Table 3.

Pathophysiology in response to hantavirus infection as discovered in cell culture, in vivo models and human biosamples

	Evidence reported in
Pathogenic mechanisms in hantavirus disease	Cell culture	In vivo models	Humans	Comments	References
Increased vascular permeability
VEGF-induced endothelial hyperpermeability	X	X	X	Orchestrated by a decrease in VE-cadherin and inactivation of the αVβ3-integrin–VEGFR2 complex	[98, 99, 105–107]
Bradykinin-induced capillary leakage	X		X		[109–111]
Cytokine-mediated hyperpermeability	X		X		[113–119]
Platelet activation
Direct viral-caused platelet consumption	X			Interaction of viral glycoproteins and integrin αIIβ3 on platelets	[124, 125]
Endothelial cell injury causing platelet activation	X		X	Release of adhesive agents, such as fibrinogen, fibronectin, extracellular vesicle tissue factor and von Willebrand factor after endothelial infection	[23, 126, 127, 131, 132]
Overreacting host immune response
Reverse CD4+:CD8+ T-cell ratio	X		X	Causes further activation of pro-inflammatory cytokines	[1, 3, 151, 152, 156]
Triggered T-cell immune response by HLA haplotypes			X	May explain interpersonal and regional differences in susceptibility and vulnerability	[153, 156–163]
Cytokine-mediated activation of innate and adaptive immune responses causing tissue damage			X	Distinct cytokine profiles in HFRS and HCPS; cytokine storm is a common central component in response in hemorrhagic fevers	[116, 118, 119, 138, 142–145]

Increased vascular permeability, platelet activation and an overreacting host immune response are the central pathomechanisms in human disease caused by pathogenic Old World and New World hantaviruses.