• Synthetic rewiring and boosting type I interferon responses for visualization and counteracting viral infections.

      Gödecke, Natascha; Riedel, Jan; Herrmann, Sabrina; Behme, Sara; Rand, Ulfert; Kubsch, Tobias; Cicin-Sain, Luka; Hauser, Hansjörg; Köster, Mario; Wirth, Dagmar; et al. (Oxford Academic, 2020-11-18)
      Mammalian first line of defense against viruses is accomplished by the interferon (IFN) system. Viruses have evolved numerous mechanisms to reduce the IFN action allowing them to invade the host and/or to establish latency. We generated an IFN responsive intracellular hub by integrating the synthetic transactivator tTA into the chromosomal Mx2 locus for IFN-based activation of tTA dependent expression modules. The additional implementation of a synthetic amplifier module with positive feedback even allowed for monitoring and reacting to infections of viruses that can antagonize the IFN system. Low and transient IFN amounts are sufficient to trigger these amplifier cells. This gives rise to higher and sustained-but optionally de-activatable-expression even when the initial stimulus has faded out. Amplification of the IFN response induced by IFN suppressing viruses is sufficient to protect cells from infection. Together, this interfaced sensor/actuator system provides a toolbox for robust sensing and counteracting viral infections.
    • Triple RNA-Seq Reveals Synergy in a Human Virus-Fungus Co-infection Model.

      Seelbinder, Bastian; Wallstabe, Julia; Marischen, Lothar; Weiss, Esther; Wurster, Sebastian; Page, Lukas; Löffler, Claudia; Bussemer, Lydia; Schmitt, Anna-Lena; Wolf, Thomas; et al. (Elsevier (Cell Press), 2020-11-17)
      High-throughput RNA sequencing (RNA-seq) is routinely applied to study diverse biological processes; however, when performed separately on interacting organisms, systemic noise intrinsic to RNA extraction, library preparation, and sequencing hampers the identification of cross-species interaction nodes. Here, we develop triple RNA-seq to simultaneously detect transcriptomes of monocyte-derived dendritic cells (moDCs) infected with the frequently co-occurring pulmonary pathogens Aspergillus fumigatus and human cytomegalovirus (CMV). Comparing expression patterns after co-infection with those after single infections, our data reveal synergistic effects and mutual interferences between host responses to the two pathogens. For example, CMV attenuates the fungus-mediated activation of pro-inflammatory cytokines through NF-κB (nuclear factor κB) and NFAT (nuclear factor of activated T cells) cascades, while A. fumigatus impairs viral clearance by counteracting viral nucleic acid-induced activation of type I interferon signaling. Together, the analytical power of triple RNA-seq proposes molecular hubs in the differential moDC response to fungal/viral single infection or co-infection that contribute to our understanding of the etiology and, potentially, clearance of post-transplant infections.
    • Virus Irradiation and COVID-19 Disease

      Durante, Marco; Schulze, Kai; Incerti, Sebastien; Francis, Ziad; Zein, Sara; Guzmán, Carlos Alberto; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Frontiers, 2020-10-20)
      Virus irradiation has been performed for many decades for basic research studies, sterilization, and vaccine development. The COVID-19 outbreak is currently causing an enormous effort worldwide for finding a vaccine against coronavirus. High doses of γ-rays can be used for the development of vaccines that exploit inactivated virus. This technique has been gradually replaced by more practical methods, in particular the use of chemicals, but irradiation remains a simple and effective method used in some cases. The technique employed for inactivating a virus has an impact on its ability to induce an adaptive immune response able to confer effective protection. We propose here that accelerated heavy ions can be used to inactivate SARS-CoV-2 viruses with small damage to the spike proteins of the envelope and can then provide an intact virion for vaccine development.
    • Towards Reduction or Substitution of Cytotoxic DMSO in Biobanking of Functional Bioengineered Megakaryocytes.

