Abstract
Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Both diseases are considered to be immunologically mediated but the exact pathological mechanisms are still poorly understood. Neutrophils are considered the first line of defense against invading microbes but little is still known of their role in virus infections. We wanted to study the role of neutrophils in HFRS using blood and tissue samples obtained from Puumala hantavirus (PUUV)-infected patients. We found that neutrophil activation products myeloperoxidase and neutrophil elastase, together with interleukin-8 (the major neutrophil chemotactic factor in humans), are strongly elevated in blood of acute PUUV-HFRS and positively correlate with kidney dysfunction, the hallmark clinical finding of HFRS. These markers localized mainly in the tubulointerstitial space in the kidneys of PUUV-HFRS patients suggesting neutrophil activation to be a likely component of the general immune response toward hantaviruses. We also observed increased levels of circulating extracellular histones at the acute stage of the disease supporting previous findings of neutrophil extracellular trap formation in PUUV-HFRS. Mechanistically, we did not find evidence for direct PUUV-mediated activation of neutrophils but instead primary blood microvascular endothelial cells acquired a pro-inflammatory phenotype and promoted neutrophil degranulation in response to PUUV infection in vitro. These results suggest that neutrophils are activated by hantavirus-infected endothelial cells and may contribute to the kidney pathology which determines the severity of HFRS.
Highlights
Hantaviruses are the causative agents of two human diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas
Elevated circulating levels of MPO and human neutrophil elastase (HNE) suggest that neutrophils are activated in acute Puumala hantavirus (PUUV)-HFRS
The circulating levels of histone H3 correlated with MPO and HNE suggesting that all these factors are released simultaneously from neutrophils during NETosis, which presence in acute PUUV-HFRS has been reported previously [21]
Summary
Hantaviruses are the causative agents of two human diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Each hantavirus species is carried by its specific rodent host with no or minimal signs of disease but cause occasional human spillover infections with immune-mediated pathology [1]. A hallmark of both hantavirus diseases is increased vascular permeability which mediates kidney and lung failure. Typical laboratory findings in acute PUUV-caused HFRS are leukocytosis, thrombocytopenia, increased Creactive protein (CRP) level, and as signs of acute kidney injury (AKI), proteinuria, haematuria and elevated serum creatinine concentration [5]. Hematological abnormalities include increased coagulation and fibrinolysis, complement activation, and elevated levels of proinflammatory cytokines which all have the potential to contribute to vascular permeability. The pathophysiology of PUUV-HFRS associated AKI is usually described as tubulointerstitial nephritis and infiltration of several immune cell types such as lymphocytes, monocytes, and polymorphonuclear leukocytes into kidneys have been observed [7, 8]
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