The Arenavirus-Host Cell Interface: At the Crossroads of Virus Replication, Host Cell Response and Pathogenesis

The arenaviruses are an important group of pathogens that includes several agents of severe human disease, with symptoms that include hemorrhagic fever and neurological complications; however, closely related family members are often apathogenic. The basis for this difference remains poorly understood, although regulation of host cell responses appears to play an important role. Our work has revealed differences in the ability of highly pathogenic arenaviruses (i.e. Junín virus) and their closely-related apathogenic relatives (i.e. Tacaribe virus) to regulate the induction of apoptosis during infection, and this has led us to study both the mechanism involved and its consequences for virus biology. In addition to identifying key proapoptotic factors responsible for triggering apoptosis in response to infection (i.e. p53, Puma, Noxa), we have recently demonstrated the upregulation of stress-activated protein kinases that appear to contribute to this process (i.e. p38, JNK), and identified the upstream viral and host interaction partners responsible for activation of this cascade. Interestingly, these studies revealed that activation of kinases during infection appears to be crucial for virus infection, while the late-stages of apoptotic cell death itself are not. Supporting this, we have also shown that the pathogenic Junín virus actively suppresses caspases activation by sacrificing a subset of its nucleoprotein as a decoy substrate for caspase cleavage - a process that appears to play a role in the regulation of the antiviral response to infection. This is consistent with our work in primary targets cells where we see dramatic differences in the regulation of innate immunity between these viruses, and also with differences in outcome in animal models (as well as in humans). Taken together these studies advance out understanding of the virus-host interface and its role in disease outcome.

Learning Objectives:

1. Describe the two key pathways responsible for the regulation of apoptotic cell death

2. Summarize the changes in the host cell that trigger apoptosis in response to arenavirus infection

3. Explain how differences in the apoptosis regulatory mechanisms of arenaviruses contribute to different disease outcomes