Currently, there are no effective therapeutics for hantavirus infections or disease. Antiviral effects of interferon or the nucleoside analog ribavirin are only effective prophylactically or at very early times postinfection [14
]. They appear to target early viral replication but neither is effective 1-2 weeks postinfection after the onset of HPS symptoms [4
]. An alternative approach against viruses with a long disease onset may be to therapeutically target the acute pathologic response instead of viral replication. Since hantaviruses infect and alter fluid barrier functions of the endothelium, targeting EC responses that transiently stabilize the vasculature has the potential to reduce the severity and mortality of HPS [50
]. This approach also has the advantage of being implemented at the onset of symptoms where antiviral approaches appear to be ineffective [163
Intracellular signaling pathways coordinately regulate the adherence of ECs to the extracellular matrix, anchor receptors to cytoskeletal elements, and induce growth factor directed migration, proliferation and permeability responses [18
]. The complexity of VEGF induced permeability is further demonstrated by the reported ability of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) signaling responses, to block VEGF-induced microvascular permeability [167
]. This multifactorial coordination indicates why so many factors are capable of permeabilizing or stabilizing the endothelium and rationalizes their potential roles in pathogen-induced capillary leakage.
Antibody to VEGFR2 reportedly suppresses VEGF-induced pulmonary edema and suggests the potential of therapeutically antagonizing VEGFR2-Src-VE-cadherin signaling pathways as a means of reducing acute pulmonary edema during HPS [18
]. Several well-studied VEGFR2 and Src inhibitors are in human clinical trials or are used therapeutically to treat human cancers and have the potential to reduce the severity of viral permeability-based diseases [18
]. In vitro
, angiopoietin-1 (Ang-1), sphingosine-1-phosphate (S1P), pazopanib, and dasatinib inhibited EC permeability directed by pathogenic hantaviruses [16
]. Ang-1 is an EC-specific growth factor that transdominantly blocks VEGFR2-directed permeability in vitro
and in vivo
by binding to Tie-2 receptors [180
]. S1P is a platelet derived lipid mediator, which enhances vascular barrier functions by binding to Edg-1 receptors on the endothelium [47
], while pazopanib and dasatinib are drugs that inhibit VEGFR2-Src signaling [174
]. Pazopanib, dasatinib, and the S1P analog FTY720 are already in clinical trials or used clinically for other purposes [34
]. Targeting EC responses provides a potential means of stabilizing HPS patient vessels and reducing edema. The use of S1P receptor agonists has also been shown to regulate the pathogenesis of influenza virus infection by acting on ECs and reducing immune cell recruitment and entry into the lung [172
]. These findings suggest the targeting of EC functions as a means of increasing capillary barrier functions and regulating immune responses that contribute to viral pathogenesis.
The regulation of additional EC receptors that stabilize interendothelial cell AJs and fluid barrier functions of the endothelium may be considered as therapeutic targets. The Robo4 receptor has been shown to inhibit VEGFR2 responses, stabilize vessels and block vascular permeability [48
]. This new potential target is highly expressed by lung microvascular ECs and is currently being evaluated as a therapeutic for a variety of vascular disorders [149
]. However, Robo4 directed stability of interendothelial cell junctions may also be applicable to reducing HPS severity.
Several additional EC receptors that bind to VEGFR2 ectodomains positively or negatively regulate αvβ3
-VEGFR2 functions and may provide additional therapeutic targets for regulating vascular permeability. Potential responses which need to be investigated as therapeutic targets include: NRP1, Syndecan1 (sdc1), and the insulin-like growth factor1 receptor (IGF1R), which are recruited to αvβ3
ectodomain complexes [49
]: Surfen, a heparan sulfate containing protein that reportedly blocks EC permeability [189
], and Fibulin-5, a matrix protein that reportedly promotes EC adherence by binding αvβ3
and is associated with emphysema [190
]. However, inhibiting β3
receptors that are present on both platelets and ECs may exacerbate permeability and thus the choice of therapeutic targets is likely to be critical to increasing fluid barrier functions of the endothelium. Targeting the VEGFR2 axis that regulates EC permeability may be a central mechanism for stabilizing the endothelium and reducing the severity of HPS [127
These findings suggest a plethora of targets that may regulate virally induced vascular permeability and which are already clinically approved for other indications. Moreover, targeting these responses may be broadly applicable to reducing the severity of HFRS and a wide range of viral infections that impact the endothelium and cause edematous diseases.