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Title: Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses

Abstract

Hantaan virus (HTNV) and Puumala virus (PUUV) are rodent-borne hantaviruses that are the primary causes of hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. The development of well characterized animal models of HTNV and PUUV infection is critical for the evaluation and the potential licensure of HFRS vaccines and therapeutics. In this study we present three animal models of HTNV infection (hamster, ferret and marmoset), and two animal models of PUUV infection (hamster, ferret). Infection of hamsters with a ~3 times the infectious dose 99% (ID99) of HTNV by the intramuscular and ~1 ID99 of HTNV by the intranasal route leads to a persistent asymptomatic infection, characterized by sporadic viremia and high levels of viral genome in the lung, brain and kidney. In contrast, infection of hamsters with ~2 ID99 of PUUV by the intramuscular or ~1 ID99 of PUUV by the intranasal route leads to seroconversion with no detectable viremia, and a transient detection of viral genome. Infection of ferrets with a high dose of either HTNV or PUUV by the intramuscular route leads to seroconversion and gradual weight loss, though kidney function remained unimpaired and serum viremia and viral dissemination to organs was not detected. Inmore » marmosets a 1,000 PFU HTNV intramuscular challenge led to robust seroconversion and neutralizing antibody production. Similarly to the ferret model of HTNV infection, no renal impairment, serum viremia or viral dissemination to organs was detected in marmosets. This is the first report of hantavirus infection in ferrets and marmosets.« less

Authors:
ORCiD logo; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Oak Ridge Associated Univ., Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1511899
Alternate Identifier(s):
OSTI ID: 1627882
Grant/Contract Number:  
SC0014664
Resource Type:
Published Article
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Name: PLoS ONE Journal Volume: 14 Journal Issue: 5; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Science & Technology - Other Topics

Citation Formats

Perley, Casey C., Brocato, Rebecca L., Kwilas, Steven A., Daye, Sharon, Moreau, Alicia, Nichols, Donald K., Wetzel, Kelly S., Shamblin, Joshua, Hooper, Jay W., and Freiberg, ed., Alexander N. Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses. United States: N. p., 2019. Web. doi:10.1371/journal.pone.0216700.
Perley, Casey C., Brocato, Rebecca L., Kwilas, Steven A., Daye, Sharon, Moreau, Alicia, Nichols, Donald K., Wetzel, Kelly S., Shamblin, Joshua, Hooper, Jay W., & Freiberg, ed., Alexander N. Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses. United States. doi:10.1371/journal.pone.0216700.
Perley, Casey C., Brocato, Rebecca L., Kwilas, Steven A., Daye, Sharon, Moreau, Alicia, Nichols, Donald K., Wetzel, Kelly S., Shamblin, Joshua, Hooper, Jay W., and Freiberg, ed., Alexander N. Fri . "Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses". United States. doi:10.1371/journal.pone.0216700.
@article{osti_1511899,
title = {Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses},
author = {Perley, Casey C. and Brocato, Rebecca L. and Kwilas, Steven A. and Daye, Sharon and Moreau, Alicia and Nichols, Donald K. and Wetzel, Kelly S. and Shamblin, Joshua and Hooper, Jay W. and Freiberg, ed., Alexander N.},
abstractNote = {Hantaan virus (HTNV) and Puumala virus (PUUV) are rodent-borne hantaviruses that are the primary causes of hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. The development of well characterized animal models of HTNV and PUUV infection is critical for the evaluation and the potential licensure of HFRS vaccines and therapeutics. In this study we present three animal models of HTNV infection (hamster, ferret and marmoset), and two animal models of PUUV infection (hamster, ferret). Infection of hamsters with a ~3 times the infectious dose 99% (ID99) of HTNV by the intramuscular and ~1 ID99 of HTNV by the intranasal route leads to a persistent asymptomatic infection, characterized by sporadic viremia and high levels of viral genome in the lung, brain and kidney. In contrast, infection of hamsters with ~2 ID99 of PUUV by the intramuscular or ~1 ID99 of PUUV by the intranasal route leads to seroconversion with no detectable viremia, and a transient detection of viral genome. Infection of ferrets with a high dose of either HTNV or PUUV by the intramuscular route leads to seroconversion and gradual weight loss, though kidney function remained unimpaired and serum viremia and viral dissemination to organs was not detected. In marmosets a 1,000 PFU HTNV intramuscular challenge led to robust seroconversion and neutralizing antibody production. Similarly to the ferret model of HTNV infection, no renal impairment, serum viremia or viral dissemination to organs was detected in marmosets. This is the first report of hantavirus infection in ferrets and marmosets.},
doi = {10.1371/journal.pone.0216700},
journal = {PLoS ONE},
number = 5,
volume = 14,
place = {United States},
year = {2019},
month = {5}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1371/journal.pone.0216700

