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Journal of Virology, August 2002, p. 8347-8359, Vol. 76, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.16.8347-8359.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Elevated Generation of Reactive Oxygen/Nitrogen Species in Hantavirus Cardiopulmonary Syndrome

Ian C. Davis,1 Allan J. Zajac,2 Kurt B. Nolte,3,4 Jason Botten,4 Brian Hjelle,4 and Sadis Matalon1*

Departments of Anesthesiology,1 Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294,2 Office of the Medical Investigator,3 Department of Pathology, School of Medicine, University of New Mexico, Albuquerque, New Mexico 871314

Received 14 February 2002/ Accepted 3 May 2002

Hantavirus cardiopulmonary syndrome (HCPS) is a life-threatening respiratory disease characterized by profound pulmonary edema and myocardial depression. Most cases of HCPS in North America are caused by Sin Nombre virus (SNV), which is carried asymptomatically by deer mice (Peromyscus maniculatus). The underlying pathophysiology of HCPS is poorly understood. We hypothesized that pathogenic SNV infection results in increased generation of reactive oxygen/nitrogen species (RONS), which contribute to the morbidity and mortality of HCPS. Human disease following infection with SNV or Andes virus was associated with increased nitrotyrosine (NT) adduct formation in the lungs, heart, and plasma and increased expression of inducible nitric oxide synthase (iNOS) in the lungs compared to the results obtained for normal human volunteers. In contrast, NT formation was not increased in the lungs or cardiac tissue from SNV-infected deer mice, even at the time of peak viral antigen expression. In a murine (Mus musculus) model of HCPS (infection of NZB/BLNJ mice with lymphocytic choriomeningitis virus clone 13), HCPS-like disease was associated with elevated expression of iNOS in the lungs and NT formation in plasma, cardiac tissue, and the lungs. In this model, intraperitoneal injection of 1400W, a specific iNOS inhibitor, every 12 h during infection significantly improved survival without affecting intrapulmonary fluid accumulation or viral replication, suggesting that cardiac damage may instead be the cause of mortality. These data indicate that elevated production of RONS is a feature of pathogenic New World hantavirus infection and that pharmacologic blockade of iNOS activity may be of therapeutic benefit in HCPS cases, possibly by ameliorating the myocardial suppressant effects of RONS.

* Corresponding author. Mailing address: Department of Anesthesiology, University of Alabama at Birmingham, THT 940, 1530 3rd Ave. South, Birmingham, AL 35294-0006. Phone: (205) 934-4231. Fax: (205) 934-7437. E-mail: sadis.Matalon{at}ccc.uab.edu.

Journal of Virology, August 2002, p. 8347-8359, Vol. 76, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.16.8347-8359.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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