection, iNKT cell percentage increased in blood, lung lymph nodes, and broncho-alveolar lavage. Our in-depth characterization of porcine iNKT cells contributes to a better understanding of porcine immune responses, thereby facilitating the design of innovative interventions against infectious diseases. Moreover, we provide new evidence that endorses the suitability of the pig as a biomedical model for iNKT cell research.
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http://dx.doi.org/10.3389/fimmu.2019.01380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611438PMC
October 2020

The Emerging Role of Myeloid-Derived Suppressor Cells in Tuberculosis.

Front Immunol 2019 30;10:917. Epub 2019 Apr 30.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, South African MRC Centre for Tuberculosis Research, DST and NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Stellenbosch, South Africa.

Myeloid cells are crucial for the host control of a () infection, however the adverse role of specific myeloid subsets has increasingly been appreciated. The relevance of such cells in therapeutic strategies and predictive/prognostic algorithms is to promote interest in regulatory myeloid cells in tuberculosis (TB). Myeloid-derived suppressor cells (MDSC) are a heterogeneous collection of phagocytes comprised of monocytic- and polymorphonuclear cells that exhibit a potent suppression of innate- and adaptive immune responses. Accumulation of MDSC under pathological conditions associated with chronic inflammation, most notably cancer, has been well-described. Evidence supporting the involvement of MDSC in TB is increasing, yet their significance in this infection continues to be viewed with skepticism, primarily due to their complex nature and the lack of genetic evidence unequivocally discriminating these cells from other terminally differentiated myeloid populations. Here we highlight recent advances in MDSC characterization and summarize findings on the TB-induced hematopoietic shift associated with MDSC expansion. Lastly, the mechanisms of MDSC-mediated disease progression and future research avenues in the context of TB therapy and prophylaxis are discussed.
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http://dx.doi.org/10.3389/fimmu.2019.00917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502992PMC
September 2020

cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity.

EMBO Rep 2019 04 14;20(4). Epub 2019 Mar 14.

Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany

Cyclic dinucleotides (CDNs) are important second messenger molecules in prokaryotes and eukaryotes. Within host cells, cytosolic CDNs are detected by STING and alert the host by activating innate immunity characterized by type I interferon (IFN) responses. Extracellular bacteria and dying cells can release CDNs, but sensing of extracellular CDNs (eCDNs) by mammalian cells remains elusive. Here, we report that endocytosis facilitates internalization of eCDNs. The DNA sensor cGAS facilitates sensing of endocytosed CDNs, their perinuclear accumulation, and subsequent STING-dependent release of type I IFN Internalized CDNs bind cGAS directly, leading to its dimerization, and the formation of a cGAS/STING complex, which may activate downstream signaling. Thus, eCDNs comprise microbe- and danger-associated molecular patterns that contribute to host-microbe crosstalk during health and disease.
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http://dx.doi.org/10.15252/embr.201846293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446192PMC
April 2019

Deciphering myeloid-derived suppressor cells: isolation and markers in humans, mice and non-human primates.

Cancer Immunol Immunother 2019 Apr 25;68(4):687-697. Epub 2019 Jan 25.

Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 28, 6500 HB, Nijmegen, The Netherlands.

In cancer, infection and inflammation, the immune system's function can be dysregulated. Instead of fighting disease, immune cells may increase pathology and suppress host-protective immune responses. Myeloid cells show high plasticity and adapt to changing conditions and pathological challenges. Despite their relevance in disease pathophysiology, the identity, heterogeneity and biology of myeloid cells is still poorly understood. We will focus on phenotypical and functional markers of one of the key myeloid regulatory subtypes, the myeloid derived suppressor cells (MDSC), in humans, mice and non-human primates. Technical issues regarding the isolation of the cells from tissues and blood, timing and sample handling of MDSC will be detailed. Localization of MDSC in a tissue context is of crucial importance and immunohistochemistry approaches for this purpose are discussed. A minimal antibody panel for MDSC research is provided as part of the Mye-EUNITER COST action. Strategies for the identification of additional markers applying state of the art technologies such as mass cytometry will be highlighted. Such marker sets can be used to study MDSC phenotypes across tissues, diseases as well as species and will be crucial to accelerate MDSC research in health and disease.
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http://dx.doi.org/10.1007/s00262-019-02302-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447515PMC
April 2019

MDSCs in infectious diseases: regulation, roles, and readjustment.

Cancer Immunol Immunother 2019 Apr 19;68(4):673-685. Epub 2018 Dec 19.

Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Av. Diagonal, 643, 3rd floor, 08028, Barcelona, Spain.

