Orthohantavirus Pathogenesis and Cell Tropism

Abstract

Orthohantaviruses are zoonotic viruses that are naturally maintained by persistent infection in specific reservoir species. Although these viruses mainly circulate among rodents worldwide, spill-over infection to humans occurs. Orthohantavirus infection in humans can result in two distinct clinical outcomes: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). While both syndromes develop following respiratory transmission and are associated with multi-organ failure and high mortality rates, little is known about the mechanisms that result in these distinct clinical outcomes. Therefore, it is important to identify which cell types and tissues play a role in the differential development of pathogenesis in humans. Here, we review current knowledge on cell tropism and its role in pathogenesis during orthohantavirus infection in humans and reservoir rodents. Orthohantaviruses predominantly infect microvascular endothelial cells (ECs) of a variety of organs (lungs, heart, kidney, liver, and spleen) in humans. However, in this review we demonstrate that other cell types (e.g., macrophages, dendritic cells, and tubular epithelium) are infected as well and may play a role in the early steps in pathogenesis. A key driver for pathogenesis is increased vascular permeability, which can be direct effect of viral infection in ECs or result of an imbalanced immune response in an attempt to clear the virus. Future studies should focus on the role of identifying how infection of organ-specific endothelial cells as well as other cell types contribute to pathogenesis.

Keywords: endothelium; hantavirus; hantavirus cardiopulmonary syndrome; hemorrhagic fever with renal syndrome; orthohantavirus; pathogenesis; tropism.

Figure 1

Pathogenic mechanisms in vascular endothelium during initial orthohantavirus infection. (A) Healthy vascular ECs contain a tightly regulated barrier, mainly based on adherens junction molecules such as VE-cadherin. (B) Important soluble factors that maintain this barrier function are bradykinin and VEGF. As response to infection, ECs produce and secrete VEGF. (C) Local VEGF binds to endothelial receptors and disengages adherens junctions by increased nitric oxide production and internalization of VE-cadherin. (D) Under hypoxic conditions (for instance due to pulmonary edema), these effects are even expanded as VEGF production is increased, causing increased vascular permeability. (E) In addition, orthohantavirus particles present on the endothelial cell surface recruit quiescent platelets to endothelial cell surfaces. This increased consumption of blood platelets may contribute in part to thrombocytopenia. Both the permeabilizing effects of secreted VEGF and the recruitment of platelets lead to internalization of VE-cadherin (i.e., loss of endothelial barrier function).

Figure 2

Overview of cell tropism during HFRS and HCPS based on human and experimental disease models. After a human host is infected by inhalation of virus containing aerosolized excreta of an infected rodent, orthohantavirus is able to reach multiple organs and infect different cell types. Potentially infected cell types during HFRS and HCPS are compared for major organs in which viral antigens have been detected in human tissues or experimental disease models; lungs, heart, kidneys, liver, and spleen. X = absence of viral antigen; ? = viral antigen presence not specified.