Neutrophil Activation in Acute Hemorrhagic Fever With Renal Syndrome Is Mediated by Hantavirus-Infected Microvascular Endothelial Cells

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.

Seoul Virus Tropism and Pathology in Naturally Infected Feeder Rats

“…Overall, in all tissues evaluated, SEOV primarily targeted endothelial cells lining the microvasculature and seldom endothelial cells lining larger blood vessels. This is in line with previous reports for SEOV and other orthohantaviruses [31,32,33]. In humans, orthohantavirus infection of the endothelial cells can result in increased permeability and hemostatic dysfunction [34,35], however the effect of infection on endothelial cells in reservoir species has not been studied in detail.…”

Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus‐associated syndromes

“…Higher levels of peripheral blood neutrophils have been observed in PUUV‐infected patients with moderate to severe symptoms than in patients with mild symptoms . Further, PUUV‐infected patients show increased levels of neutrophil activation products . Hantavirus infection has also been shown to induce neutrophil extracellular trap formation, though the mechanism behind this finding is debated .…”

“…Hantavirus infection has also been shown to induce neutrophil extracellular trap formation, though the mechanism behind this finding is debated . These observations, along with findings showing that HFRS patients display elevated systemic levels of histone‐double‐stranded DNA complexes as well as antinuclear antigen antibodies, suggest a potential role for neutrophils in hantavirus‐induced immunopathology .…”

Predictive value of pentraxin-3 on disease severity and prognosis in patients with hemorrhagic fever with renal syndrome

“…As one of the most important immune cells in innate immunity, neutrophils play a crucial part in resisting bacterial infection. Nevertheless, the neutrophil counts are also elevated in most HFRS patients triggered by the Hantavirus infection, and which are also positively correlated with the disease severity of HFRS [18,20]. Therefore, neutrophils may also play an important role in the immunopathological injury of HFRS.…”