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Works referenced in this record:

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease
journal, August 2016

  • Kozak, Robert; He, Shihua; Kroeker, Andrea
  • Journal of Virology, Vol. 90, Issue 20
  • DOI: 10.1128/JVI.01033-16

Pathogenesis of Avian Influenza A (H5N1) Viruses in Ferrets
journal, May 2002


Isolation of the Etiologic Agent of Korean Hemorrhagic Fever
journal, March 1978

  • Lee, H. W.; Lee, P. W.; Johnson, K. M.
  • Journal of Infectious Diseases, Vol. 137, Issue 3
  • DOI: 10.1093/infdis/137.3.298

Vaccines for hantaviruses
journal, November 2009


A Global Perspective on Hantavirus Ecology, Epidemiology, and Disease
journal, April 2010

  • Jonsson, C. B.; Figueiredo, L. T. M.; Vapalahti, O.
  • Clinical Microbiology Reviews, Vol. 23, Issue 2
  • DOI: 10.1128/CMR.00062-09

Gastrointestinal Tract As Entry Route for Hantavirus Infection
journal, September 2017

  • Witkowski, Peter T.; Perley, Casey C.; Brocato, Rebecca L.
  • Frontiers in Microbiology, Vol. 8
  • DOI: 10.3389/fmicb.2017.01721

Hamster-Adapted Sin Nombre Virus Causes Disseminated Infection and Efficiently Replicates in Pulmonary Endothelial Cells without Signs of Disease
journal, February 2013

  • Safronetz, D.; Prescott, J.; Haddock, E.
  • Journal of Virology, Vol. 87, Issue 8
  • DOI: 10.1128/JVI.03291-12

Blurred vision and myopic shift in Puumala virus infections are independent of disease severity
journal, October 2012


Hantaviruses: A Global Disease Problem
journal, June 1997


Hypophyseal Hemorrhage and Panhypopituitarism during Puumala Virus Infection: Magnetic Resonance Imaging and Detection of Viral Antigen in the Hypophysis
journal, July 2002

  • Hautala, Timo; Sironen, Tarja; Vapalahti, Olli
  • Clinical Infectious Diseases, Vol. 35, Issue 1
  • DOI: 10.1086/340859

Biphasic Emetic Response of Cyclophosphamide in the Ferret
journal, September 1997


Development of a GB Virus B Marmoset Model and Its Validation with a Novel Series of Hepatitis C Virus NS3 Protease Inhibitors
journal, January 2004


Clinical Characteristics of Nephropathia Epidemica in Sweden: Prospective Study of 74 Cases
journal, November 1989


Characterization of Two Substrains of Puumala Virus That Show Phenotypes That Are Different from Each Other and from the Original Strain
journal, November 2010

  • Sundstrom, K. B.; Stoltz, M.; Lagerqvist, N.
  • Journal of Virology, Vol. 85, Issue 4
  • DOI: 10.1128/JVI.01428-10

Intranasal monkeypox marmoset model: Prophylactic antibody treatment provides benefit against severe monkeypox virus disease
journal, June 2018

  • Mucker, Eric M.; Wollen-Roberts, Suzanne E.; Kimmel, Adrienne
  • PLOS Neglected Tropical Diseases, Vol. 12, Issue 6
  • DOI: 10.1371/journal.pntd.0006581

A small nonhuman primate model for filovirus-induced disease
journal, November 2011


A Macaque Model for Hantavirus Infection
journal, July 1995

  • Groen, J.; Gerding, M.; Koeman, J. P.
  • Journal of Infectious Diseases, Vol. 172, Issue 1
  • DOI: 10.1093/infdis/172.1.38

Synthesis of 1-β-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole and its in vitro and in vivo efficacy against Hantavirus
journal, July 2008