      Pogozhykh, Denys; Eicke, Dorothee; Gryshkov, Oleksandr; Wolkers, Willem F; Schulze, Kai; Guzmán, Carlos A; Blasczyk, Rainer; Figueiredo, Constança; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2020-10-16)
      Donor platelet transfusion is currently the only efficient treatment of life-threatening thrombocytopenia, but it is highly challenged by immunological, quality, and contamination issues, as well as short shelf life of the donor material. Ex vivo produced megakaryocytes and platelets represent a promising alternative strategy to the conventional platelet transfusion. However, practical implementation of such strategy demands availability of reliable biobanking techniques, which would permit eliminating continuous cell culture maintenance, ensure time for quality testing, enable stock management and logistics, as well as availability in a ready-to-use manner. At the same time, protocols applying DMSO-based cryopreservation media were associated with increased risks of adverse long-term side effects after patient use. Here, we show the possibility to develop cryopreservation techniques for iPSC-derived megakaryocytes under defined xeno-free conditions with significant reduction or complete elimination of DMSO. Comprehensive phenotypic and functional in vitro characterization of megakaryocytes has been performed before and after cryopreservation. Megakaryocytes cryopreserved DMSO-free, or using low DMSO concentrations, showed the capability to produce platelets in vivo after transfusion in a mouse model. These findings propose biobanking approaches essential for development of megakaryocyte-based replacement and regenerative therapies.
    • The avid competitors of memory inflation.

      Abassi, Leila; Cicin-Sain, Luka; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier, 2020-10-08)
      Cytomegaloviruses (CMV) coevolve with their hosts and latently persist in the vast majority of adult mammals. Therefore, persistent T-cell responses to CMV antigens during virus latency offer a fascinating perspective on the evolution of the T-cell repertoire in natural settings. We addressed here the life-long interactions between CMV antigens presented on MHC-I molecules and the CD8 T-cell response. We present the mechanistic evidence from the murine model of CMV infection and put it in context of clinical laboratory results. We will highlight the remarkable parallels in T-cell responses between the two biological systems, and focus in particular on memory inflation as a result of competitive processes, both between viral antigenic peptides and between T-cell receptors on the host’s cytotoxic lymphocytes
    • Next Generation Influenza Vaccines: Looking into the Crystal Ball.

      Guzmán, Carlos Alberto; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2020-08-21)
      Influenza infections are responsible for significant number of deaths and overwhelming costs worldwide every year. Vaccination represents the only cost-efficient alternative to address this major problem in human health. However, current vaccines are fraught by many limitations, being far from optimal. Among them, the need to upgrade vaccines every year through a time-consuming process open to different caveats, and the critical fact that they exhibit poorer efficacy in individuals who are at high risk for severe infections. Where are we? How can knowledge and technologies contribute towards removing current roadblocks? What does the future offer in terms of next generation vaccines?
    • Seropositivity for pathogens associated with chronic infections is a risk factor for all-cause mortality in the elderly: findings from the Memory and Morbidity in Augsburg Elderly (MEMO) Study.

      Zeeb, Marius; Kerrinnes, Tobias; Cicin-Sain, Luka; Guzman, Carlos A; Puppe, Wolfram; Schulz, Thomas F; Peters, Annette; Berger, Klaus; Castell, Stefanie; Karch, André; et al. (Springer, 2020-07-09)
      Immunostimulation by chronic infection has been linked to an increased risk for different non-communicable diseases, which in turn are leading causes of death in high- and middle-income countries. Thus, we investigated if a positive serostatus for pathogens responsible for common chronic infections is individually or synergistically related to reduced overall survival in community dwelling elderly. We used data of 365 individuals from the German MEMO (Memory and Morbidity in Augsburg Elderly) cohort study with a median age of 73 years at baseline and a median follow-up of 14 years. We examined the effect of a positive serostatus at baseline for selected pathogens associated with chronic infections (Helicobacter pylori, Borrelia burgdorferi sensu lato, Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1/2, and human herpesvirus 6) on all-cause mortality with multivariable parametric survival models. We found a reduced survival time in individuals with a positive serostatus for Helicobacter pylori (accelerated failure time (AFT) - 15.92, 95% CI - 29.96; - 1.88), cytomegalovirus (AFT - 22.81, 95% CI - 36.41; - 9.22) and Borrelia burgdorferi sensu lato (AFT - 25.25, 95% CI - 43.40; - 7.10), after adjusting for potential confounders. The number of infectious agents an individual was seropositive for had a linear effect on all-cause mortality (AFT per additional infection - 12.42 95% CI - 18.55; - 6.30). Our results suggest an effect of seropositivity for Helicobacter pylori, cytomegalovirus, and Borrelia burgdorferi sensu lato on all-cause mortality in older community dwelling individuals. Further research with larger cohorts and additional biomarkers is required, to assess mediators and molecular pathways of this effect.
    • Responsiveness to Influenza Vaccination Correlates with NKG2C-Expression on NK Cells.

