Role of Heat Shock Response in a Zoonotic Virus

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DESCRIPTION: (provided by the applicant): Deer mice (Peromyscus maniculatus) are the natural reservoirs for Sin Nombre (SN) Hantavirus, the cause of an often-fatal acute cardiorespiratory illness, Hantavirus cardiopulmonary syndrome (HCPS). HCPS is most common in the western United States, with more than 50 cases recorded in New Mexico alone. Minorities, especially American Indians, and the poor are especially affected. Virtually nothing is known of how SN virus is maintained in wild rodents, and thus it is very difficult to predict outbreaks or to prevent spread of the virus in the wild. The virus is spread among adult wild rodents and despite being locally extinct at times, it dramatically increase to infect up to 50 percent of the mice in a population. Deer mice develop lifelong infection after exposure, but after about 60 days the virus is vastly diminished, with residual low levels of viral expression can be found primarily in the heart, lungs, and brown adipose tissue (BAT). SN virus has evolved some mysterious means by which it can reactivate in a population in response to seasonal influences, and that reactivation leads to spread among mice. Recently we found that cold stress may cause a reactivation of viral infection in deer mice. This finding suggests that the virus may be using the host?s normal stress response to support reactivation. To pursue this further we propose to determine (1) how stress responses promote the reactivation of hantaviruses in the laboratory; (2) what events cause hantaviruses to reactivate in deer mice; and (3) the molecular interactions that lead to the activation of the virus in infected cells and animals. This study will open a new window of study of the mechanisms of maintenance of persistent viral infections in populations, and will have special relevance to zoonotic RNA virus diseases such as those caused by hantaviruses, arenaviruses such as Lassa, Ebola virus and rabies virus.