publications of the research group infection genetics (INFG)http://hdl.handle.net/10033/6206272024-03-29T05:07:05Z2024-03-29T05:07:05ZItaconate 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.
2022-01-13T00:00:00ZExogenous and Endogenous Triggers Differentially Stimulate Pigr Expression and Antibacterial Secretory Immunity in the Murine Respiratory Tract.Pausder, AlexanderFricke, JenniferSchughart, KlausSchreiber, JensStrowig, TillBruder, DunjaBoehme, Juliahttp://hdl.handle.net/10033/6231462022-01-19T01:58:26Z2021-11-26T00:00:00ZExogenous and Endogenous Triggers Differentially Stimulate Pigr Expression and Antibacterial Secretory Immunity in the Murine Respiratory Tract.
Pausder, Alexander; Fricke, Jennifer; Schughart, Klaus; Schreiber, Jens; Strowig, Till; Bruder, Dunja; Boehme, Julia
Purpose: Transport of secretory immunoglobulin A (SIgA) through the airway epithelial cell barrier into the mucosal lumen by the polymeric immunoglobulin receptor (pIgR) is an important mechanism of respiratory mucosal host defense. Identification of immunomodulating substances that regulate secretory immunity might have therapeutic implications with regard to an improved immune exclusion. Thus, we sought to analyze secretory immunity under homeostatic and immunomodulating conditions in different compartments of the murine upper and lower respiratory tract (URT&LRT).
Methods: Pigr gene expression in lung, trachea, and nasal-associated lymphoid tissue (NALT) of germ-free mice, specific pathogen-free mice, mice with an undefined microbiome, as well as LPS- and IFN-γ-treated mice was determined by quantitative real-time PCR. IgA levels in bronchoalveolar lavage (BAL), nasal lavage (NAL), and serum were determined by ELISA. LPS- and IFN-γ-treated mice were colonized with Streptococcus pneumoniae and bacterial CFUs were determined in URT and LRT.
Results: Respiratory Pigr expression and IgA levels were dependent on the degree of exposure to environmental microbial stimuli. While immunostimulation with LPS and IFN-γ differentially impacts respiratory Pigr expression and IgA in URT vs. LRT, only prophylactic IFN-γ treatment reduces nasal colonization with S. pneumoniae.
Conclusion: Airway-associated secretory immunity can be partly modulated by exposure to microbial ligands and proinflammatory stimuli. Prophylactic IFN-γ-treatment modestly improves antibacterial immunity in the URT, but this does not appear to be mediated by SIgA or pIgR.
2021-11-26T00:00:00ZThe Host Response to Viral Infections Reveals Common and Virus-Specific Signatures in the Peripheral Blood.Tsalik, Ephraim LFiorino, CassandraAqeel, AmmaraLiu, YilingHenao, RicardoKo, Emily RBurke, Thomas WReller, Megan EBodinayake, Champica KNagahawatte, AjithArachchi, Wasantha KDevasiri, VasanthaKurukulasooriya, RuviniMcClain, Micah TWoods, Christopher WGinsburg, Geoffrey STillekeratne, L GayaniSchughart, Klaushttp://hdl.handle.net/10033/6231442022-01-15T01:50:02Z2021-10-27T00:00:00ZThe Host Response to Viral Infections Reveals Common and Virus-Specific Signatures in the Peripheral Blood.
Tsalik, Ephraim L; Fiorino, Cassandra; Aqeel, Ammara; Liu, Yiling; Henao, Ricardo; Ko, Emily R; Burke, Thomas W; Reller, Megan E; Bodinayake, Champica K; Nagahawatte, Ajith; Arachchi, Wasantha K; Devasiri, Vasantha; Kurukulasooriya, Ruvini; McClain, Micah T; Woods, Christopher W; Ginsburg, Geoffrey S; Tillekeratne, L Gayani; Schughart, Klaus
Viruses cause a wide spectrum of clinical disease, the majority being acute respiratory infections (ARI). In most cases, ARI symptoms are similar for different viruses although severity can be variable. The objective of this study was to understand the shared and unique elements of the host transcriptional response to different viral pathogens. We identified 162 subjects in the US and Sri Lanka with infections due to influenza, enterovirus/rhinovirus, human metapneumovirus, dengue virus, cytomegalovirus, Epstein Barr Virus, or adenovirus. Our dataset allowed us to identify common pathways at the molecular level as well as virus-specific differences in the host immune response. Conserved elements of the host response to these viral infections highlighted the importance of interferon pathway activation. However, the magnitude of the responses varied between pathogens. We also identified virus-specific responses to influenza, enterovirus/rhinovirus, and dengue infections. Influenza-specific differentially expressed genes (DEG) revealed up-regulation of pathways related to viral defense and down-regulation of pathways related to T cell and neutrophil responses. Functional analysis of entero/rhinovirus-specific DEGs revealed up-regulation of pathways for neutrophil activation, negative regulation of immune response, and p38MAPK cascade and down-regulation of virus defenses and complement activation. Functional analysis of dengue-specific up-regulated DEGs showed enrichment of pathways for DNA replication and cell division whereas down-regulated DEGs were mainly associated with erythrocyte and myeloid cell homeostasis, reactive oxygen and peroxide metabolic processes. In conclusion, our study will contribute to a better understanding of molecular mechanisms to viral infections in humans and the identification of biomarkers to distinguish different types of viral infections.
2021-10-27T00:00:00ZImpaired beta-oxidation increases vulnerability to influenza A infection.van Liempd, SebastiaanCabrera, DianaPilzner, CarolinKollmus, HeikeSchughart, KlausFalcón-Pérez, Juan Mhttp://hdl.handle.net/10033/6230932021-11-12T14:42:52Z2021-10-09T00:00:00ZImpaired beta-oxidation increases vulnerability to influenza A infection.
van Liempd, Sebastiaan; Cabrera, Diana; Pilzner, Carolin; Kollmus, Heike; Schughart, Klaus; Falcón-Pérez, Juan M
Influenza A virus (IAV) infection casts a significant burden on society. It has particularly high morbidity and mortality rates in patients suffering from metabolic disorders. The aim of this study was to relate metabolic changes with IAV susceptibility using well-characterized inbred mouse models. We compared the highly susceptible DBA/2J (D2) mouse strain for which IAV infection is lethal with the C57BL/6J (B6) strain, which exhibits a moderate course of disease and survives IAV infection. Previous studies showed that D2 has higher insulin and glucose levels and is predisposed to develop diet-induced type 2 diabetes. Using high-resolution liquid chromatography-coupled MS, the plasma metabolomes of individual animals were repeatedly measured up to 30 days postinfection. The biggest metabolic difference between these strains in healthy and infected states was in the levels of malonylcarnitine, which was consistently increased 5-fold in D2. Other interstrain and intrastrain differences in healthy and infected animals were observed for acylcarnitines, glucose, branched-chain amino acids, and oxidized fatty acids. By mapping metabolic changes to canonical pathways, we found that mitochondrial beta-oxidation is likely disturbed in D2 animals. In noninfected D2 mice, this leads to increased glycerolipid production and reduced acylcarnitine production, whereas in infected D2 animals, peroxisomal beta-oxidation becomes strongly increased. From these studies, we conclude that metabolic changes caused by a distortion of mitochondrial and peroxisomal metabolism might impact the innate immune response in D2, leading to high viral titers and mortality.
2021-10-09T00:00:00Z