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The fundamental role of endothelial cells in hantavirus pathogenesis.

Hepojoki J, Vaheri A, Strandin T - Front Microbiol (2014)

Bottom Line: Hantaviruses cause hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome in man, often with severe consequences.Vascular leakage is evident in severe hantavirus infections, and increased permeability contributes to the pathogenesis.This review summarizes the current knowledge on hantavirus interactions with hematopoietic and endothelial cells, and their effects on the increased vascular permeability.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Haartman Institute, University of Helsinki Helsinki, Finland.

ABSTRACT
Hantavirus, a genus of rodent- and insectivore-borne viruses in the family Bunyaviridae, is a group of emerging zoonotic pathogens. Hantaviruses cause hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome in man, often with severe consequences. Vascular leakage is evident in severe hantavirus infections, and increased permeability contributes to the pathogenesis. This review summarizes the current knowledge on hantavirus interactions with hematopoietic and endothelial cells, and their effects on the increased vascular permeability.

No MeSH data available.


Related in: MedlinePlus

Mechanisms of vasculopathy in hantavirus infections. The recognition of hantaviruses by macrophages (Mφ) or dendritic cells (DCs) induces proinflammatory cytokines, which evoke a change from anti- to pro-adhesive phenotype of endothelial cells (ECs). Pro-adhesive ECs bind monocytes (MOs) through ICAM-1 – integrin β2 interaction, and platelets (PLTs) through vWF through αIIbβ3 integrin interaction. Activated MOs and PLTs then respectively promote coagulation through tissue factor (TF) and contact activation pathway (factor XII), to restrict the spread of the virus. Simultaneously hantavirus-infected ECs display viral glycoproteins on their surface, which respectively bind β2 and β3 integrins of polymorphonuclear neutrophils (PMNs) and PLTs. The binding results in the release of neutrophil extracellular traps (NETs) from PMNs and increased activation of PLTs. These virus-induced events enhance inflammation and may result in an excessive formation of immunothrombosis. Complement and contact pathway activations, both associated with immunothrombosis, contribute to vascular leakage through anaphylatoxins C5a and C3a, membrane attack complex (MAC) and bradykinin (BK).
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Figure 1: Mechanisms of vasculopathy in hantavirus infections. The recognition of hantaviruses by macrophages (Mφ) or dendritic cells (DCs) induces proinflammatory cytokines, which evoke a change from anti- to pro-adhesive phenotype of endothelial cells (ECs). Pro-adhesive ECs bind monocytes (MOs) through ICAM-1 – integrin β2 interaction, and platelets (PLTs) through vWF through αIIbβ3 integrin interaction. Activated MOs and PLTs then respectively promote coagulation through tissue factor (TF) and contact activation pathway (factor XII), to restrict the spread of the virus. Simultaneously hantavirus-infected ECs display viral glycoproteins on their surface, which respectively bind β2 and β3 integrins of polymorphonuclear neutrophils (PMNs) and PLTs. The binding results in the release of neutrophil extracellular traps (NETs) from PMNs and increased activation of PLTs. These virus-induced events enhance inflammation and may result in an excessive formation of immunothrombosis. Complement and contact pathway activations, both associated with immunothrombosis, contribute to vascular leakage through anaphylatoxins C5a and C3a, membrane attack complex (MAC) and bradykinin (BK).

Mentions: Plasma leakage from vasculature into tissues is a hallmark of hantavirus infection. Clinically, this is presented by hemorrhages (the presence of plasma fluid in tissues), hemoconcentration (relative cell number increase in plasma), and hypotension (decreased blood pressure). Vascular leakage can be caused by either enhanced endothelial cell (EC) permeability or by direct injury to the vasculature. In HFRS, widespread EC swelling, perivascular edema, diapedesis of erythrocytes, and mononuclear cell infiltrates without evidence of EC damage have been observed by microscopy (Tsai, 1987). This suggests that endothelial barrier function is lost due to enhanced permeability rather than by direct cellular cytotoxicity or injury of the vasculature. Hantavirus antigens are present in ECs during HFRS (Cosgriff, 1991) and in ECs of lung capillary during HCPS (Zaki et al., 1995), but based on in vitro studies hantavirus infection of ECs does not induce direct cytopathic effects (Yanagihara and Silverman, 1990; Pensiero et al., 1992; Valbuena and Walker, 2006; Mackow and Gavrilovskaya, 2009; Vaheri et al., 2013). However, virus-induced general inflammation may compromise the barrier function of the endothelium and induce vascular leakage. If so, similar mechanisms could be behind the hemorrhages seen in other viral infections. On the other hand, the infection of ECs might lead to virus-specific promotion of permeability. Evidence in favor for both scenarios is discussed in the following paragraphs. Hypotheses on increased vascular permeability in hantavirus diseases are presented in Figure 1.