      Riese, Peggy; Trittel, Stephanie; Pathirana, Rishi D; Klawonn, Frank; Cox, Rebecca J; Guzmán, Carlos A; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2020-06-05)
      Influenza vaccination often results in a large percentage of low responders, especially in high-risk groups. As a first line of defense, natural killer (NK) cells play a crucial role in the fight against infections. However, their implication with regard to vaccine responsiveness is insufficiently assessed. Therefore, this study aimed at the validation of essential NK cell features potentially associated with differential vaccine responsiveness with a special focus on NKG2C- and/or CD57-expressing NK cells considered to harbor memory-like functions. To this end, 16 healthy volunteers were vaccinated with an adjuvanted pandemic influenza vaccine. Vaccine responders and low responders were classified according to their hemagglutination inhibition antibody titers. A majority of responders displayed enhanced frequencies of NKG2C-expressing NK cells 7- or 14-days post-vaccination as compared to low responders, whereas the expression of CD57 was not differentially modulated. The NK cell cytotoxic potential was found to be confined to CD56dimCD16+ NKG2C-expressing NK cells in the responders but not in the low responders, which was further confirmed by stochastic neighbor embedding analysis. The presented study is the first of its kind that ascribes CD56dimCD16+ NKG2C-expressing NK cells a crucial role in biasing adaptive immune responses upon influenza vaccination and suggests NKG2C as a potential biomarker in predicting pandemic influenza vaccine responsiveness.
    • Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells.

      Chaudhry, M Zeeshan; Casalegno-Garduno, Rosaely; Sitnik, Katarzyna M; Kasmapour, Bahram; Pulm, Ann-Kathrin; Brizic, Ilija; Eiz-Vesper, Britta; Moosmann, Andreas; Jonjic, Stipan; Mocarski, Edward S; et al. (National Academy of Sciences, 2020-05-22)
      Viral immune evasion is currently understood to focus on deflecting CD8 T cell recognition of infected cells by disrupting antigen presentation pathways. We evaluated viral interference with the ultimate step in cytotoxic T cell function, the death of infected cells. The viral inhibitor of caspase-8 activation (vICA) conserved in human cytomegalovirus (HCMV) and murine CMV (MCMV) prevents the activation of caspase-8 and proapoptotic signaling. We demonstrate the key role of vICA from either virus, in deflecting antigen-specific CD8 T cell-killing of infected cells. vICA-deficient mutants, lacking either UL36 or M36, exhibit greater susceptibility to CD8 T cell control than mutants lacking the set of immunoevasins known to disrupt antigen presentation via MHC class I. This difference is evident during infection in the natural mouse host infected with MCMV, in settings where virus-specific CD8 T cells are adoptively transferred. Finally, we identify the molecular mechanism through which vICA acts, demonstrating the central contribution of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.
    • Innate signalling molecules as genetic adjuvants do not alter the efficacy of a DNA-based influenza A vaccine.

