A 1993 outbreak of severe respiratory disease among rural residents of the southwestern US was caused by the emergence of a previously-unknown hantavirus, Sin Nombre virus (SNV). Well before SNV was isolated in culture and could be virologically characterized, large amounts of RNA sequence were available from the SNV genome, and used to characterize it antigenically and to develop diagnostic tests. SNV thus represents an excellent model organism for situations in which rapid development and deployment of empirically-designed DNA vaccines could be used to intervene in an outbreak caused by newly-emerged or poorly- characterized pathogens. Virtually nothing is known of how SNV is carried by its reservoir host, the deer mouse. We wish to investigate the mechanisms of transmission of SNV among deer mice in a field setting and to explore mechanisms of immune responses and protection from SNV challenge, using both deer mice and standard laboratory mice (C57/Bl). We will prepare large open-air outdoor enclosures on a patrolled, remote wildlife refuge in western New Mexico to explore transmission of SNV by directly introducing a defined number of infected and uninfected deer mice, which will be fitted with radiotransmitters. The demographics of input rodents will be carefully controlled to investigate the routes of transmission. Their nesting behavior within the enclosure will be monitored by radiotelemetry and correlated with efficiency of transmission of SNV. Studies to determine whether virus-contaminated nest bedding is associated with transmission will also be conducted. Both deer mice and C57/Bl mice will be used to determine the efficacy and immune reactivity to naked DNA immunization using the GI, G2, and N genes of SNV. Lab mice will be used to determine what portions of the SNV genome elicit strong B-cell and T-cell responses, and deer mice will be used to study protection against SNV challenge. Both experimental infection and field transmission challenges will be used. Our long-term goals are to establish the mechanisms by which deer mouse populations maintain SNV infection in natural settings, to identify genetic immunization strategies that may be used to protect at-risk human populations in an outbreak, and to identify ways to disrupt the transmission of SNV among deer mice, and thus to design prevention, control, and treatment strategies.
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