Division of experimental infection research ([TC] EXPI)http://hdl.handle.net/10033/6206012024-03-29T05:00:11Z2024-03-29T05:00:11ZItaconate 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.
2022-01-13T00:00:00ZBeneficial and detrimental functions of microglia during viral encephalitis.Waltl, InkenKalinke, Ulrichhttp://hdl.handle.net/10033/6231582022-02-04T01:56:49Z2021-12-11T00:00:00ZBeneficial and detrimental functions of microglia during viral encephalitis.
Waltl, Inken; Kalinke, Ulrich
icroglia are resident immune cells of the central nervous system (CNS) with multiple functions in health and disease. Their response during encephalitis depends on whether inflammation is triggered in a sterile or infectious manner, and in the latter case on the type of the infecting pathogen. Even though recent technological innovations advanced the understanding of the broad spectrum of microglia responses during viral encephalitis (VE), it is not entirely clear which microglia gene expression profiles are associated with antiviral and detrimental activities. Here, we review novel approaches to study microglia and the latest concepts of their function in VE. Improved understanding of microglial functions will be essential for the development of new therapeutic interventions for VE.
2021-12-11T00:00:00ZToll-like Receptors in Viral Encephalitis.Gern, Olivia LuiseMulenge, FelixPavlou, AndreasGhita, LucaSteffen, ImkeStangel, MartinKalinke, Ulrichhttp://hdl.handle.net/10033/6231562022-02-02T02:04:24Z2021-10-14T00:00:00ZToll-like Receptors in Viral Encephalitis.
Gern, Olivia Luise; Mulenge, Felix; Pavlou, Andreas; Ghita, Luca; Steffen, Imke; Stangel, Martin; Kalinke, Ulrich
Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections.
2021-10-14T00:00:00ZCongenital deficiency reveals critical role of ISG15 in skin homeostasis.Malik, Muhammad Nasir HayatWaqas, Syed F HassnainZeitvogel, JanaCheng, JingyuanGeffers, RobertGouda, Zeinab Abu-ElbahaElsaman, Ahmed MahrousRadwan, Ahmed RSchefzyk, MatthiasBraubach, PeterAuber, BerndOlmer, RuthMüsken, MathiasRoesner, Lennart MGerold, GisaSchuchardt, SvenMerkert, SylviaMartin, UlrichMeissner, FelixWerfel, ThomasPessler, Frankhttp://hdl.handle.net/10033/6231362022-01-12T01:50:58Z2021-11-30T00:00:00ZCongenital deficiency reveals critical role of ISG15 in skin homeostasis.
Malik, Muhammad Nasir Hayat; Waqas, Syed F Hassnain; Zeitvogel, Jana; Cheng, Jingyuan; Geffers, Robert; Gouda, Zeinab Abu-Elbaha; Elsaman, Ahmed Mahrous; Radwan, Ahmed R; Schefzyk, Matthias; Braubach, Peter; Auber, Bernd; Olmer, Ruth; Müsken, Mathias; Roesner, Lennart M; Gerold, Gisa; Schuchardt, Sven; Merkert, Sylvia; Martin, Ulrich; Meissner, Felix; Werfel, Thomas; Pessler, Frank
Ulcerating skin lesions are manifestations of human ISG15 deficiency, a type I interferonopathy. However, chronic inflammation may not be their exclusive cause. We describe two siblings with recurrent skin ulcers that healed with scar formation upon corticosteroid treatment. Both had a homozygous nonsense mutation in the ISG15 gene, leading to unstable ISG15 protein lacking the functional domain. We characterized ISG15-/- dermal fibroblasts, HaCaT keratinocytes, and human induced pluripotent stem cell-derived vascular endothelial cells. ISG15-deficient cells exhibited the expected hyperinflammatory phenotype, but also dysregulated expression of molecules critical for connective tissue and epidermis integrity, including reduced collagens and adhesion molecules, but increased matrix metalloproteases. ISG15-/- fibroblasts exhibited elevated ROS levels and reduced ROS scavenger expression. As opposed to hyperinflammation, defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15. Cell migration was retarded in ISG15-/- fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an ISG15-/- 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-β1. These results reveal critical roles of ISG15 in maintaining cell migration and epidermis and connective tissue homeostasis, whereby the latter likely requires its conjugation to yet unidentified targets.
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