Many pathogens, ranging from viruses to multicellular parasites, promote expansion of MDSCs, which are myeloid cells that exhibit immunosuppressive features. The roles of MDSCs in infection depend on the class and virulence mechanisms of the pathogen, the stage of the disease, and the pathology associated with the infection. This work compiles evidence supported by functional assays on the roles of different subsets of MDSCs in acute and chronic infections, including pathogen-associated malignancies, and discusses strategies to modulate MDSC dynamics to benefit the host.
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http://dx.doi.org/10.1007/s00262-018-2277-yDOI Listing
April 2019

Human Monocytic Suppressive Cells Promote Replication of and Alter Stability of Generated Granulomas.

Front Immunol 2018 23;9:2417. Epub 2018 Oct 23.

Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany.

Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with () and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon infection. We employed an granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
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http://dx.doi.org/10.3389/fimmu.2018.02417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205994PMC
September 2019

Nuclear cGAS suppresses DNA repair and promotes tumorigenesis.

Nature 2018 11 24;563(7729):131-136. Epub 2018 Oct 24.

Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.
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http://dx.doi.org/10.1038/s41586-018-0629-6DOI Listing
November 2018

How to measure the immunosuppressive activity of MDSC: assays, problems and potential solutions.

Cancer Immunol Immunother 2019 Apr 21;68(4):631-644. Epub 2018 May 21.

Research Division, Department of Otorhinolaryngology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of mononuclear and polymorphonuclear myeloid cells, which are present at very low numbers in healthy subjects, but can expand substantially under disease conditions. Depending on disease type and stage, MDSC comprise varying amounts of immature and mature differentiation stages of myeloid cells. Validated unique phenotypic markers for MDSC are still lacking. Therefore, the functional analysis of these cells is of central importance for their identification and characterization. Various disease-promoting and immunosuppressive functions of MDSC are reported in the literature. Among those, the capacity to modulate the activity of T cells is by far the most often used and best-established read-out system. In this review, we critically evaluate the assays available for the functional analysis of human and murine MDSC under in vitro and in vivo conditions. We also discuss critical issues and controls associated with those assays. We aim at providing suggestions and recommendations useful for the contemporary biological characterization of MDSC.
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http://dx.doi.org/10.1007/s00262-018-2170-8DOI Listing
April 2019

Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections.

Front Immunol 2017 4;8:1895. Epub 2018 Jan 4.

Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, SAMRC Centre for Tuberculosis Research, DST and NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Tygerberg, South Africa.

Heterogeneous populations of myeloid regulatory cells (MRC), including monocytes, macrophages, dendritic cells, and neutrophils, are found in cancer and infectious diseases. The inflammatory environment in solid tumors as well as infectious foci with persistent pathogens promotes the development and recruitment of MRC. These cells help to resolve inflammation and establish host immune homeostasis by restricting T lymphocyte function, inducing regulatory T cells and releasing immune suppressive cytokines and enzyme products. Monocytic MRC, also termed monocytic myeloid-derived suppressor cells (M-MDSC), are phagocytes, capable of pathogen internalization and persistence, while exerting localized suppressive activity. Here, we summarize molecular pathways controlling M-MDSC genesis and functions in microbial-induced non-resolved inflammation and immunopathology. We focus on the roles of M-MDSC in infections, including opportunistic extracellular bacteria and fungi as well as persistent intracellular pathogens, such as mycobacteria and certain viruses. Better understanding of M-MDSC biology in chronic infections and their role in antimicrobial immunity, will advance development of novel, more effective and broad-range anti-infective therapies.
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http://dx.doi.org/10.3389/fimmu.2017.01895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758551PMC
January 2018

The E3 ubiquitin ligase NEDD4 enhances killing of membrane-perturbing intracellular bacteria by promoting autophagy.

Autophagy 2017 17;13(12):2041-2055. Epub 2017 Dec 17.

a Department of Immunology , Max Planck Institute for Infection Biology , Berlin , Germany.

The E3 ubiquitin ligase NEDD4 has been intensively studied in processes involved in viral infections, such as virus budding. However, little is known about its functions in bacterial infections. Our investigations into the role of NEDD4 in intracellular bacterial infections demonstrate that Mycobacterium tuberculosis and Listeria monocytogenes, but not Mycobacterium bovis BCG, replicate more efficiently in NEDD4 knockdown macrophages. In parallel, NEDD4 knockdown or knockout impaired basal macroautophagy/autophagy, as well as infection-induced autophagy. Conversely, NEDD4 expression promoted autophagy in an E3 catalytic activity-dependent manner, thereby restricting intracellular Listeria replication. Mechanistic studies uncovered that endogenous NEDD4 interacted with BECN1/Beclin 1 and this interaction increased during Listeria infection. Deficiency of NEDD4 resulted in elevated K48-linkage ubiquitination of endogenous BECN1. Further, NEDD4 mediated K6- and K27- linkage ubiquitination of BECN1, leading to elevated stability of BECN1 and increased autophagy. Thus, NEDD4 participates in killing of intracellular bacterial pathogens via autophagy by sustaining the stability of BECN1.
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http://dx.doi.org/10.1080/15548627.2017.1376160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788543PMC
July 2019

Hemostasis and Lipoprotein Indices Signify Exacerbated Lung Injury in TB With Diabetes Comorbidity.

