Hantaviral mechanisms driving <scp>HLA</scp> class I antigen presentation require both <scp>RIG</scp>‐<scp>I</scp> and <scp>TRIF</scp>

Lalwani, Pritesh; Raftery, Martin; Kobak, Lidija; Rang, Andreas; Giese, Thomas; Matthaei, Markus; Elsen, Peter J. van den; Wolff, Thorsten; Krüger, Detlev H.; Schönrich, Günther

doi:10.1002/eji.201243066

Cited by 14 publications

(12 citation statements)

References 48 publications

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“…Similar results were obtained with uninfected and HTNV-infected epithelial cells ( Figure S4 ). As previously reported [3] , [35] , HTNV-infection of endothelial cells increases their HLA class I expression ( Figure 5B ). This increase may, at least in part, contribute to weaker effector responses of activated NK cells towards HTNV-infected target cells.…”

Section: Resultssupporting

confidence: 88%

NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL15Rα Expression

et al. 2014

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Clinical infection with hantaviruses cause two severe acute diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases are characterized by strong immune activation, increased vascular permeability, and up to 50% case-fatality rates. One prominent feature observed in clinical hantavirus infection is rapid expansion of natural killer (NK) cells in peripheral blood of affected individuals. We here describe an unusually high state of activation of such expanding NK cells in the acute phase of clinical Puumala hantavirus infection. Expanding NK cells expressed markedly increased levels of activating NK cell receptors and cytotoxic effector molecules. In search for possible mechanisms behind this NK cell activation, we observed virus-induced IL-15 and IL-15Rα on infected endothelial and epithelial cells. Hantavirus-infected cells were shown to strongly activate NK cells in a cell-cell contact-dependent way, and this response was blocked with anti-IL-15 antibodies. Surprisingly, the strength of the IL-15-dependent NK cell response was such that it led to killing of uninfected endothelial cells despite expression of normal levels of HLA class I. In contrast, hantavirus-infected cells were resistant to NK cell lysis, due to a combination of virus-induced increase in HLA class I expression levels and hantavirus-mediated inhibition of apoptosis induction. In summary, we here describe a possible mechanism explaining the massive NK cell activation and proliferation observed in HFRS patients caused by Puumala hantavirus infection. The results add further insights into mechanisms behind the immunopathogenesis of hantavirus infections in humans and identify new possible targets for intervention.

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Section: Resultssupporting

confidence: 88%

NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL15Rα Expression

et al. 2014

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“…Human A549 and HEK293T cells were grown in Dulbecco's modified Eagle medium supplemented with 10% fetal bovine serum and 2 mM L-glutamine (complete DMEM). Constructions of the A549 PKR KD and A549 NT cell lines, which contain a stable integrate of the PKR-specific shRNA (PKR KD) or nontarget shRNA (NT) expression cassette, have been described elsewhere (83). Madin-Darby canine kidney type II (MDCKII) cells were grown in minimal essential medium supplemented with 10% fetal bovine serum and 2 mM L-glutamine (complete MEM).…”

Section: Methodsmentioning

confidence: 99%

Influenza A Virus Virulence Depends on Two Amino Acids in the N-Terminal Domain of Its NS1 Protein To Facilitate Inhibition of the RNA-Dependent Protein Kinase PKR

Schierhorn

Jolmes

Bespalowa

et al. 2017

J Virol

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The RNA-dependent protein kinase (PKR) has broad antiviral activity inducing translational shutdown of viral and cellular genes and is therefore targeted by various viral proteins to facilitate pathogen propagation. The pleiotropic NS1 protein of influenza A virus acts as silencer of PKR activation and ensures high-level viral replication and virulence. However, the exact manner of this inhibition remains controversial. To elucidate the structural requirements within the NS1 protein for PKR inhibition, we generated a set of mutant viruses, identifying highly conserved arginine residues 35 and 46 within the NS1 N terminus as being most critical not only for binding to and blocking activation of PKR but also for efficient virus propagation. Biochemical and Förster resonance energy transfer (FRET)-based interaction studies showed that mutation of R35 or R46 allowed formation of NS1 dimers but eliminated any detectable binding to PKR as well as to double-stranded RNA (dsRNA). Using in vitro and in vivo approaches to phenotypic restoration, we demonstrated the essential role of the NS1 N terminus for blocking PKR. The strong attenuation conferred by NS1 mutation R35A or R46A was substantially alleviated by stable knockdown of PKR in human cells. Intriguingly, both NS1 mutant viruses did not trigger any signs of disease in PKR ϩ/ϩ mice, but replicated to high titers in lungs of PKR Ϫ/Ϫ mice and caused lethal infections. These data not only establish the NS1 N terminus as highly critical for neutralization of PKR's antiviral activity but also identify this blockade as an indispensable contribution of NS1 to the viral life cycle. IMPORTANCE Influenza A virus inhibits activation of the RNA-dependent protein kinase (PKR) by means of its nonstructural NS1 protein, but the underlying mode of inhibition is debated. Using mutational analysis, we identified arginine residues 35 and 46 within the N-terminal NS1 domain as highly critical for binding to and functional silencing of PKR. In addition, our data show that this is a main activity of amino acids 35 and 46, as the strong attenuation of corresponding mutant viruses in human cells was rescued to a large extent by lowering of PKR expression levels. Significantly, this corresponded with restoration of viral virulence for NS1 R35A and R46A mutant viruses in PKR Ϫ/Ϫ mice. Therefore, our data establish a model in which the NS1 N-terminal domain engages in a binding interaction to inhibit activation of PKR and ensure efficient viral propagation and virulence.KEYWORDS PKR, influenza, innate immunity, virulence regulation

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“…In this respect, hantavirus infection in different cell types up-regulates the expression of HLA-I, which is involved in antigen presentation, as well as DC cross-presentation to CD8+ T cells [107]. …”

Section: Interaction Of Hantaviruses With the Immune Systemmentioning

confidence: 99%

What Do We Know about How Hantaviruses Interact with Their Different Hosts?

Ermonval

Baychelier

Tordo

2016

Viruses

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Hantaviruses, like other members of the Bunyaviridae family, are emerging viruses that are able to cause hemorrhagic fevers. Occasional transmission to humans is due to inhalation of contaminated aerosolized excreta from infected rodents. Hantaviruses are asymptomatic in their rodent or insectivore natural hosts with which they have co-evolved for millions of years. In contrast, hantaviruses cause different pathologies in humans with varying mortality rates, depending on the hantavirus species and its geographic origin. Cases of hemorrhagic fever with renal syndrome (HFRS) have been reported in Europe and Asia, while hantavirus cardiopulmonary syndromes (HCPS) are observed in the Americas. In some cases, diseases caused by Old World hantaviruses exhibit HCPS-like symptoms. Although the etiologic agents of HFRS were identified in the early 1980s, the way hantaviruses interact with their different hosts still remains elusive. What are the entry receptors? How do hantaviruses propagate in the organism and how do they cope with the immune system? This review summarizes recent data documenting interactions established by pathogenic and nonpathogenic hantaviruses with their natural or human hosts that could highlight their different outcomes.

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Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

Cited by 14 publications

References 48 publications

NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL15Rα Expression

NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL15Rα Expression

Influenza A Virus Virulence Depends on Two Amino Acids in the N-Terminal Domain of Its NS1 Protein To Facilitate Inhibition of the RNA-Dependent Protein Kinase PKR

What Do We Know about How Hantaviruses Interact with Their Different Hosts?

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