Cellular Receptors and Hantavirus Pathogenesis

Mackow, Erich R.; Gavrilovskaya, Irina N.

doi:10.1007/978-3-642-56753-7_6

Cited by 77 publications

(71 citation statements)

References 91 publications

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“…The data clearly indicate that the S-and Lsegments of PHV and PUUV seem to be decisive for the differential induction of innate responses and replication efficiency in the experimental system used. PUUV and PHV have been shown to enter host cells via different integrin receptors (Gavrilovskaya et al, 1998;Mackow & Gavrilovskaya, 2001). Since entry of hantaviruses is determined by the viral glycoproteins G1/G2, the M-segment should direct the reassortant PHPUV to the same uptake pathway that is also used by the parental PUUV.…”

Section: Discussionmentioning

confidence: 99%

“…First, pathogenic hantaviruses including NYV, HTNV and PUUV were reported to enter host cells via integrin-av/-b3. Hantaviruses considered to be nonpathogenic, like PHV, were found to enter the cell via integrin-aII/-bI (Gavrilovskaya et al, 1998;Mackow & Gavrilovskaya, 2001). Second, several pathogenic hantaviruses elicit delayed innate antiviral responses when compared with an immediate response triggered by nonpathogenic hantaviruses (Alff et al, 2006(Alff et al, , 2008Geimonen et al, 2002;Handke et al, 2009b;Khaiboullina et al, 2004;Kraus et al, 2004;Spiropoulou et al, 2007).…”

Section: Members Of the Genus Hantavirus In The Familymentioning

confidence: 99%

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Generation and characterization of genetic reassortants between Puumala and Prospect Hill hantavirus in vitro

Handke

Oelschlegel

Franke

et al. 2010

Journal of General Virology

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Hantaviruses belong to the family Bunyaviridae characterized by tri-segmented RNA genomes. Depending on the hantavirus species, infection can lead to hantavirus cardiopulmonary or haemorrhagic fever with renal syndrome. In vitro studies suggest that pathogenic hantaviruses evade induction of innate antiviral responses, and this ability might determine the virulence in humans. Since reverse genetic systems are not available, in vitro reassortment is currently the only way to culture defined hantavirus variants. Here, we demonstrate for the first time the generation of a reassortant between a pathogenic Old World and a non-pathogenic New World hantavirus in vitro. The reassortant contained the glycoprotein coding M-segment derived from the pathogenic Puumala virus (PUUV) and the other genomic segments coding for the nucleocapsid protein and RNA-dependent RNA-polymerase from Prospect Hill virus (PHV), which is taken as nonpathogenic in humans. Exchange of the M-segment was confirmed by sequencing and virus neutralization test with PUUV-specific sera. Functional analysis of the reassortant and parental viruses revealed characteristic growth kinetics and innate immune responses as determined by expression analyses for lambda interferon and MxA, and by interferon-stimulated response element reporter gene studies. Consistent with previous studies with other pathogenic hantaviruses, PUUV elicited reduced innate responses if compared with PHV. In all these functional assays the reassortant revealed PHV-like phenotypes. Thus, neither the PUUV Msegment nor entry via specific M-segment directed pathways modulated the virus type-specific innate responses. Moreover, the data imply that this approach might be an option for production of attenuated viruses that could be used as vaccines against pathogenic hantaviruses.

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Section: Discussionmentioning

confidence: 99%

Section: Members Of the Genus Hantavirus In The Familymentioning

confidence: 99%

Generation and characterization of genetic reassortants between Puumala and Prospect Hill hantavirus in vitro

Handke

Oelschlegel

Franke

et al. 2010

Journal of General Virology

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“…Infection of human cells with pathogenic and putatively nonpathogenic hantaviruses are mediated by integrins ␤ 3 and ␤ 1 , respectively (5). Despite involvement of different receptors, both pathogenic and nonpathogenic hantaviruses seem to share the same cell and tissue tropism in vivo (2).…”

