Date Published: June 28, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Irina Gavrilovskaya, Elena Gorbunova, Valery Matthys, Nadine Dalrymple, Erich Mackow.
American hantaviruses cause a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). Hantaviruses nonlytically infect endothelial cells and cause dramatic changes in barrier functions of the endothelium without disrupting the endothelium. Instead hantaviruses cause changes in the function of infected endothelial cells that normally regulate fluid barrier functions of capillaries. The endothelium of arteries, veins, and lymphatic vessels is unique and central to the function of vast pulmonary capillary beds, which regulate pulmonary fluid accumulation. The endothelium maintains vascular barrier functions through a complex series of redundant receptors and signaling pathways that serve to both permit fluid and immune cell efflux into tissues and restrict tissue edema. Infection of the endothelium provides several mechanisms for hantaviruses to alter capillary permeability but also defines potential therapeutic targets for regulating acute pulmonary edema and HPS disease. Here we discuss interactions of HPS causing hantaviruses with the endothelium, potential endothelial cell-directed permeability mechanisms, and therapeutic targeting of the endothelium as a means of reducing the severity of HPS disease.
Hantaviruses predominantly infect microvascular endothelial cells (ECs), which line vessels and nonlytically cause two vascular diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) [1–14]. The mechanisms by which hantaviruses cause capillary leak syndromes and disrupt fluid barrier integrity of the endothelium are beginning to be disclosed and appear to involve dysregulating EC functions that normally limit fluid leakage from the vasculature [6, 15–21].
Hantaviruses are enveloped, tripartite, negative-sense RNA viruses and form their own genus within the Bunyaviridae family [14, 65]. Hantaviruses are the only members of the Bunyaviridae that are transmitted to humans by mammalian hosts, and hantaviruses contain highly divergent RNA and protein sequences, which are likely the result of coadaptation with their hosts [13, 14, 66–68]. Single genes have been exchanged between closely related HPS causing hantaviruses ; however, gene reassortment has not permitted the discovery of pathogenic determinants and reverse genetics approaches have thus far proven elusive.
The endothelium lines a series of discrete vessel types that conduct fluids to and from tissues, directs the transfer of nutrients, wastes and oxygen and coordinates tissue responses to changing conditions and pathogens [22, 24, 27, 54, 59, 113–119]. Vascular ECs serve mainly as a conduit in the lining of high pressure arteries but take on a variety of fluid and cellular barrier functions in low pressure veins and capillaries that innervate organs and tissues . Lymphatic vessels have a primary role in draining fluid, proteins, and immune cells from tissues and returning these components to the venous circulation [42, 52–54, 114]. Depending on their location, lymphatic vessels serve discrete fluid barrier and regulatory functions, keeping pulmonary alveolar spaces dry and clearing fluid influx from the lungs [54, 61, 120]. These diverse EC settings require discrete EC functions to effect exchange within large capillary beds of the kidney, liver, and lung [27, 54].
The endothelium contains many unique receptors that regulate AJ assembly and positively or negatively impact AJ stability and vascular integrity [33, 96, 126–129]. Vascular endothelial growth factor (VEGF) binds to EC-specific VEGFR2 receptors and activates a Src-Rac-Pak-VE-cadherin pathway resulting in AJ disassembly and vascular permeability [25, 30, 117]. Specialized ECs contain unique VEGFR1/2/3 that respond to novel forms of VEGF (VEGF A-E) and control AJ disassembly [61, 96, 130]. LECs uniquely express VEGFR3 on their surfaces and respond to VEGF-C/D but also coexpress VEGF-A responsive VEGFR2 receptors and are further regulated by the formation of VEGFR 2/3 heterodimers [39, 42, 53, 131].
Only ANDV infection of Syrian hamsters (Mesocricetus auratus) serves as a model of hantavirus pathogenesis that mimics human HPS in onset symptoms and lethal acute respiratory disease [19, 160, 161]. Inoculation of Syrian hamsters with ANDV, but not SNV or other HPS causing hantaviruses, induces pathology approximating human disease. ANDV causes a fatal infection of Syrian hamsters with an LD50 of 8 plaque-forming units. The disease is characterized by large pleural effusions, congested lungs, and interstitial pneumonitis in the absence of disrupted endothelium [19, 160, 161]. The onset of pulmonary edema coincides with a rapid increase in viremia on day 6, and large inclusion bodies and vacuoles in ultrastructural studies of infected pulmonary ECs [160, 161]. Viral antigen was localized to capillary ECs, alveolar macrophages, and splenic follicular marginal zones populated by dendritic cells. Interestingly, depletion of CD4 and CD8 T-cells had no effect on the onset, course, symptoms, or outcome of ANDV infection and indicates the absence of T-cell responses . Consistent with the potential involvement of β3 integrins and VEGF in this process, ANDV binds to conserved residues within PSI domains of both human and hamster β3 integrins [20, 79]. Thus the mechanism of pathogenesis caused by ANDV is consistent with hypoxia-VEGF- directed acute pulmonary edema that occurs in the absence of T-cell-mediated pathology . These findings differ from a report associating T-cell responses with HPS disease, although the same data support a lack of T-cell involvement, since half of HPS patients had no elevated T-cell responses regardless of disease severity . Observed T-cell responses may instead correlate with viral clearance [63, 162]. The mechanism of pathogenesis may be further elucidated by studies in Syrian hamsters and thus provides a model of ANDV pathogenesis that permits the evaluation of therapeutics that target barrier functions of the endothelium.
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, 163]. They appear to target early viral replication but neither is effective 1-2 weeks postinfection after the onset of HPS symptoms [4–6, 163]. 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, 129, 164]. This approach also has the advantage of being implemented at the onset of symptoms where antiviral approaches appear to be ineffective .
The endothelium plays a fundamental role in vascular disease, and stabilizing the vasculature needs to be evaluated as a means for reducing the severity and mortality of viral vascular diseases. This is especially important for viral infections that cause disease 1-2 weeks after infection, at time points when antiviral approaches are no longer viable. The ability of hantaviruses to infect LECs and alter normal fluid clearance from tissues needs to be investigated and provides a unique target and mechanism for reducing edema that has yet to be considered in HPS disease. The ability of the endothelium to regulate platelet functions, complement activation, and immune responses should also be considered as central targets for reducing the severity of viral hemorrhagic and edematous diseases.