Molecular pathogenesis of viral hemorrhagic fever

Abstract

The clinical syndrome referred to as viral hemorrhagic fever (VHF) can be caused by several different families of RNA viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. VHF is characterized by malaise, fever, vascular permeability, decreased plasma volume, coagulation abnormalities, and varying degrees of hemorrhage. Study of the filovirus Ebola virus has demonstrated a critical role for suppression of innate antiviral defenses in viral pathogenesis. Additionally, antigen-presenting cells are targets of productive infection and immune dysregulation. Among these cell populations, monocytes and macrophages are proposed to produce damaging inflammatory cytokines, while infected dendritic cells fail to undergo proper maturation, potentially impairing adaptive immunity. Uncontrolled virus replication and accompanying inflammatory responses are thought to promote vascular leakage and coagulopathy. However, the specific molecular pathways that underlie these features of VHF remain poorly understood. The arenavirus Lassa virus and the flavivirus yellow fever virus exhibit similar molecular pathogenesis suggesting common underlying mechanisms. Because non-human primate models that closely mimic VHF are available for Ebola, Lassa, and yellow fever viruses, we propose that comparative molecular studies using these models will yield new insights into the molecular underpinnings of VHF and suggest new therapeutic approaches.

Keywords: Ebola virus; Hemorrhagic fever; Lassa virus; yellow fever virus.

Figure 1.. Model of viral hemorrhagic fever.

This model is largely based on Ebola virus, but is consistent with what is also known about Lassa and yellow fever virus pathogenesis. Ebola virus infects at a mucosal surface and infects macrophages and dendritic cells which migrate to lymph nodes. The infection suppresses innate and adaptive immune responses, allowing the virus to disseminate systemically. This systemic spread leads to damage in a variety of tissues, excessive cytokine responses, vascular leakage and disseminated intravascular coagulation. See text for details.