Hantavirus Infection of Dendritic Cells

Raftery, Martin; Kraus, Annette; Ulrich, Rainer G.; Krüger, Detlev H.; Schönrich, Günther

doi:10.1128/jvi.76.21.10724-10733.2002

Cited by 118 publications

(119 citation statements)

References 77 publications

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“…In contrast, cross-presenting uninfected DCs that are activated indirectly by proinflammatory cytokines may induce tolerance rather than immunity [41]. It has been shown that HTNVinfected DCs do not undergo cell death [23]. Thus, lung DCs infected with HTNV after inhalation of virion containing aerosols could migrate to the draining lymph nodes and cross-prime powerful antiviral cytotoxic T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Compared to DCs stimulated with TNF-α, HTNV-infected DCs show increased macropinocytosis and receptor-mediated endocytosis [23], a prerequisite of cross-presentation. Indeed, we observed in this study that HTNV confers upon DCs the capacity to efficiently cross-present pp65, a HCMV-encoded model antigen.…”

Section: Discussionmentioning

confidence: 99%

“…FCScontaining medium was added to stop trypsin action and cells were passaged. PBMCs were isolated by density gradient centrifugation as previously described [23]. In brief, blood was diluted 1:1 with RPMI medium (2% FCS and 0.2 mM EDTA) and carefully layered on top of Ficoll-Hypaque (PAA).…”

Section: Cellsmentioning

confidence: 99%

“…TLR ligation events result in recruitment of the adaptor molecule MyD88 with the exception of TLR3, which uses TIR domain containing adaptor inducing IFN-β (TRIF) for downstream signaling [22]. Hantavirus are known to potently induce HLA-I on various cell types including DCs [23], but how detection of hantaviral virions translates into HLA-I-restricted T-cell responses and which viral sensors are involved are as yet unknown.In this study, we elucidate in detail how hantaviruses modulate the HLA-I antigen presentation machinery. …”

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confidence: 99%

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

et al. 2013

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Hantaviruses are emerging human pathogens. They induce an unusually strong antiviral response of human HLA class I (HLA-I) restricted CD8 + T cells that may contribute to tissue damage and hantavirus-associated disease. In this study, we analyzed possible hantaviral mechanisms that enhance the HLA-I antigen presentation machinery. Upon hantavirus infection of various human and primate cell lines, we observed transactivation of promoters controlling classical HLA molecules. Hantavirus-induced HLA-I upregulation required proteasomal activity and was associated with increased TAP expression. Intriguingly, human DCs acquired the capacity to cross-present antigen upon hantavirus infection. Furthermore, knockdown of TIR domain containing adaptor inducing IFN-β or retinoic acid inducible gene I abolished hantavirus-driven HLA-I induction. In contrast, MyD88-dependent viral sensors were not involved in HLA-I induction. Our results show that hantaviruses strongly boost the HLA-I antigen presentation machinery by mechanisms that are dependent on both retinoic acid inducible gene I and TIR domain containing adaptor inducing IFN-β.Keywords: Antigen presentation/processing · Cross-presentation/priming · Immunopathology · Infectious diseases · Innate immunity IntroductionRapidly changing ecosystems and climate facilitate the emergence of human infections with hantaviruses [1][2][3]. In Germany, increasing numbers of hantavirus-associated disease cases have been observed [4]. The enhanced health hazard emanating from pathogenic hantavirus species has been recognized by the German National Health Institute, which has recently reprioritized infecCorrespondence: Prof. Günther Schönrich e-mail: guenther.schoenrich@charite.de tious pathogens and placed hantaviruses in the highest priority group [5].Hantaviruses belong to the family Bunyaviridae and have segmented genomes [6]. The three viral RNA segments code for a nucleoprotein (N), two glycoproteins (Gn and Gc), and a RNA-dependent RNA polymerase. Hantaviruses are transmitted to humans by inhalation of virus-containing aerosols that are derived from the excreta of hantavirus-infected rodents. These natural reservoir hosts remain asymptomatic, although they are persistently infected. In striking contrast, hantaviruses are eliminated in humans at the cost of severe symptoms such as pulmonary or renal failure. Currently, no suitable vaccines or therapeutics are C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2566-2576 Antigen processing 2567 available for prevention or treatment of human hantavirus infections [7,8].Hantaviruses are not directly cytopathic for infected cells, suggesting that the antiviral immune response itself causes hantavirus-associated syndromes [9,10]. In accordance, hantaviruses trigger an unusually potent reaction of CD8 + T lymphocytes, that is devoid of regulatory T cells, and still detectable years after resolution [11][12][13][14]. Human CD8 + T cells are stimulated by HLA class I (HLA-I) molecules that prese...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2013

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“…Increased expression of cytokines, especially of TNF-␣ in the peritubular area of the distal nephron, was reported during HFRS (67,68), and in the lungs of patients with HPS, increased numbers of IFN-␥-, IL-1␣-, IL-1␤-, IL-2-, IL-4 -, IL-6 -, and TNF-␣/␤-producing cells were observed (37). Hantaviruses are also able to infect dendritic cells, resulting in secretion of proinflammatory cytokines, e.g., IFN-␣ and TNF-␣ that could also contribute to increased endothelial permeability (65,69). In vitro infection of human lung microvascular endothelial cells with HTNV or Sin Nombre virus generated increased amounts of RANTES and 10-kD IFN-inducible protein (42).…”

Section: Secretion Of Cytokines and Chemokinesmentioning

confidence: 99%