Pathogenesis of Marburg Hemorrhagic Fever in Cynomolgus Macaques

Abstract

Marburg virus (MARV) infection causes a severe and often fatal hemorrhagic disease in primates; however, little is known about the development of MARV hemorrhagic fever. In this study we evaluated the progression of MARV infection in nonhuman primates. Eighteen cynomolgus monkeys were infected with MARV; blood and tissues were examined sequentially over an 8-day period to investigate disease pathogenesis. Disease caused by MARV in cynomolgus macaques was very similar to disease previously described for Ebola virus-infected macaques. Monocytes, macrophages, Kupffer cells, and dendritic cells (DCs) were identified as the initial targets of MARV infection. Bystander lymphocyte apoptosis occurred at early stages in the disease course in intravascular and extravascular locations. The loss of splenic and lymph node DCs or downregulation of dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) on DCs as early as day 2 and continuing through day 8 after MARV infection was a prominent finding. Evidence of disseminated intravascular coagulation was noted; however, the degree of fibrin deposition in tissues was less prominent than was reported in Ebola-infected macaques. The sequence of pathogenic events identified in this study provides an understanding of the development of disease processes and also may provide new targets for rational prophylactic and chemotherapeutic interventions.