      Lapuente, Dennis; Stab, Viktoria; Storcksdieck Genannt Bonsmann, Michael; Maaske, Andre; Köster, Mario; Xiao, Han; Ehrhardt, Christina; Tenbusch, Matthias; HZI, Helmholtz Zentrum für Infektionsforschung, GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (PLOS, 2020-04-03)
      In respect to the heterogeneity among influenza A virus strains and the shortcomings of current vaccination programs, there is a huge interest in the development of alternative vaccines that provide a broader and more long-lasting protection. Gene-based approaches are considered as promising candidates for such flu vaccines. In our study, innate signalling molecules from the RIG-I and the NALP3 pathways were evaluated as genetic adjuvants in intramuscular DNA immunizations. Plasmids encoding a constitutive active form of RIG-I (cRIG-I), IPS-1, IL-1β, or IL-18 were co-administered with plasmids encoding the hemagglutinin and nucleoprotein derived from H1N1/Puerto Rico/8/1934 via electroporation in BALB/c mice. Immunogenicity was analysed in detail and efficacy was demonstrated in homologous and heterologous influenza challenge experiments. Although the biological activities of the adjuvants have been confirmed by in vitro reporter assays, their single or combined inclusion in the vaccine did not result in superior vaccine efficacy. With the exception of significantly increased levels of antigen-specific IgG1 after the co-administration of IL-1β, there were only minor alterations concerning the immunogenicity. Since DNA electroporation alone induced substantial inflammation at the injection site, as demonstrated in this study using Mx2-Luc reporter mice, it might override the adjuvants´ contribution to the inflammatory microenvironment and thereby minimizes the influence on the immunogenicity. Taken together, the DNA immunization was protective against subsequent challenge infections but could not be further improved by the genetic adjuvants analysed in this study.
    • Nanoparticles as A Tool for Broadening Antifungal Activities.

      Renzi, Daniele Fernanda; de Almeida Campos, Laís; Miranda, Eduardo Hösel; Mainardes, Rubiana Mara; Abraham, Wolf-Rainer; Grigoletto, Diana Fortkamp; Khalil, Najeh Maissar; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Bentham Science Publisher, 2020-03-30)
      The Fungal infections are diseases that are considered neglected although their infection rates have increased worldwide in the last decades. Thus, since the antifungal arsenal is restricted and many strains have shown resistance new therapeutic alternatives are necessary. Nanoparticles are considered important alternatives to promote drug delivery. In this sense, the objective of the present study was to evaluate the contributions of newly developed nanoparticles to the treatment of fungal infections. Studies have shown that nanoparticles generally improve the biopharmaceutical and pharmacokinetic characteristics of antifungals, which is reflected in a greater pharmacodynamic potential and lower toxicity, as well as the possibility of prolonged action. It also offers the proposition of new routes of administration. Nanotechnology is known to contribute to a new drug delivery system, not only for the control of infectious diseases, but for various other diseases as well. In recent years, several studies have emphasized its application in infectious diseases, presenting better alternatives for the treatment of fungal infections.
    • Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17.

      Bugatti, Antonella; Marsico, Stefania; Mazzuca, Pietro; Schulze, Kai; Ebensen, Thomas; Giagulli, Cinzia; Peña, Esther; Badimón, Lina; Slevin, Mark; Caruso, Arnaldo; et al. (MDPI, 2020-03-16)
    • Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging.

      Nikolich-Žugich, Janko; Čicin-Šain, Luka; Collins-McMillen, Donna; Jackson, Sarah; Oxenius, Annette; Sinclair, John; Snyder, Christopher; Wills, Mark; Lemmermann, Niels (Springer, 2020-03-11)
      The complexity of host-associated microbial ecosystems requires host-specific reference catalogs to survey the functions and diversity of these communities. We generate a comprehensive resource, the integrated mouse gut metagenome catalog (iMGMC), comprising 4.6 million unique genes and 660 metagenome-assembled genomes (MAGs), many (485 MAGs, 73%) of which are linked to reconstructed full-length 16S rRNA gene sequences. iMGMC enables unprecedented coverage and taxonomic resolution of the mouse gut microbiota; i.e., more than 92% of MAGs lack species-level representatives in public repositories (<95% ANI match). The integration of MAGs and 16S rRNA gene data allows more accurate prediction of functional profiles of communities than predictions based on 16S rRNA amplicons alone. Accompanying iMGMC, we provide a set of MAGs representing 1,296 gut bacteria obtained through complementary assembly strategies. We envision that integrated resources such as iMGMC, together with MAG collections, will enhance the resolution of numerous existing and future sequencing-based studies.
    • Mucosal Heterologous Prime/Boost Vaccination Induces Polyfunctional Systemic Immunity, Improving Protection Against .

