Biology subjects

Massberg, S.

Publications and source records attributed to Massberg, S..

5 recordsLinked to original sources

bioRxiv2026

Neutrophils are critical for placental and fetal infection with the human pathogen Listeria monocytogenes

Fetal listeriosis, caused by Listeria monocytogenes (Lm), represents a severe infectious disease. During pregnancy, the unique intrauterine environment permits Lm to breach the maternal-fetal barrier by infiltrating the placental trophoblast layer and ultimately leading to significant fetal morbidity and mortality. However, the exact pathways remain incompletely understood. In this study, we sought to elucidate the molecular mechanisms underlying the early stages of placental and fetal Lm infection. Our results reveal that neutrophils serve as a survival niche for Lm within the vasculature, facilitating placental and fetal infection in the mouse in vivo. This finding was further substantiated by in vitro studies using TLR2-stimulated trophoblast cells and Lm-infected neutrophils. Additionally, tissue-clearing analysis of Lm-infected placentas demonstrated neutrophil colocalization with Lm is rare within placental tissue. Collectively, our findings identify maternal neutrophils as an essential viability niche for Lm enabling their entry into trophoblast cells, thereby promoting placental and fetal infection. One Sentence SummaryMaternal circulating neutrophils act as survival niche for Listeria monocytogenes and facilitate placental/fetal infection with Listeria during pregnancy.

immunology↗

bioRxiv2024

Immunothrombolytic monocyte-neutrophil axes dominate the single-cell landscape of human thrombosis

AbstractThrombotic diseases remain the major cause of death and disability worldwide with insufficient preventive and therapeutic strategies available. In the last decades a prominent inflammatory component has been identified as a key driver in the initiation and propagation of thrombosis - named thromboinflammation. However, a comprehensive investigation of the human immune system in thromboinflammation, beyond histological quantification, is lacking, which is essential for the development of novel therapeutic approaches. We therefore mapped the trajectories, functional states, and intercommunication of immune cells in stroke thrombi, retrieved by thrombectomy, at single-cell resolution. We reveal distinct leukocyte subpopulations with prothrombotic and, surprisingly, prominent fibrinolytic properties characterized by aberrant activation of intracellular host defense as well as hypoxia induced pathways. A prominent thrombolytic PLAUhigh, PLAURhigh, THBDhigh thrombus neutrophil subset, also expressing high levels of pro-recanalizing VEGFA and VEGFB, dominated the thrombus neutrophil environment. On the other hand CD16high NR4A1high non-classical monocytes with strong CXCL8, CXCL2, CXCL1 and CXCL16 mediated neutrophil- attracting and PLAU, PLAUR, THBD and TFPI mediated thrombolytic properties defined the thrombus monocyte environment. These thrombus monocyte subsets were characterized by high expression of TIMP1 and TREM1. These novel innate immune- cell subsets provide insights into the thrombogenic and pro-resolving properties of innate immune-cells. To provide mechanistic insight into these multi-omic findings, we utilized reverse translation approaches. In vitro as well as murine in vivo thrombosis models underlined the causal relevance of these immune-cell axes for thrombolysis: NR4A1high thrombus monocytes acquired a neutrophil-chemoattractive transcriptomic phenotype, neutrophils continuously infiltrated established murine thrombi in vivo and acquired a HIF1-mediated thrombolytic phenotype in vitro. A depletion of NR4A1high thrombus monocytes reduced thrombus neutrophil influx and exacerbated thrombosis in vivo. Together, this unravels cross-communicating monocyte and neutrophil subsets with thrombus-resolving properties and provide a publicly accessible immune-landscape of thrombosis. This provides a valuable resource for future research on thrombo- inflammation and might pave the way for novel immune-modulatory approaches for prevention or resolution of thrombosis.

immunology↗

bioRxiv2022

Plasmacytoid dendritic cells regulate megakaryocyte and platelet homeostasis

Platelet homeostasis is essential for vascular integrity and immune defense. While the process of platelet formation by fragmenting megakaryocytes (thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of megakaryocytes by their progenitor cells (megakaryopoiesis) remains unclear. Here we use intravital 2 photon microscopy to track individual megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as crucial bone marrow niche cells that regulate megakaryopoiesis. pDCs monitor the bone marrow for platelet-producing megakaryocytes and deliver IFN- to the megakaryocytic niche to trigger local on-demand proliferation of megakaryocyte progenitors. This fine-tuned coordination between thrombopoiesis and megakaryopoiesis is crucial for megakaryocyte and platelet homeostasis in steady state and stress. However, uncontrolled pDC function within the megakaryocytic niche is detrimental. Accordingly, we show that pDCs activated by SARS-CoV2 drive inappropriate megakaryopoiesis associated with thrombotic complications. Together, we uncover a hitherto unknown megakaryocytic bone marrow niche maintained by the constitutive delivery of pDC-derived IFN-.

immunology↗

bioRxiv2021

Thrombocytopenia and splenic platelet directed immune responses after intravenous ChAdOx1 nCov-19 administration

Summary paragraphVaccines against SARS-CoV-2 are based on a range of novel vaccine platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently a rare and novel complication of SARS-CoV-2 targeted adenovirus vaccines has emerged: thrombosis with thrombocytopenia syndrome (TTS). TTS is characterized by low platelet counts, clot formation at unusual anatomic sites and platelet-activating PF4-polyanion antibodies reminiscent of heparin-induced thrombocytopenia. Here, we employ in vitro and in vivo models to characterize the possible mechanisms of this platelet-targeted autoimmunity. We show that intravenous but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation. After intravenous injection, these aggregates are phagocytosed by macrophages in the spleen and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of TTS and highlights accidental intravenous injection as potential mechanism for post-vaccination TTS. Hence, safe intramuscular injection, with aspiration prior to injection, could be a potential preventive measure when administering adenovirus-based vaccines.

immunology↗

bioRxiv2021

Protective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection

The immune system of most SARS-CoV-2 infected individuals limits viral spread to the upper airways without pulmonary involvement. This prevents the development of pneumonic COVID-19. However, the protective immunological responses causative of successful viral containment in the upper airways remain unclear. Here, we combine longitudinal single-cell RNA sequencing, proteomic profiling, multidimensional flow cytometry, RNA-Seq of FACS-sorted leukocyte subsets and multiplex plasma interferon profiling to uncover temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients. We compare host responses in a high-risk patient population infected with SARS-CoV-2 but without pulmonary involvement to patients with COVID-19 pneumonia. Our data reveal a distinct immunological signature of successful viral containment, characterized by an early prominent interferon stimulated gene (ISG) upregulation across immune cell subsets. In addition, reduced cytotoxic potential of Natural Killer (NK) and T cells, as well as a monocyte phenotype with immune-modulatory potential are hallmarks of protective immunity. Temporal resolution across disease trajectories highlights ISG upregulation as particularly prominent early in the disease and confirms increased expression also in comparison to healthy controls. We validate this distinct temporal ISG signature by in-depth RNA-seq of FACS-sorted leukocyte subsets in a large prospective ambulatory SARS-CoV-2 infected cohort confirming early and robust ISG upregulation particularly in monocytes and T cells. In conclusion, our data demonstrate a protective ISG phenotype in patients with successful containment of SARS-CoV-2 infection without progression to COVID-19. This early protective interferon response might be exploited as a therapeutic approach and for disease course prediction.

immunology↗