Differential Antiviral Response of Endothelial Cells after Infection with Pathogenic and Nonpathogenic Hantaviruses

Kraus, Annette; Raftery, Martin; Giese, Thomas; Ulrich, Rainer G.; Zawatzky, Rainer; Hippenstiel, Stefan; Suttorp, Norbert; Krüger, Detlev H.; Schönrich, Günther

doi:10.1128/jvi.78.12.6143-6150.2004

Cited by 98 publications

(92 citation statements)

References 49 publications

(43 reference statements)

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“…The efficiency to activate innate IFN responses, that is, induction of ISG expression by HTNV and PHV, inversely correlated with the amount of infectious virus produced in HuH7 and A549 cells. This is consistent with results with primary endothelial cells (26,29). Furthermore, infectivity loss by high-energy irradiation abrogated induction of innate responses by Andes hantavirus and PHV in primary endothelial cells (30).…”

Section: Discussionsupporting

confidence: 80%

“…In both HTNV-infected HuH7.5 and HuH7 cells, no or only marginal MxA induction was detectable, although slightly higher amounts of HTNV N protein compared with PHV were found. These data clearly demonstrate that HTNV and PHV provoke differential induction of antiviral responses in the established cell lines with a similar pattern as in primary endothelial cells (29,30).…”

Section: Htnv and Phv Differentially Induce Mxa In A549 And Huh7 Cellsmentioning

confidence: 48%

“…Whereas infection of primary endothelial cells with putatively nonpathogenic Prospect Hill (PHV) or with Tula hantavirus led to pronounced activation of the innate IFN system and early induction of the IFNstimulated MxA protein, an innate response to infection with pathogenic Hantaan (HTNV), New York-1, and Andes hantavirus was induced in a retarded manner or even not detected (26 -30). Furthermore, the velocity to induce innate responses by New York-1 hantavirus, HTNV, PHV, and Tula hantavirus is inversely correlated with the virus titer produced in primary endothelial cells (26,29). Note that designation of hantaviruses as nonpathogenic is difficult, since suited animal systems to determine the virulence are not available.…”

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confidence: 99%

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Hantaan Virus Triggers TLR3-Dependent Innate Immune Responses

Handke

Oelschlegel

Franke

et al. 2009

The Journal of Immunology

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Immediately after viral infection, innate responses including expression of IFN-α/β and IFN-stimulated genes (ISGs) are elicited ubiquitously by recruitment of specific pathogen recognition receptors. The velocity to induce IFN-α/β and ISGs in response to an infection is often decisive for virulence. Interestingly, in primary endothelial cells ISGs are induced later by hantaviruses pathogenic to humans than those considered to be nonpathogenic or of low virulence. Here we demonstrate that pathogenic Hantaan (HTNV) and putatively nonpathogenic Prospect Hill hantavirus (PHV) differentially activate innate responses in the established cell lines A549 and HuH7. STAT1α phosphorylation was detectable 3 h after PHV inoculation but not within the first 2 days after HTNV inoculation. The velocity to induce the ISGs MxA and ISG15 correlated inversely with amounts of virus produced. Moreover, expression of the inflammatory chemokine CCL5 was also induced differentially. Both hantaviruses induced innate responses via TRAF3 (TNF receptor-associated factor 3), and TLR3 was required for HTNV-induced expression of MxA, but not for the MxA induction triggered by PHV. Infection of RIG-I-deficient HuH7.5 cells revealed that RIG-I (retinoic acid receptor I) was not necessary for induction of innate responses by PHV. Taken together, these data suggest that HTNV and PHV elicit different signaling cascades that converge via TRAF3. Early induction of antiviral responses might contribute to efficient elimination of PHV. Subsequent to clearance of the infection, innate responses most likely cease; vice versa, retarded induction of antiviral responses could lead to increased HTNV replication and dissemination, which might cause a prolonged inflammatory response and might contribute to the in vivo virulence.

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Section: Discussionsupporting

confidence: 80%

Section: Htnv and Phv Differentially Induce Mxa In A549 And Huh7 Cellsmentioning

confidence: 48%

mentioning

confidence: 99%

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Hantaan Virus Triggers TLR3-Dependent Innate Immune Responses

Handke

Oelschlegel

Franke

et al. 2009

The Journal of Immunology

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“…This points to an IFN-independent mechanism contributing to HTNV-associated MHC-I upregulation. On the other hand, we have previously observed that upregulation of HLA-I on human endothelial cells infected with hantavirus can be blocked in part by antibodies directed against type I IFN [35]. Taken together, our results suggest that both direct and indirect (IFN-driven) hantaviral mechanisms are required for efficient HLA-I upregulation.…”

Section: Discussionsupporting

confidence: 59%

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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“…Pathogenic rodent-borne hantaviruses, such as HTNV, evade early innate immune responses by downregulating antiviral responsive gene expression immediately after infection. By contrast, upregulation of antiviral gene expression is observed in nonpathogenic Prospect Hill virus (PHV) infection (35). The pathogenesis of HFRS and HCPS is hypothesized to be mediated by increased pro-inflammatory responses (46).…”

Section: Introductionmentioning

confidence: 99%

Hantaviruses Induce Antiviral and Pro-Inflammatory Innate Immune Responses in Astrocytic Cells and the Brain

Shin

Song²,

Kumar

et al. 2014

Viral Immunology

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Although hantaviruses are not generally considered neurotropic, neurological complications have been reported occasionally in patients with hemorrhagic fever renal syndrome (HFRS). In this study, we analyzed innate immune responses to hantavirus infection in vitro in human astrocytic cells (A172) and in vivo in suckling ICR mice. Infection of A172 cells with pathogenic Hantaan virus (HTNV) or a novel shrew-borne hantavirus, known as Imjin virus (MJNV), induced activation of antiviral genes and pro-inflammatory cytokines/chemokines. MicroRNA expression profiles of HTNV-and MJNV-infected A172 cells showed distinct changes in a set of miRNAs. Following intraperitoneal inoculation with HTNV or MJNV, suckling ICR mice developed rapidly progressive, fatal central nervous system-associated disease. Immunohistochemical staining of virus-infected mouse brains confirmed the detection of viral antigens within astrocytes. Taken together, these findings suggest that the neurological findings in HFRS patients may be associated with hantavirus-directed modulation of innate immune responses in the brain.

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Differential Antiviral Response of Endothelial Cells after Infection with Pathogenic and Nonpathogenic Hantaviruses

Cited by 98 publications

References 49 publications

Hantaan Virus Triggers TLR3-Dependent Innate Immune Responses

Hantaan Virus Triggers TLR3-Dependent Innate Immune Responses

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

Hantaviruses Induce Antiviral and Pro-Inflammatory Innate Immune Responses in Astrocytic Cells and the Brain

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