mentioning

confidence: 99%

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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“…Perhaps paradoxically for these rodent-borne viruses, human integrins such as ␣ v ␤ 3 confer susceptibility to infection to CHO (Chinese hamster ovary) cells, whereas their murine (Mus musculus) counterparts do not. The pathogenic hantaviruses examined thus far, which include Hantaan virus (HTNV), Seoul virus (SEOV), Sin Nombre virus (SNV), New York virus (NYV), and Puumala virus (PUUV), are able to enter cells that have been transfected by human ␣ v ␤ 3 , whereas two hantaviruses that have not yet been linked conclusively to human disease, Tula virus and Prospect Hill virus (PHV), do not (21). The entry of SNV and other pathogenic viruses can be prevented by treatment with neutralizing antibodies directed either against the virus or against the integrin receptor; entry is also inhibited by vitronectin but not by fibronectin.…”

mentioning

confidence: 99%

Peptide Antagonists That Inhibit Sin Nombre Virus and Hantaan Virus Entry through the β ₃ -Integrin Receptor

Larson¹,

Brown²,

Ye³

et al. 2005

J Virol

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Specific therapy is not available for the treatment of hantavirus cardiopulmonary syndrome caused by Sin Nombre virus (SNV). The entry of pathogenic hantaviruses into susceptible human cells is dependent upon expression of the ␣ v ␤ 3 integrin, and transfection of human ␤ 3 integrin is sufficient to confer infectibility onto CHO (Chinese hamster ovary) cells. Furthermore, pretreatment of susceptible cells with anti-␤ 3 antibodies such as c7E3 or its Fab fragment ReoPro prevents hantavirus entry. By using repeated selection of a cyclic nonamer peptide phage display library on purified ␣ v ␤ 3 , we identified 70 peptides that were competitively eluted with ReoPro. Each of these peptides was examined for its ability to reduce the number of foci of SNV strain SN77734 in a fluorescence-based focus reduction assay according to the method of Gavrilovskaya et al. (I. N. Gavrilovskaya, M. Shepley, R. Shaw, M. H. Ginsberg, and E. R. Mackow, Proc. Natl. Acad. Sci. USA 95:7074-7079, 1998). We found that 11 peptides reduced the number of foci to a greater extent than did 80 g/ml ReoPro when preincubated with Vero E6 cells. In addition, 8 of the 70 peptides had sequence similarity to SNV glycoproteins. We compared all 18 peptide sequences (10 most potent, 7 peptides with sequence similarity to hantavirus glycoproteins, and 1 peptide that was in the group that displayed the greatest potency and had significant sequence similarity) for their abilities to inhibit SNV, Hantaan virus (HTNV), and Prospect Hill virus (PHV) infection. There was a marked trend for the peptides to inhibit SNV and HTNV to a greater extent than they inhibited PHV, a finding that supports the contention that SNV and HTNV use ␤ 3 integrins and PHV uses a different receptor, ␤1 integrin. We then chemically synthesized the four peptides that showed the greatest ability to neutralize SNV. These peptides inhibited viral entry in vitro as free peptides outside of the context of a phage. Some combinations of peptides proved more inhibitory than did individual peptides. In all, we have identified novel peptides that inhibit entry by SNV and HTNV via ␤ 3 integrins and that can be used as lead compounds for further structural optimization and consequent enhancement of activity.

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Cellular Receptors and Hantavirus Pathogenesis

Cited by 77 publications

References 91 publications

Generation and characterization of genetic reassortants between Puumala and Prospect Hill hantavirus in vitro

Generation and characterization of genetic reassortants between Puumala and Prospect Hill hantavirus in vitro

Hantaan Virus Triggers TLR3-Dependent Innate Immune Responses

Peptide Antagonists That Inhibit Sin Nombre Virus and Hantaan Virus Entry through the β ₃ -Integrin Receptor

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Cellular Receptors and Hantavirus Pathogenesis

Cited by 77 publications

References 91 publications

Generation and characterization of genetic reassortants between Puumala and Prospect Hill hantavirus in vitro

Generation and characterization of genetic reassortants between Puumala and Prospect Hill hantavirus in vitro

Hantaan Virus Triggers TLR3-Dependent Innate Immune Responses

Peptide Antagonists That Inhibit Sin Nombre Virus and Hantaan Virus Entry through the β 3 -Integrin Receptor

Contact Info

Product

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Peptide Antagonists That Inhibit Sin Nombre Virus and Hantaan Virus Entry through the β ₃ -Integrin Receptor