      Sanchez Alberti, Andrés; Bivona, Augusto E; Matos, Marina N; Cerny, Natacha; Schulze, Kai; Weißmann, Sebastian; Ebensen, Thomas; González, Germán; Morales, Celina; Cardoso, Alejandro C; et al. (Frontiers, 2020-02-21)
      There are several unmet needs in modern immunology. Among them, vaccines against parasitic diseases and chronic infections lead. Trypanosoma cruzi, the causative agent of Chagas disease, is an excellent example of a silent parasitic invasion that affects millions of people worldwide due to its progression into the symptomatic chronic phase of infection. In search for novel vaccine candidates, we have previously introduced Traspain, an engineered trivalent immunogen that was designed to address some of the known mechanisms of T. cruzi immune evasion. Here, we analyzed its performance in different DNA prime/protein boost protocols and characterized the systemic immune response associated with diverse levels of protection. Formulations that include a STING agonist, like c-di-AMP in the boost doses, were able to prime a Th1/Th17 immune response. Moreover, comparison between them showed that vaccines that were able to prime polyfunctional cell-mediated immunity at the CD4 and CD8 compartment enhanced protection levels in the murine model. These findings contribute to a better knowledge of the desired vaccine-elicited immunity against T. cruzi and promote the definition of a vaccine correlate of protection against the infection.
    • Knockdown of Virus Antigen Expression Increases Therapeutic Vaccine Efficacy in High-titer HBV Carrier Mice.

      Michler, Thomas; Kosinska, Anna D; Festag, Julia; Bunse, Till; Su, Jinpeng; Ringelhan, Marc; Imhof, Hortenzia; Grimm, Dirk; Steiger, Katja; Mogler, Carolin; et al. (Elsevier, 2020-01-28)
      In both models of HBV infection, mice that express hepatocyte-specific small hairpin RNAs or that were given subcutaneous injections of siRNAs had reduced levels of HBV antigens, HBV replication, and viremia (1-3 log10 reduction), compared to mice given control RNAs. Vaccination induced production of HBV-neutralizing antibodies, and increased numbers and functionality of HBV-specific, CD8+ T-cells in mice with low, but not in mice with high levels of HBV antigen. Mice with initially high titers of HBV and knockdown of HBV antigen expression, but not mice with reduced viremia following administration of entecavir, developed polyfunctional, HBV-specific CD8+ T cells and HBV was eliminated.
    • Secondary metabolites produced by endophytic fungi: novel antifungal activity of fumiquinone B

      Grigoletto, Diana Fortkamp; Correia, Ana Maria Lima; Abraham, Wolf-Rainer; Rodrigues, Andre; Assis, Marco Antonio; Ferreira, Antonio Gilberto; Massaroli, Michelli; Lira, Simone Possedente de; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Universidade Estadual de Maringa, 2019-12-18)
      Fungi are present in the most diverse environments including the interior of plant tissues, living as endophytes without causing apparent damage. These endophytes are producers of secondary metabolites, also known as natural products, such as fungicides. Here, we evaluated the ethyl acetate fractions obtained from endophytic fungi isolated from plants in the genus Begonia. The fractions were submitted to inhibitory test against the plant pathogens Diaporthe phaseolorum and Colletotrichum gloeosporioides. From the 88 ethyl acetate fractions evaluated, 14.7 % inhibited C. gloeosporioides and 11.3 % inhibited D. phaseolorum. One fungal isolate displaying an active fraction was selected for chemical investigation. The fungus identified as Neopestalotiopsis sp., produced a compound that was active against D. phaseolorum, with a MIC of 312 µg mL-1 (1,695.3 µM). The compound was identified by mass spectrometry and 1H NMR as the known compound fumiquinone B. The results highlight that the endophytes are capable of producing compounds that may be used to control plant pathogens. The compound fumiquinone B is reported for the first time as an antifungal agent against D. phaseolorum, a relevant plant pathogen worldwide. This is also the first report of the production of fumiquinone B by the genus Neopestalotiopsis.
    • Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use