Immune Serum Produced by DNA Vaccination Protects Hamsters against Lethal Respiratory Challenge with Andes Virus
journal, November 2007

  • Hooper, J. W.; Ferro, A. M.; Wahl-Jensen, V.
  • Journal of Virology, Vol. 82, Issue 3
  • DOI: 10.1128/JVI.01822-07

Ocular characteristics in Nephropathia epidemica or Puumala virus infection
journal, December 1996


A Novel Nonhuman Primate Model for Influenza Transmission
journal, November 2013


A Lethal Disease Model for Hantavirus Pulmonary Syndrome in Immunosuppressed Syrian Hamsters Infected with Sin Nombre Virus
journal, November 2013

  • Brocato, R. L.; Hammerbeck, C. D.; Bell, T. M.
  • Journal of Virology, Vol. 88, Issue 2
  • DOI: 10.1128/JVI.02906-13

DNA Vaccination with Hantavirus M Segment Elicits Neutralizing Antibodies and Protects against Seoul Virus Infection
journal, March 1999


Hantavirus Infections in Europe
journal, October 2003


Efficacy of arbidol on lethal hantaan virus infections in suckling mice and in vitro
journal, June 2009

  • Deng, Hai-ying; Luo, Fan; Shi, Li-qiao
  • Acta Pharmacologica Sinica, Vol. 30, Issue 7
  • DOI: 10.1038/aps.2009.53

Observations on Natural and Laboratory Infection of Rodents with the Etiologic Agent of Korean Hemorrhagic Fever *
journal, March 1981

  • French, G. R.; Tsuchiya, K.; Baek, L. J.
  • The American Journal of Tropical Medicine and Hygiene, Vol. 30, Issue 2
  • DOI: 10.4269/ajtmh.1981.30.477

Detection of Puumala Hantavirus Antigen in Human Intestine during Acute Hantavirus Infection
journal, May 2014


Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus
journal, January 2011

  • Rasmuson, J.; Andersson, C.; Norrman, E.
  • European Journal of Clinical Microbiology & Infectious Diseases, Vol. 30, Issue 5
  • DOI: 10.1007/s10096-010-1141-6

Nephropathia Epidemica in Finland: A Retrospective Study of 126 Cases
journal, January 1994

  • Mustonen, Jukka; Brummer-Korvenkontio, Markus; Hedman, Klaus
  • Scandinavian Journal of Infectious Diseases, Vol. 26, Issue 1
  • DOI: 10.3109/00365549409008583

Lassa Virus Infection in Experimentally Infected Marmosets: Liver Pathology and Immunophenotypic Alterations in Target Tissues
journal, April 2007

  • Carrion, R.; Brasky, K.; Mansfield, K.
  • Journal of Virology, Vol. 81, Issue 12
  • DOI: 10.1128/JVI.02876-06

Quantification of Hantaan Virus with a SYBR Green Ⅰ-Based One-Step qRT-PCR Assay
journal, November 2013


A Novel Highly Reproducible and Lethal Nonhuman Primate Model for Orthopox Virus Infection
journal, April 2010


DNA vaccine-derived human IgG produced in transchromosomal bovines protect in lethal models of hantavirus pulmonary syndrome
journal, November 2014


Pathology of Experimental SARS Coronavirus Infection in Cats and Ferrets
journal, July 2008

  • van den Brand, J. M. A.; Haagmans, B. L.; Leijten, L.
  • Veterinary Pathology, Vol. 45, Issue 4
  • DOI: 10.1354/vp.45-4-551

Antigenic and genetic properties of viruses linked to hemorrhagic fever with renal syndrome
journal, March 1985


Andes Virus Antigens Are Shed in Urine of Patients with Acute Hantavirus Cardiopulmonary Syndrome
journal, March 2009

  • Godoy, P.; Marsac, D.; Stefas, E.
  • Journal of Virology, Vol. 83, Issue 10
  • DOI: 10.1128/JVI.02409-08

Case Report: Clinical Pathologic Changes in Two Marmosets with Wasting Syndrome
journal, November 1996


Development of a Novel Nonhuman Primate Model for Rift Valley Fever
journal, December 2011

  • Smith, D. R.; Bird, B. H.; Lewis, B.
  • Journal of Virology, Vol. 86, Issue 4
  • DOI: 10.1128/JVI.06190-11

