Temporal Analysis of Andes Virus and Sin Nombre Virus Infection of Syrian Hamsters

Virology Division, U.S. Army Medical Research Institute of Infectious Deseases, Fort Detrick, MD 21702, USA.
Journal of Virology (Impact Factor: 4.44). 08/2007; 81(14):7449-62. DOI: 10.1128/JVI.00238-07
Source: PubMed


Andes virus (ANDV) and Sin Nombre virus (SNV) are rodent-borne hantaviruses that cause a highly lethal hemorrhagic fever in humans known as hantavirus pulmonary syndrome (HPS). There are no vaccines or specific drugs to prevent or treat HPS, and the pathogenesis is not understood. Syrian hamsters infected with ANDV, but not SNV, develop a highly lethal disease that closely resembles HPS in humans. Here, we performed a temporal pathogenesis study comparing ANDV and SNV infections in hamsters. SNV was nonpathogenic and viremia was not detected despite the fact that all animals were infected. ANDV was uniformly lethal with a mean time to death of 11 days. The first pathology detected was lymphocyte apoptosis starting on day 4. Animals were viremic and viral antigen was first observed in multiple organs by days 6 and 8, respectively. Levels of infectious virus in the blood increased 4 to 5 logs between days 6 and 8. Pulmonary edema was first detected ultrastructurally on day 6. Ultrastructural analysis of lung tissues revealed the presence of large inclusion bodies and substantial numbers of vacuoles within infected endothelial cells. Paraendothelial gaps were not observed, suggesting that fluid leakage was transcellular and directly attributable to infecting virus. Taken together, these data imply that HPS treatment strategies aimed at preventing virus replication and dissemination will have the greatest probability of success if administered before the viremic phase; however, because vascular leakage is associated with infected endothelial cells, a therapeutic strategy targeting viral replication might be effective even at later times (e.g., after disease onset).

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Available from: Jay W Hooper, Oct 23, 2014
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    • "However, not all HPS-causing hantaviruses uniformly produce HPS-like diseases in Syrian hamsters. For example, SNV and CHOV, two hantaviruses known to cause HPS in North and South America, produce subclinical infection in hamsters (Eyzaguirre et al., 2008; Wahl-Jensen et al., 2007). Recently, transient immunosuppression with dexamethasone Fig. 5 "
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    ABSTRACT: To gain insights into the pathogenicity of Imjin virus (MJNV), a newfound hantavirus isolated from the Ussuri white-toothed shrew (Crocidura lasiura), groups of Syrian hamsters (Mesocricetus auratus) of varying ages (<1, 5, 10, 14, 21, 35 and 56days) were inoculated by the intraperitoneal route with 1000 pfu of MJNV strains 04-55 and 05-11. MJNV-infected Syrian hamsters, aged 21days or less, exhibited reduced activity, weight loss, respiratory distress, hind-limb paralysis and seizures. Death ensued 1 to 6days after onset of clinical disease. MJNV RNA was detected in brain and other major organs by RT-PCR and real time-PCR. Histopathological examination showed alveolar hemorrhage, interstitial pneumonia and severe pulmonary congestion; focal hepatic necrosis and portal inflammation; and acute meningoencephalitis. By immunohistochemistry, MJNV antigen was detected in pulmonary microvascular endothelial cells and glial cells. Older hamsters (35 and 56days of age) developed subclinical infection without histopathological changes. Future studies are warranted to determine the pathophysiologic bases for the differential age susceptibility of Syrian hamsters to lethal MJNV disease.
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    • "SNV infects hamsters as measured by seroconversion to the N protein as determined with N-specific ELISA, but does not cause disease. In contrast, ANDV not only infects hamsters but also causes an endothelium-leak disease that resembles human HPS [17, 20]. The mean day-to-death following a 200 PFU challenge with ANDV is 11 days. "
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    • "ANDV causes a fatal infection of Syrian hamsters with an LD50 of 8 plaque-forming units. The disease is characterized by large pleural effusions, congested lungs, and interstitial pneumonitis in the absence of disrupted endothelium [19, 160, 161]. The onset of pulmonary edema coincides with a rapid increase in viremia on day 6, and large inclusion bodies and vacuoles in ultrastructural studies of infected pulmonary ECs [160, 161]. "
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    ABSTRACT: American hantaviruses cause a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). Hantaviruses nonlytically infect endothelial cells and cause dramatic changes in barrier functions of the endothelium without disrupting the endothelium. Instead hantaviruses cause changes in the function of infected endothelial cells that normally regulate fluid barrier functions of capillaries. The endothelium of arteries, veins, and lymphatic vessels is unique and central to the function of vast pulmonary capillary beds, which regulate pulmonary fluid accumulation. The endothelium maintains vascular barrier functions through a complex series of redundant receptors and signaling pathways that serve to both permit fluid and immune cell efflux into tissues and restrict tissue edema. Infection of the endothelium provides several mechanisms for hantaviruses to alter capillary permeability but also defines potential therapeutic targets for regulating acute pulmonary edema and HPS disease. Here we discuss interactions of HPS causing hantaviruses with the endothelium, potential endothelial cell-directed permeability mechanisms, and therapeutic targeting of the endothelium as a means of reducing the severity of HPS disease.
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