      Beauclair, Guillaume; Naimo, Eleonora; Dubich, Tatyana; Rückert, Jessica; Koch, Sandra; Dhingra, Akshay; Wirth, Dagmar; Schulz, Thomas F; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (American Society for Microbiology (ASM), 2019-12-11)
      Kaposi's Sarcoma-associated herpesvirus (KSHV) is the cause of three human malignancies, Kaposi's Sarcoma, Primary Effusion Lymphoma and the plasma cell variant of Multicentric Castleman's Disease. Previous research has shown that several cellular tyrosine kinases play crucial roles during several steps in the virus replication cycle. Two KSHV proteins also have protein kinase function: open reading frame (ORF) 36 encodes a serin-threonine kinase, while ORF21 encodes a thymidine kinase (TK), which has recently been found to be an efficient tyrosine kinase. In this study, we explore the role of the ORF21 tyrosine kinase function in KSHV lytic replication. By generating a recombinant KSHV mutant with an enzymatically inactive ORF21 protein we show that the tyrosine kinase function of ORF21/TK is not required for the progression of the lytic replication in tissue culture, but that it is essential for the phosphorylation and activation to toxic moieties of the antiviral drugs zidovudine and brivudine. In addition, we identify several tyrosine kinase inhibitors, already in clinical use against human malignancies, which potently inhibit not only ORF21 TK kinase function, but also viral lytic reactivation and the development of KSHV-infected endothelial tumors in mice. As they target both cellular tyrosine kinases and a viral kinase, some of these compounds might find a use in the treatment of KSHV-associated malignancies.Importance: Our findings address the role of KSHV ORF21 as a tyrosine kinase during lytic replication and the activation of prodrugs in KSHV-infected cells. We also show the potential of selected clinically approved tyrosine kinase inhibitors to inhibit KSHV TK, KSHV lytic replication, infectious virions release and the development of an endothelial tumor. Since they target both cellular tyrosine kinases supporting productive viral replication and a viral kinase, these drugs, which are already approved for clinical use, may be suitable for repurposing for the treatment of KSHV-related tumors in AIDS patients or transplant recipients.
    • PD-1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator-activated receptor-γ.

      Batyrova, Banu; Luwaert, Fien; Maravelia, Panagiota; Miyabayashi, Yuria; Vashist, Neha; Stark, Julian M; Soori, Sara Y; Tibbitt, Christopher A; Riese, Peggy; Coquet, Jonathan M; et al. (Wiley, 2019-11-19)
      Innate lymphoid cells (ILCs) can provide early cytokine help against a variety of pathogens in the lungs and gastrointestinal tract. Type 2 ILC (ILC2) are comparable to T helper 2 cells found in the adaptive immune system, which secrete cytokines such as interleukin 5 (IL-5) and IL-13 and have been found to play roles in host defense against helminth infections and in allergic responses. Recent studies have identified that programmed cell death protein 1 (PD-1) and peroxisome proliferator activated receptor-γ (PPAR-γ) are highly expressed by ILC2. We examined whether PD-1 plays a role in ILC2 function and whether there was any connection between PD-1 and PPAR-γ METHODS: To ensure that only innate immune cells were present, ILC2 cells were examined from RAG1-/- and PD-1-/- xRAG1-/- mice under steady-state or following inoculation with IL-33. We also tested ILC2 generated from bone marrow of RAG1-/- and PD-1-/- xRAG1-/- mice for their production of cytokines. These in vitro-derived ILC2 were also exposed to agonist and antagonist of PPAR-γ.
    • Key features and homing properties of NK cells in the liver are shaped by activated iNKT cells.

      Trittel, Stephanie; Chambers, Benedict J; Heise, Ulrike; Guzmán, Carlos A; Riese, Peggy; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Springer-Nature, 2019-11-08)
      The contribution of natural killer (NK) cells to the clearance of hepatic viral infections is well recognized. The recently discovered heterogeneity of NK cell populations renders them interesting targets for immune interventions. Invariant natural killer T (iNKT) cells represent a key interaction partner for hepatic NK cells. The present study addressed whether characteristics of NK cells in the liver can be shaped by targeting iNKT cells. For this, the CD1d-binding pegylated glycolipid αGalCerMPEG was assessed for its ability to modulate the features of NK cells permanently or transiently residing in the liver. In vivo administration resulted in enhanced functionality of educated and highly differentiated CD27+ Mac-1+ NK cells accompanied by an increased proliferation. Improved liver homing was supported by serum-derived and cellular factors. Reduced viral loads in a mCMV infection model confirmed the beneficial effect of NK cells located in the liver upon stimulation with αGalCerMPEG. Thus, targeting iNKT cell-mediated NK cell activation in the liver represents a promising approach for the establishment of liver-directed immune interventions.