Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog.
A growing number of arenaviruses can cause a devastating viral hemorrhagic fever (VHF) syndrome. They pose a public health threat as emerging viruses and because of their potential use as bioterror agents. All of the highly pathogenic New World arenaviruses (NWA) phylogenetically segregate into clad...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-09-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2940843?pdf=render |
| _version_ | 1828722455830593536 |
|---|---|
| author | Brian B Gowen Min-Hui Wong Deanna Larson Wei Ye Kie-Hoon Jung Eric J Sefing Ramona Skirpstunas Donald F Smee John D Morrey Stewart W Schneller |
| author_facet | Brian B Gowen Min-Hui Wong Deanna Larson Wei Ye Kie-Hoon Jung Eric J Sefing Ramona Skirpstunas Donald F Smee John D Morrey Stewart W Schneller |
| author_sort | Brian B Gowen |
| collection | DOAJ |
| description | A growing number of arenaviruses can cause a devastating viral hemorrhagic fever (VHF) syndrome. They pose a public health threat as emerging viruses and because of their potential use as bioterror agents. All of the highly pathogenic New World arenaviruses (NWA) phylogenetically segregate into clade B and require maximum biosafety containment facilities for their study. Tacaribe virus (TCRV) is a nonpathogenic member of clade B that is closely related to the VHF arenaviruses at the amino acid level. Despite this relatedness, TCRV lacks the ability to antagonize the host interferon (IFN) response, which likely contributes to its inability to cause disease in animals other than newborn mice.Here we describe a new mouse model based on TCRV challenge of AG129 IFN-α/β and -γ receptor-deficient mice. Titration of the virus by intraperitoneal (i.p.) challenge of AG129 mice resulted in an LD(50) of ∼100 fifty percent cell culture infectious doses. Virus replication was evident in the serum, liver, lung, spleen, and brain 4-8 days after inoculation. MY-24, an aristeromycin derivative active against TCRV in cell culture at 0.9 µM, administered i.p. once daily for 7 days, offered highly significant (P<0.001) protection against mortality in the AG129 mouse TCRV infection model, without appreciably reducing viral burden. In contrast, in a hamster model of arenaviral hemorrhagic fever based on challenge with clade A Pichinde arenavirus, MY-24 did not offer significant protection against mortality.MY-24 is believed to act as an inhibitor of S-adenosyl-L-homocysteine hydrolase, but our findings suggest that it may ameliorate disease by blunting the effects of the host response that play a role in disease pathogenesis. The new AG129 mouse TCRV infection model provides a safe and cost-effective means to conduct early-stage pre-clinical evaluations of candidate antiviral therapies that target clade B arenaviruses. |
| first_indexed | 2024-04-12T05:21:10Z |
| format | Article |
| id | doaj.art-52bab0d888fb4ba3868369e1a35d95f2 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T05:21:10Z |
| publishDate | 2010-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-52bab0d888fb4ba3868369e1a35d95f22022-12-22T03:46:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-09-015910.1371/journal.pone.0012760Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog.Brian B GowenMin-Hui WongDeanna LarsonWei YeKie-Hoon JungEric J SefingRamona SkirpstunasDonald F SmeeJohn D MorreyStewart W SchnellerA growing number of arenaviruses can cause a devastating viral hemorrhagic fever (VHF) syndrome. They pose a public health threat as emerging viruses and because of their potential use as bioterror agents. All of the highly pathogenic New World arenaviruses (NWA) phylogenetically segregate into clade B and require maximum biosafety containment facilities for their study. Tacaribe virus (TCRV) is a nonpathogenic member of clade B that is closely related to the VHF arenaviruses at the amino acid level. Despite this relatedness, TCRV lacks the ability to antagonize the host interferon (IFN) response, which likely contributes to its inability to cause disease in animals other than newborn mice.Here we describe a new mouse model based on TCRV challenge of AG129 IFN-α/β and -γ receptor-deficient mice. Titration of the virus by intraperitoneal (i.p.) challenge of AG129 mice resulted in an LD(50) of ∼100 fifty percent cell culture infectious doses. Virus replication was evident in the serum, liver, lung, spleen, and brain 4-8 days after inoculation. MY-24, an aristeromycin derivative active against TCRV in cell culture at 0.9 µM, administered i.p. once daily for 7 days, offered highly significant (P<0.001) protection against mortality in the AG129 mouse TCRV infection model, without appreciably reducing viral burden. In contrast, in a hamster model of arenaviral hemorrhagic fever based on challenge with clade A Pichinde arenavirus, MY-24 did not offer significant protection against mortality.MY-24 is believed to act as an inhibitor of S-adenosyl-L-homocysteine hydrolase, but our findings suggest that it may ameliorate disease by blunting the effects of the host response that play a role in disease pathogenesis. The new AG129 mouse TCRV infection model provides a safe and cost-effective means to conduct early-stage pre-clinical evaluations of candidate antiviral therapies that target clade B arenaviruses.http://europepmc.org/articles/PMC2940843?pdf=render |
| spellingShingle | Brian B Gowen Min-Hui Wong Deanna Larson Wei Ye Kie-Hoon Jung Eric J Sefing Ramona Skirpstunas Donald F Smee John D Morrey Stewart W Schneller Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog. PLoS ONE |
| title | Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog. |
| title_full | Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog. |
| title_fullStr | Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog. |
| title_full_unstemmed | Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog. |
| title_short | Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog. |
| title_sort | development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog |
| url | http://europepmc.org/articles/PMC2940843?pdf=render |
| work_keys_str_mv | AT brianbgowen developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT minhuiwong developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT deannalarson developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT weiye developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT kiehoonjung developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT ericjsefing developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT ramonaskirpstunas developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT donaldfsmee developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT johndmorrey developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog AT stewartwschneller developmentofanewtacaribearenavirusinfectionmodelanditsusetoexploreantiviralactivityofanovelaristeromycinanalog |