β2 integrin mediates hantavirus-induced release of neutrophil extracellular traps

Raftery, Martin; Lalwani, Pritesh; Krautkrämer, Ellen; Peters, Thorsten; Scharffetter‐­Kochanek, Karin; Krüger, Renate; Hofmann, Jörg; Seeger, Karl; Krüger, Detlev H.; Schönrich, Günther

doi:10.1084/jem.20131092

Cited by 166 publications

(160 citation statements)

References 72 publications

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“…NETs contribute to host defense by trapping microorganisms and limiting their spread, and by serving as a scaffold for thrombus formation on endothelium. However, excess NET formation (or impaired NET clearance) can lead to tissue damage and coagulopathies, and has been implicated in the pathogenesis of highly inflammatory conditions (e.g., sepsis) and other viral hemorrhagic fevers (Kaplan and Radic, 2012; Raftery et al, 2014). Consistent with the possibility of NET formation in EVD, core histone proteins (e.g., HIST3H2BB), and azurophilic granule proteins (MPO, CTSG, PRTN3, and AZU1) are present in the plasma of EVD patients but not that of healthy individuals (Fig.…”

Section: Resultsmentioning

confidence: 99%

Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

Eisfeld

Halfmann

Wendler

et al. 2017

Cell Host & Microbe

113

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SUMMARY The pathogenesis of Human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform ‘omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that EBOV infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity.

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Section: Resultsmentioning

confidence: 99%

Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

Eisfeld

Halfmann

Wendler

et al. 2017

Cell Host & Microbe

113

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“…Previous studies have shown that neutrophils are capable of recognizing IAV and IAV-infected cells (91)(92)(93)(94), although discrepancies in data suggest that neutrophil responses to IAV are dependent on the viral strain (92)(93)(94)(95). Interest in the role of neutrophils in viral disease is quickly growing (56,(96)(97)(98), and the topic deserves further research.…”

Section: Discussionmentioning

confidence: 99%

Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils

Camp

Bağcı

Chu

et al. 2015

J Virol

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Infection of the lower respiratory tract by influenza A viruses results in increases in inflammation and immune cell infiltration in the lung. The dynamic relationships among the lung microenvironments, the lung, and systemic host responses during infection remain poorly understood. Here we used extensive systematic histological analysis coupled with live imaging to gain access to these relationships in ferrets infected with the 2009 H1N1 pandemic influenza A virus (H1N1pdm virus). Neutrophil levels rose in the lungs of H1N1pdm virus-infected ferrets 6 h postinfection and became concentrated at areas of the H1N1pdm virusinfected bronchiolar epithelium by 1 day postinfection (dpi). In addition, neutrophil levels were increased throughout the alveolar spaces during the first 3 dpi and returned to baseline by 6 dpi. Histochemical staining revealed that neutrophil infiltration in the lungs occurred in two waves, at 1 and 3 dpi, and gene expression within microenvironments suggested two types of neutrophils. Specifically, CCL3 levels, but not CXCL8/interleukin 8 (IL-8) levels, were higher within discrete lung microenvironments and coincided with increased infiltration of neutrophils into the lung. We used live imaging of ferrets to monitor host responses within the lung over time with [18 F]fluorodeoxyglucose (FDG). Sites in the H1N1pdm virus-infected ferret lung with high FDG uptake had high levels of proliferative epithelium. In summary, neutrophils invaded the H1N1pdm virus-infected ferret lung globally and focally at sites of infection. Increased neutrophil levels in microenvironments did not correlate with increased FDG uptake; hence, FDG uptake may reflect prior infection and inflammation of lungs that have experienced damage, as evidenced by bronchial regeneration of tissues in the lungs at sites with high FDG levels. IMPORTANCESevere influenza disease is characterized by an acute infection of the lower airways that may progress rapidly to organ failure and death. Well-developed animal models that mimic human disease are essential to understanding the complex relationships of the microenvironment, organ, and system in controlling virus replication, inflammation, and disease progression. Employing the ferret model of H1N1pdm virus infection, we used live imaging and comprehensive histological analyses to address specific hypotheses regarding spatial and temporal relationships that occur during the progression of infection and inflammation. We show the general invasion of neutrophils at the organ level (lung) but also a distinct pattern of localized accumulation within the microenvironment at the site of infection. Moreover, we show that these responses were biphasic within the lung. Finally, live imaging revealed an early and sustained host metabolic response at sites of infection that may reflect damage and repair of tissues in the lungs.T he annual impact of seasonal influenza A viruses (IAV) on public health is fairly predictable and is mostly preventable in normal, healthy populations with currently...

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“…Cell susceptibility to hantavirus, however, depends not only on the expression of ITB3 [9, 10]; other cellular factors, such as decay-accelerating factor (DAF1) and the receptor of complement C1q are also important in hantavirus entry [11–14]. In addition, integrin β2 was recently identified as a receptor for HTNV and as responsible for hantavirus pathogenesis [15]. The precise roles of each of these factors in hantavirus cell entry are currently unclear, however.…”

Section: Introductionmentioning

confidence: 99%

Endocytic Pathways Used by Andes Virus to Enter Primary Human Lung Endothelial Cells

et al. 2016

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Andes virus (ANDV) is the major cause of hantavirus pulmonary syndrome (HPS) in South America. Despite a high fatality rate (up to 40%), no vaccines or antiviral therapies are approved to treat ANDV infection. To understand the role of endocytic pathways in ANDV infection, we used 3 complementary approaches to identify cellular factors required for ANDV entry into human lung microvascular endothelial cells. We screened an siRNA library targeting 140 genes involved in membrane trafficking, and identified 55 genes required for ANDV infection. These genes control the major endocytic pathways, endosomal transport, cell signaling, and cytoskeleton rearrangement. We then used infectious ANDV and retroviral pseudovirions to further characterize the possible involvement of 9 of these genes in the early steps of ANDV entry. In addition, we used markers of cellular endocytosis along with chemical inhibitors of known endocytic pathways to show that ANDV uses multiple routes of entry to infect target cells. These entry mechanisms are mainly clathrin-, dynamin-, and cholesterol-dependent, but can also occur via a clathrin-independent manner.

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β2 integrin mediates hantavirus-induced release of neutrophil extracellular traps

Abstract: β2 Integrin–mediated systemic release of neutrophil extracellular traps is a novel mechanism of immunopathology associated with hantavirus infection.

Cited by 166 publications

References 72 publications

Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils

Endocytic Pathways Used by Andes Virus to Enter Primary Human Lung Endothelial Cells

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