| Hantaviruses cause two distinct human diseases termed hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), caused by Old World and New World viruses respectively. Sin Nombre virus (SNV) (family Bunyaviridae, genus hantavirus) is the primary etiologic agent of HCPS in North America. A common feature of hantaviruses is their close association with species-specific rodent hosts where they do not cause disease. Pathology is manifested by increased vascular permeability and microvascular endothelial cells are the primary targets of infection in vivo. No virus-induced cytopathology is observed and high levels of inflammatory cytokines are observed in the lungs of patients who succumb to HCPS. These observations suggest that mal-adaptive immune responses contribute to the pathogenic process. The innate immune system responds to viral infection by expression of antiviral proteins with wide-ranging functions, and secretion of soluble mediators that regulate downstream immune responses. Here, I sought to investigate the viral and cellular requirements in the context of the initial transcription of antiviral genes using human primary cells and cell lines. I found that SNV induces the transcription of interferon-stimulated genes (ISGs) at early time points following infection in primary endothelial cells. Furthermore, live and replication-defective virus is able to induce a similar set of genes, indicating that the particle itself is recognized by the host cell and not products of replication. These observations prompted us to examine the cellular requirements for the detection of SNV particles. To do this, I used tractable cell lines to systematically investigate the requirements of viral entry, common virus-sensing molecules and signaling pathways, and transcription factors following treatment with SNV. As a result, I describe a novel system in which SNV activates ISG transcription independent of interferon regulatory factor 3 (IRF3), which is thought to be essential for the transcription of ISGs in response to viral infection. I also found that this response is independent of viral entry and the viral RNA-sensing molecules that are commonly used to detect viruses and signal the activation of innate immune responses. In this dissertation, I have begun to characterize how non-immune cells recognize and respond to hantaviruses. |