Chest 2018 05 7;153(5):1187-1200. Epub 2017 Dec 7.

Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China; Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China. Electronic address:

Background: Exacerbated immunopathology is a frequent consequence of TB that is complicated by diabetes mellitus (DM); however, the underlying mechanisms are still poorly defined.

Methods: In the two groups of age- and sex-matched patients with TB and DM (DM-TB) and with TB and without DM, we microscopically evaluated the areas of caseous necrosis and graded the extent of perinecrotic fibrosis in lung biopsies from the sputum smear-negative (SN) patients. We scored acid-fast bacilli in sputum smear-positive (SP) patients and compiled CT scan data from both the SN and SP patients. We compared inflammatory biomarkers and routine hematologic and biochemical parameters. Binary logistic regression analyses were applied to define the indices associated with the extent of lung injury.

Results: Enlarged caseous necrotic areas with exacerbated fibrotic encapsulations were found in SN patients with DM-TB, consistent with the higher ratio of thick-walled cavities and more bacilli in the sputum from SP patients with DM-TB. Larger necrotic foci were detected in men compared with women within the SN TB groups. Significantly higher fibrinogen and lower high-density lipoprotein cholesterol (HDL-C) were observed in SN patients with DM-TB. Regression analyses revealed that diabetes, activation of the coagulation pathway (shown by increased platelet distribution width, decreased mean platelet volume, and shortened prothrombin time), and dyslipidemia (shown by decreased low-density lipoprotein cholesterol, HDL-C, and apolipoprotein A) are risk factors for severe lung lesions in both SN and SP patients with TB.

Conclusions: Hemostasis and dyslipidemia are associated with granuloma necrosis and fibroplasia leading to exacerbated lung damage in TB, especially in patients with DM-TB.
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http://dx.doi.org/10.1016/j.chest.2017.11.029DOI Listing
May 2018

Mycobacterium tuberculosis infection modulates adipose tissue biology.

PLoS Pathog 2017 Oct 17;13(10):e1006676. Epub 2017 Oct 17.

Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.

Mycobacterium tuberculosis (Mtb) primarily resides in the lung but can also persist in extrapulmonary sites. Macrophages are considered the prime cellular habitat in all tissues. Here we demonstrate that Mtb resides inside adipocytes of fat tissue where it expresses stress-related genes. Moreover, perigonadal fat of Mtb-infected mice disseminated the infection when transferred to uninfected animals. Adipose tissue harbors leukocytes in addition to adipocytes and other cell types and we observed that Mtb infection induces changes in adipose tissue biology depending on stage of infection. Mice infected via aerosol showed infiltration of inducible nitric oxide synthase (iNOS) or arginase 1 (Arg1)-negative F4/80+ cells, despite recruitment of CD3+, CD4+ and CD8+ T cells. Gene expression analysis of adipose tissue of aerosol Mtb-infected mice provided evidence for upregulated expression of genes associated with T cells and NK cells at 28 days post-infection. Strikingly, IFN-γ-producing NK cells and Mtb-specific CD8+ T cells were identified in perigonadal fat, specifically CD8+CD44-CD69+ and CD8+CD44-CD103+ subpopulations. Gene expression analysis of these cells revealed that they expressed IFN-γ and the lectin-like receptor Klrg1 and down-regulated CD27 and CD62L, consistent with an effector phenotype of Mtb-specific CD8+ T cells. Sorted NK cells expressed higher abundance of Klrg1 upon infection, as well. Our results reveal the ability of Mtb to persist in adipose tissue in a stressed state, and that NK cells and Mtb-specific CD8+ T cells infiltrate infected adipose tissue where they produce IFN-γ and assume an effector phenotype. We conclude that adipose tissue is a potential niche for Mtb and that due to infection CD8+ T cells and NK cells are attracted to this tissue.
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http://dx.doi.org/10.1371/journal.ppat.1006676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695609PMC
October 2017

Host-directed therapies for bacterial and viral infections.

Nat Rev Drug Discov 2018 01 22;17(1):35-56. Epub 2017 Sep 22.

Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.

Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and additional alternative approaches to treat infectious diseases are urgently needed. Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives. The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathology. Although HDTs encompassing interferons are well established for the treatment of chronic viral hepatitis, novel strategies aimed at the functional cure of persistent viral infections and the development of broad-spectrum antivirals against emerging viruses seem to be crucial. In chronic bacterial infections, such as tuberculosis, HDT strategies aim to enhance the antimicrobial activities of phagocytes and to curtail inflammation through interference with soluble factors (such as eicosanoids and cytokines) or cellular factors (such as co-stimulatory molecules). This Review describes current progress in the development of HDTs for viral and bacterial infections, including sepsis, and the challenges in bringing these new approaches to the clinic.
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http://dx.doi.org/10.1038/nrd.2017.162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097079PMC
January 2018

Concordant and discordant gene expression patterns in mouse strains identify best-fit animal model for human tuberculosis.

Sci Rep 2017 09 21;7(1):12094. Epub 2017 Sep 21.

Max Planck Institute for Infection Biology, Department of Immunology, Charitéplatz 1, D-10117, Berlin, Germany.

Immunity in infection, inflammation and malignancy differs markedly in man and mouse. Still, we learn about human immunity in large extent from experimental mouse models. We propose a novel data integration approach which identifies concordant and discordant gene expression patterns of the immune responses in heterologous data sets. We have conducted experiments to compare human and murine transcriptional responses to Mycobacterium tuberculosis (Mtb) infection in whole blood (WB) as well as macrophages and compared them with simulated as well as publicly available data. Our results indicate profound differences between patterns of gene expression in innate and adaptive immunity in man and mouse upon Mtb infection. We characterized differential expression of T-cell related genes corresponding to the differences in phenotype between tuberculosis (TB) highly and low susceptible mouse strains. Our approach is general and facilitates the choice of optimal animal model for studies of the human immune response to a particular disease.
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http://dx.doi.org/10.1038/s41598-017-11812-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608750PMC
September 2017

The CARD9 Polymorphisms rs4077515, rs10870077 and rs10781499 Are Uncoupled from Susceptibility to and Severity of Pulmonary Tuberculosis.

PLoS One 2016;11(9):e0163662. Epub 2016 Sep 29.

Max Planck Institute for Infection Biology, 10117 Berlin, Germany.

Genetic variants in the CARD9 gene predispose to inflammatory disorders and chronic infectious diseases. Tuberculosis (TB), a chronic infectious disease affecting the lung, is lethal in Card9-deficient mice. We hypothesized that polymorphisms in the CARD9 gene influence TB progression and disease-associated lung damage in humans. We tested genotype distributions of the CARD9 polymorphisms rs4077515, rs10781499 and rs10870077 in TB patients and healthy subjects in a Caucasian cohort. SNPs were in linkage disequilibrium and none of the haplotypes was significantly enriched in the TB group. We determined total and differential leukocyte count, erythrocyte sedimentation rate and plasma abundance of cytokines and chemokines as markers for systemic inflammation and scored chest X-rays to assess lung involvement in TB subjects. Most disease parameters segregated independently of the CARD9 haplotypes. In contrast to multifactorial chronic inflammation, selected genetic variants in the CARD9 gene leave host responses apparently unaffected in TB, at least in the population analyzed here.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163662PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042433PMC
September 2016

Neonatal Fc Receptor Regulation of Lung Immunoglobulin and CD103+ Dendritic Cells Confers Transient Susceptibility to Tuberculosis.

Infect Immun 2016 10 19;84(10):2914-21. Epub 2016 Sep 19.

Max Planck Institute for Infection Biology, Berlin, Germany

The neonatal Fc receptor (FcRn) extends the systemic half-life of IgG antibodies by chaperoning bound Fc away from lysosomal degradation inside stromal and hematopoietic cells. FcRn also transports IgG across mucosal barriers into the lumen, and yet little is known about how FcRn modulates immunity in the lung during homeostasis or infection. We infected wild-type (WT) and FcRn-deficient (fcgrt(-/-)) mice with Pseudomonas aeruginosa or Mycobacterium tuberculosis to investigate whether recycling and transport of IgG via FcRn influences innate and adaptive immunity in the lung in response to bacterial infection. We found that FcRn expression maintains homeostatic IgG levels in lung and leads to preferential secretion of low-affinity IgG ligands into the lumen. Fcgrt(-/-) animals exhibited no evidence of developmental impairment of innate immunity in the lung and were able to efficiently recruit neutrophils in a model of acute bacterial pneumonia. Although local humoral immunity in lung increased independently of the presence of FcRn during tuberculosis, there was nonetheless a strong impact of FcRn deficiency on local adaptive immunity. We show that the quantity and quality of IgG in airways, as well as the abundance of dendritic cells in the lung, are maintained by FcRn. FcRn ablation transiently enhanced local T cell immunity and neutrophil recruitment during tuberculosis, leading to a lower bacterial burden in lung. This novel understanding of tissue-specific modulation of mucosal IgG isotypes in the lung by FcRn sheds light on the role of mucosal IgG in immune responses in the lung during homeostasis and bacterial disease.
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http://dx.doi.org/10.1128/IAI.00533-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038074PMC
October 2016