Hamster-Adapted Sin Nombre Virus Causes Disseminated Infection and Efficiently Replicates in Pulmonary Endothelial Cells without Signs of Disease

Safronetz, David; Prescott, Joseph; Haddock, Elaine; Scott, Dana; Feldmann, Heinz; Ebihara, Hideki

doi:10.1128/jvi.03291-12

Cited by 29 publications

(34 citation statements)

References 14 publications

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“…Tissues were stained with H&E or phosphotungstic acid-hematoxylin using standard methods. Viral antigen and RNA was detected by IHC or ISH as previously described (41)(42)(43). CD3, IL-4, TNF, and INF-γ were stained in selected tissue specimens using standard IHC methodologies.…”

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confidence: 99%

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

Safronetz¹,

Prescott²,

Feldmann³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The pathophysiology of hantavirus pulmonary syndrome (HPS) remains unclear because of a lack of surrogate disease models with which to perform pathogenesis studies. Nonhuman primates (NHP) are considered the gold standard model for studying the underlying immune activation/suppression associated with immunopathogenic viruses such as hantaviruses; however, to date an NHP model for HPS has not been described. Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress. This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. We anticipate this model will advance our understanding of HPS pathogenesis and will greatly facilitate research toward the development of effective therapeutics and vaccines against hantaviral diseases.

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confidence: 99%

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

Safronetz¹,

Prescott²,

Feldmann³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…To assess the in vivo antiviral effect of T-705 against SNV, we utilized a recently described infection model based on a serially passaged SNV that achieves prolonged and systemic infection in Syrian hamsters (24). As in the ANDV studies, twice-daily administration of T-705 (100 mg/kg/day) reduced the detection of viral RNA in blood and, most notably, lung samples (P Ͻ 0.0001) collected at day 8 postinfection (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Currently no disease model for SNV exists; however, an infection model based on a serially passaged hamster-adapted SNV (HA-SNV) was described recently (24). Therefore, to evaluate the effect of T-705 on SNV replication in vivo, three groups of 6 hamsters were infected with HA-SNV (10% [wt/vol]) via i.p.…”

Section: Methodsmentioning

confidence: 99%

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Antiviral Efficacy of Favipiravir against Two Prominent Etiological Agents of Hantavirus Pulmonary Syndrome

Safronetz

Falzarano

Scott

et al. 2013

Antimicrob Agents Chemother

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dHantavirus pulmonary syndrome (HPS) is caused by infection with several Sigmodontinae-and Neotominae-borne hantaviruses and has a case fatality rate of 30 to 50%. Humans often become infected by inhalation of materials contaminated with virusladen rodent urine or saliva, although human-to-human transmission has also been documented for Andes virus (ANDV). The ability to transmit via aerosolization, coupled with the high mortality rates and lack of therapeutic options, makes the development of medical countermeasures against HPS imperative. In the present study, we evaluated the efficacy of the broad-spectrum antiviral agent favipiravir (T-705) against Sin Nombre virus (SNV) and ANDV, the predominant causes of HPS in North and South America, respectively. In vitro, T-705 potently inhibited SNV and ANDV, as evidenced by decreased detection of viral RNA and reduced infectious titers. For both viruses, the 90% effective concentration was estimated at <5 g/ml (<31.8 M). In the lethal ANDV hamster model, daily administration of oral T-705 at 50 or 100 mg/kg of body weight diminished the detection of viral RNA and antigen in tissue specimens and significantly improved survival rates. Oral T-705 therapy remained protective against HPS when treatment was initiated prior to the onset of viremia. No disease model for SNV exists; however, using a hamster-adapted SNV, we found that daily administration of oral T-705 significantly reduced the detection of SNV RNA and antigen in tissue specimens, suggesting that the compound would also be effective against HPS in North America. Combined, these results suggest that T-705 treatment is beneficial for postexposure prophylaxis against HPS-causing viruses and should be considered for probable exposures.

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“…13 Syrian hamsters do not succumb to SNV infection, the causative agent of HPS in North America. 16,19 Investigations of HPS pathogenesis could be improved by expanding the scope of surrogate animal models used to study the disease and host responses. We hypothesized that additional members of the Cricetidae family might be susceptible to infection with 1 or more of the distinct hantaviruses.…”

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Laguna Negra Virus Infection Causes Hantavirus Pulmonary Syndrome in Turkish Hamsters (Mesocricetus brandti)

et al. 2015

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Laguna Negra virus (LNV) is a New World hantavirus associated with severe and often fatal cardiopulmonary disease in humans, known as hantavirus pulmonary syndrome (HPS). Five hamster species were evaluated for clinical and serologic responses following inoculation with 4 hantaviruses. Of the 5 hamster species, only Turkish hamsters infected with LNV demonstrated signs consistent with HPS and a fatality rate of 43%. Clinical manifestations in infected animals that succumbed to disease included severe and rapid onset of dyspnea, weight loss, leukopenia, and reduced thrombocyte numbers as compared to uninfected controls. Histopathologic examination revealed lung lesions that resemble the hallmarks of HPS in humans, including interstitial pneumonia and pulmonary edema, as well as generalized infection of endothelial cells and macrophages in major organ tissues. Histologic lesions corresponded to the presence of viral antigen in affected tissues. To date, there have been no small animal models available to study LNV infection and pathogenesis. The Turkish hamster model of LNV infection may be important in the study of LNV-induced HPS pathogenesis and development of disease treatment and prevention strategies.

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Hamster-Adapted Sin Nombre Virus Causes Disseminated Infection and Efficiently Replicates in Pulmonary Endothelial Cells without Signs of Disease

Cited by 29 publications

References 14 publications

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques

Antiviral Efficacy of Favipiravir against Two Prominent Etiological Agents of Hantavirus Pulmonary Syndrome

Laguna Negra Virus Infection Causes Hantavirus Pulmonary Syndrome in Turkish Hamsters (Mesocricetus brandti)

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