publications of the service unit animal experimentation: (TEE)http://hdl.handle.net/10033/6206292024-03-16T01:00:41Z2024-03-16T01:00:41ZItaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.Sohail, AaqibIqbal, Azeem ASahini, NishikaChen, FangfangTantawy, MohamedWaqas, FakharWinterhoff, MoritzEbensen, ThomasSchultz, KristinGeffers, RobertSchughart, KlausPreusse, MatthiasShehata, MahmoudBähre, HeikePils, Marina CGuzman, Carlos AMostafa, AhmedPleschka, StephanFalk, ChristineMichelucci, AlessandroPessler, Frankhttp://hdl.handle.net/10033/6231642022-02-16T02:00:10Z2022-01-13T00:00:00ZItaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection.
Sohail, Aaqib; Iqbal, Azeem A; Sahini, Nishika; Chen, Fangfang; Tantawy, Mohamed; Waqas, Fakhar; Winterhoff, Moritz; Ebensen, Thomas; Schultz, Kristin; Geffers, Robert; Schughart, Klaus; Preusse, Matthias; Shehata, Mahmoud; Bähre, Heike; Pils, Marina C; Guzman, Carlos A; Mostafa, Ahmed; Pleschka, Stephan; Falk, Christine; Michelucci, Alessandro; Pessler, Frank
Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. Itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.
2022-01-13T00:00:00ZA Central Role for Atg5 in Microbiota-Dependent Foxp3 RORγt Treg Cell Preservation to Maintain Intestinal Immune Homeostasis.Plaza-Sirvent, CarlosZhao, BeiBronietzki, Alisha WPils, Marina CTafrishi, NedaSchuster, MarcStrowig, TillSchmitz, Ingohttp://hdl.handle.net/10033/6230822021-10-29T01:58:33Z2021-08-26T00:00:00ZA Central Role for Atg5 in Microbiota-Dependent Foxp3 RORγt Treg Cell Preservation to Maintain Intestinal Immune Homeostasis.
Plaza-Sirvent, Carlos; Zhao, Bei; Bronietzki, Alisha W; Pils, Marina C; Tafrishi, Neda; Schuster, Marc; Strowig, Till; Schmitz, Ingo
Autophagy is an evolutionary conserved catabolic pathway that ensures the degradation of intracellular components. The autophagic pathway is regulated by autophagy-related (Atg) proteins that govern formation of double-membraned vesicles called autophagosomes. Autophagy deficiency in regulatory T (Treg) cells leads to increased apoptosis of these cells and to the development of autoimmune disorders, predominantly characterized by intestinal inflammation. Recently, RORγt-expressing Treg cells have been identified as key regulators of gut homeostasis, preventing intestinal immunopathology. To study the role of autophagy in RORγt+ Foxp3+ Treg cells, we generated mice lacking the essential component of the core autophagy machinery Atg5 in Foxp3+ cells. Atg5 deficiency in Treg cells led to a predominant intestinal inflammation. While Atg5-deficient Treg cells were reduced in peripheral lymphoid organs, the intestinal RORγt+ Foxp3+ subpopulation of Treg cells was most severely affected. Our data indicated that autophagy is essential to maintain the intestinal RORγt+ Foxp3+ Treg population, thereby protecting the mice from gut inflammatory disorders.
2021-08-26T00:00:00ZCurbing gastrointestinal infections by defensin fragment modifications without harming commensal microbiota.Koeninger, LouisOsbelt, LisaBerscheid, AnneWendler, JudithBerger, JügenHipp, KatharinaMarina C Pils, Marina C.Nisar P Malek, Nisar P.Heike Brötz-Oesterhelt, HeikeStrowig, TillWehkamp, Janhttp://hdl.handle.net/10033/6227022021-01-27T01:35:37Z2021-01-08T00:00:00ZCurbing gastrointestinal infections by defensin fragment modifications without harming commensal microbiota.
Koeninger, Louis; Osbelt, Lisa; Berscheid, Anne; Wendler, Judith; Berger, Jügen; Hipp, Katharina; Marina C Pils, Marina C.; Nisar P Malek, Nisar P.; Heike Brötz-Oesterhelt, Heike; Strowig, Till; Wehkamp, Jan
The occurrence and spread of multidrug-resistant pathogens, especially bacteria from the ESKAPE panel, increases the risk to succumb to untreatable infections. We developed a novel antimicrobial peptide, Pam-3, with antibacterial and antibiofilm properties to counter this threat. The peptide is based on an eight-amino acid carboxyl-terminal fragment of human β-defensin 1. Pam-3 exhibited prominent antimicrobial activity against multidrug-resistant ESKAPE pathogens and additionally eradicated already established biofilms in vitro, primarily by disrupting membrane integrity of its target cell. Importantly, prolonged exposure did not result in drug-resistance to Pam-3. In mouse models, Pam-3 selectively reduced acute intestinal Salmonella and established Citrobacter infections, without compromising the core microbiota, hence displaying an added benefit to traditional broad-spectrum antibiotics. In conclusion, our data support the development of defensin-derived antimicrobial agents as a novel approach to fight multidrug-resistant bacteria, where Pam-3 appears as a particularly promising microbiota-preserving candidate.
2021-01-08T00:00:00ZPerturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation.Iljazovic, AidaRoy, UrmiGálvez, Eric J CLesker, Till RZhao, BeiGronow, AchimAmend, LenaWill, Sabine EHofmann, Julia DPils, Marina CSchmidt-Hohagen, KerstinNeumann-Schaal, MeinaStrowig, Tillhttp://hdl.handle.net/10033/6225412020-11-04T04:37:39Z2020-05-20T00:00:00ZPerturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation.
Iljazovic, Aida; Roy, Urmi; Gálvez, Eric J C; Lesker, Till R; Zhao, Bei; Gronow, Achim; Amend, Lena; Will, Sabine E; Hofmann, Julia D; Pils, Marina C; Schmidt-Hohagen, Kerstin; Neumann-Schaal, Meina; Strowig, Till
Diverse microbial signatures within the intestinal microbiota have been associated with intestinal and systemic inflammatory diseases, but whether these candidate microbes actively modulate host phenotypes or passively expand within the altered microbial ecosystem is frequently not known. Here we demonstrate that colonization of mice with a member of the genus Prevotella, which has been previously associated to colitis in mice, exacerbates intestinal inflammation. Our analysis revealed that Prevotella intestinalis alters composition and function of the ecosystem resulting in a reduction of short-chain fatty acids, specifically acetate, and consequently a decrease in intestinal IL-18 levels during steady state. Supplementation of IL-18 to Prevotella-colonized mice was sufficient to reduce intestinal inflammation. Hence, we conclude that intestinal Prevotella colonization results in metabolic changes in the microbiota, which reduce IL-18 production and consequently exacerbate intestinal inflammation, and potential systemic autoimmunity.
2020-05-20T00:00:00Z