Common Marmosets (Callithrix jacchus) as a Nonhuman Primate Model To Assess the Virulence of Eastern Equine Encephalitis Virus Strains
journal, July 2008

  • Adams, A. P.; Aronson, J. F.; Tardif, S. D.
  • Journal of Virology, Vol. 82, Issue 18
  • DOI: 10.1128/JVI.00674-08

The Protean Manifestations of Hemorrhagic Fever with Renal Syndrome: A Retrospective Review of 26 Cases from Korea
journal, September 1990


Characterization and outcome following Puumala virus infection: a retrospective analysis of 75 cases
journal, March 2010

  • Braun, N.; Haap, M.; Overkamp, D.
  • Nephrology Dialysis Transplantation, Vol. 25, Issue 9
  • DOI: 10.1093/ndt/gfq118

A lethal disease model for New World hantaviruses using immunosuppressed Syrian hamsters
journal, October 2017


Puumala virus infection in Syrian hamsters (Mesocricetus auratus) resembling hantavirus infection in natural rodent hosts
journal, September 2011


A unifying hypothesis and a single name for a complex globally emerging infection: hantavirus disease
journal, November 2011

  • Clement, J.; Maes, P.; Lagrou, K.
  • European Journal of Clinical Microbiology & Infectious Diseases, Vol. 31, Issue 1
  • DOI: 10.1007/s10096-011-1456-y

A Phase 1 clinical trial of Hantaan virus and Puumala virus M-segment DNA vaccines for hemorrhagic fever with renal syndrome
journal, March 2012


The SARS-CoV ferret model in an infection–challenge study
journal, April 2008


A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection
journal, October 2009


Morbillivirus Control of the Interferon Response: Relevance of STAT2 and mda5 but Not STAT1 for Canine Distemper Virus Virulence in Ferrets
journal, December 2013

  • Svitek, N.; Gerhauser, I.; Goncalves, C.
  • Journal of Virology, Vol. 88, Issue 5
  • DOI: 10.1128/JVI.03076-13

The pathogenesis of nephropathia epidemica: New knowledge and unanswered questions
journal, December 2013


Prolonged survival of Puumala hantavirus outside the host: evidence for indirect transmission via the environment
journal, August 2006


The ferret as a model organism to study influenza A virus infection
journal, August 2011

  • Belser, J. A.; Katz, J. M.; Tumpey, T. M.
  • Disease Models & Mechanisms, Vol. 4, Issue 5
  • DOI: 10.1242/dmm.007823

Central nervous system-related symptoms and findings are common in acute Puumala hantavirus infection
journal, May 2010


Ribavirin Therapy for Hantaan Virus Infection in Suckling Mice
journal, March 1986

  • Huggins, J. W.; Kim, G. R.; Brand, O. M.
  • Journal of Infectious Diseases, Vol. 153, Issue 3
  • DOI: 10.1093/infdis/153.3.489

Ferrets: Clinical Pathology and Sample Collection
journal, September 1999

  • Morrisey, James K.; Ramer, Jan C.
  • Veterinary Clinics of North America: Exotic Animal Practice, Vol. 2, Issue 3
  • DOI: 10.1016/S1094-9194(17)30110-X

Susceptibility of Marmosets (Callithrix jacchus) to Monkeypox Virus: A Low Dose Prospective Model for Monkeypox and Smallpox Disease
journal, July 2015


Reference intervals for some clinical chemical parameters in the marmoset ( Callithrix jacchus ): effect of age and sex
journal, April 1984


A Lethal Disease Model for Hantavirus Pulmonary Syndrome
journal, October 2001


Ecology of Hantaan virus at Twin Bridges Training Area, Gyeonggi Province, Republic of Korea, 2005-2007
journal, November 2009


Appearance of renal hemorrhage in adult mice after inoculation of patient-derived hantavirus
journal, January 2017


Temporal Analysis of Andes Virus and Sin Nombre Virus Infections of Syrian Hamsters
journal, May 2007

  • Wahl-Jensen, V.; Chapman, J.; Asher, L.
  • Journal of Virology, Vol. 81, Issue 14
  • DOI: 10.1128/JVI.00238-07

Haematological and serum chemistry profiles of ferrets ( Mustela putorius furo )
journal, April 1982