The fundamental role of endothelial cells in hantavirus pathogenesis.

Hepojoki J, Vaheri A, Strandin T - Front Microbiol (2014)

Mechanisms of vasculopathy in hantavirus infections. The recognition of hantaviruses by macrophages (Mφ) or dendritic cells (DCs) induces proinflammatory cytokines, which evoke a change from anti- to pro-adhesive phenotype of endothelial cells (ECs). Pro-adhesive ECs bind monocytes (MOs) through ICAM-1 – integrin β2 interaction, and platelets (PLTs) through vWF through αIIbβ3 integrin interaction. Activated MOs and PLTs then respectively promote coagulation through tissue factor (TF) and contact activation pathway (factor XII), to restrict the spread of the virus. Simultaneously hantavirus-infected ECs display viral glycoproteins on their surface, which respectively bind β2 and β3 integrins of polymorphonuclear neutrophils (PMNs) and PLTs. The binding results in the release of neutrophil extracellular traps (NETs) from PMNs and increased activation of PLTs. These virus-induced events enhance inflammation and may result in an excessive formation of immunothrombosis. Complement and contact pathway activations, both associated with immunothrombosis, contribute to vascular leakage through anaphylatoxins C5a and C3a, membrane attack complex (MAC) and bradykinin (BK).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4273638&req=5

Figure 1: Mechanisms of vasculopathy in hantavirus infections. The recognition of hantaviruses by macrophages (Mφ) or dendritic cells (DCs) induces proinflammatory cytokines, which evoke a change from anti- to pro-adhesive phenotype of endothelial cells (ECs). Pro-adhesive ECs bind monocytes (MOs) through ICAM-1 – integrin β2 interaction, and platelets (PLTs) through vWF through αIIbβ3 integrin interaction. Activated MOs and PLTs then respectively promote coagulation through tissue factor (TF) and contact activation pathway (factor XII), to restrict the spread of the virus. Simultaneously hantavirus-infected ECs display viral glycoproteins on their surface, which respectively bind β2 and β3 integrins of polymorphonuclear neutrophils (PMNs) and PLTs. The binding results in the release of neutrophil extracellular traps (NETs) from PMNs and increased activation of PLTs. These virus-induced events enhance inflammation and may result in an excessive formation of immunothrombosis. Complement and contact pathway activations, both associated with immunothrombosis, contribute to vascular leakage through anaphylatoxins C5a and C3a, membrane attack complex (MAC) and bradykinin (BK).
Mentions: Plasma leakage from vasculature into tissues is a hallmark of hantavirus infection. Clinically, this is presented by hemorrhages (the presence of plasma fluid in tissues), hemoconcentration (relative cell number increase in plasma), and hypotension (decreased blood pressure). Vascular leakage can be caused by either enhanced endothelial cell (EC) permeability or by direct injury to the vasculature. In HFRS, widespread EC swelling, perivascular edema, diapedesis of erythrocytes, and mononuclear cell infiltrates without evidence of EC damage have been observed by microscopy (Tsai, 1987). This suggests that endothelial barrier function is lost due to enhanced permeability rather than by direct cellular cytotoxicity or injury of the vasculature. Hantavirus antigens are present in ECs during HFRS (Cosgriff, 1991) and in ECs of lung capillary during HCPS (Zaki et al., 1995), but based on in vitro studies hantavirus infection of ECs does not induce direct cytopathic effects (Yanagihara and Silverman, 1990; Pensiero et al., 1992; Valbuena and Walker, 2006; Mackow and Gavrilovskaya, 2009; Vaheri et al., 2013). However, virus-induced general inflammation may compromise the barrier function of the endothelium and induce vascular leakage. If so, similar mechanisms could be behind the hemorrhages seen in other viral infections. On the other hand, the infection of ECs might lead to virus-specific promotion of permeability. Evidence in favor for both scenarios is discussed in the following paragraphs. Hypotheses on increased vascular permeability in hantavirus diseases are presented in Figure 1.

Bottom Line: Hantaviruses cause hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome in man, often with severe consequences.Vascular leakage is evident in severe hantavirus infections, and increased permeability contributes to the pathogenesis.This review summarizes the current knowledge on hantavirus interactions with hematopoietic and endothelial cells, and their effects on the increased vascular permeability.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Haartman Institute, University of Helsinki Helsinki, Finland.

ABSTRACT
Hantavirus, a genus of rodent- and insectivore-borne viruses in the family Bunyaviridae, is a group of emerging zoonotic pathogens. Hantaviruses cause hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome in man, often with severe consequences. Vascular leakage is evident in severe hantavirus infections, and increased permeability contributes to the pathogenesis. This review summarizes the current knowledge on hantavirus interactions with hematopoietic and endothelial cells, and their effects on the increased vascular permeability.

No MeSH data available.


Related in: MedlinePlus