Serum levels of inflammatory and regulatory cytokines in patients with hemorrhagic fever with renal syndrome
Hantaviruses are the causative agents of two zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The pathogenesis of HFRS is poorly understood. However, it has been suggested that immune mechanisms, including cytokines, might have an important role in HFRS pathogenesis. Thus, the aim of our study was to investigate cytokine profiles in serum samples of HFRS patients from Slovenia and explore a possible correlation between cytokine levels and disease severity. Acute-phase serum samples from 52 patients, diagnosed with DOBV infection, and 61 patients, diagnosed with PUUV infection, were included in this study. Patients were divided into two groups--severe or mild--based on disease severity. Levels of IL-10, IL-12, INF-γ and TNF-α were measured in the serum samples with commercial ELISA tests. Increased levels of IL-10, INF-γ, and TNF-α were found in almost all the serum samples tested. On average, higher concentrations were detected in patients infected with DOBV than PUUV. Furthermore, significantly higher levels of IL-10 (P=0.001) and TNF-α (P=0.003) were found in patients with a more severe clinical course of disease. The same association between IL-10 (P<0.001) and TNF-α (P=0.021), and the severity of the disease was observed also when only patients infected with DOBV were considered. No differences in cytokine concentrations according to disease severity were observed in patients infected with PUUV. Concentrations of serum IL-12 in HFRS patients were in the normal range, however, higher levels were detected in patients infected with PUUV than in patients infected with DOBV. We suggest that imbalance in production of proinflammatory and regulatory cytokines might be in part responsible for a more severe course of HFRS.
Get notified about updates to this publicationFollow publication
[Show abstract] [Hide abstract] ABSTRACT: Background Hantaviruses are emerging zoonotic pathogens which cause hemorrhagic fever with renal syndrome, an immune-mediated pathogenesis is discussed. The aim of the present study was to investigate the role of TGF-β expression in acute hantavirus infection. Results We retrospectively studied 77 patients hospitalised with acute Puumala infection during a hantavirus epidemic in Germany in 2012. Hantavirus infection was confirmed by positive anti-Puumala hantavirus IgG and IgM. Plasma levels of transforming growth factor (TGF)-β1 and TGF-β2 were analysed. Based on glomerular filtration rate on admission, patients were divided in mild and severe course of disease. Puumala virus RNA was detected by PCR amplification of the viral L segment gene. Out of 77 Puumala virus infected patients, 52 (68%) were male. A seasonal distribution was detected in our cohort with a peak in summer 2012, the highest incidence was observed in the age group of 30–39 years. Puumala virus RNA was detectable in 4/77 cases. Patients with severe disease had a significant longer hospital stay than patients with mild disease (6.2 vs 3.6 days). Thrombocyte count (186 vs 225 per nl), serum TGF-β1 (74 vs 118 ng/l) and TGF-β2 (479 vs 586 pg/l) were significantly lower in severe compared to mild disease. However, C-reactive protein (CRP) was significantly higher in patients with severe disease (62 vs 40 mg/l). TGF-β1/Cr was the most sensitive and specific marker associated with renal dysfunction. Conclusion High serum CRP and low serum TGF-β in the early phase of hantavirus infection is associated with a severe course of disease. Our results support the hypothesis of an immune-mediated pathogenesis in hantavirus infection.
- "The long-term prognosis of nephropathia epidemica (NE) caused by Puumala virus is favorable and most patients fully recover renal function . Several previous studies reported an association of pro-inflammatory cytokines and severity of hantavirus infections [14,23242526. There are only few reports about the role of anti-inflammatory and suppressive cytokines such as TGF-β in hantavirus infection. "
[Show abstract] [Hide abstract] ABSTRACT: Viral hemorrhagic fever caused by hantaviruses is an emerging infectious disease for which suitable treatments are not available. In order to improve this situation a better understanding of hantaviral pathogenesis is urgently required. Hantaviruses infect endothelial cell layers in vitro without causing any cytopathogenic effect and without increasing permeability. This implies that the mechanisms underlying vascular hyperpermeability in hantavirus-associated disease are more complex and that immune mechanisms play an important role. In this review we highlight the latest developments in hantavirus-induced immunopathogenesis. A possible contribution of neutrophils has been neglected so far. For this reason, we place special emphasis on the pathogenic role of neutrophils in disrupting the endothelial barrier.
- "High levels of proinflammatory cytokines are detected in sera from hantavirus-infected patients especially TNF-α (Linderholm et al., 1996; Mori et al., 1999; Borges et al., 2008; Klingstrom et al., 2008; Sadeghi et al., 2011; Saksida et al., 2011; Libraty et al., 2012; Kyriakidis and Papa, 2013). TNF-α is released by activated antiviral immune cells such as neutrophils, NK cells and CD8 + T cells as well as hantavirus-infected DC and macrophages (Raftery et al., 2002; Marsac et al., 2011; Shin et al., 2012). "
[Show abstract] [Hide abstract] 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.
- "Upregulated levels of soluble EC receptors: E-Selectin (Takala et al., 2000 ), intercellular adhesion molecule (ICAM; Han et al., 2010), and tumor necrosis factor receptor (TNFR)-1 (Kyriakidis and Papa, 2013) are released into circulation during acute HFRS. While there is no evidence on EC activation in HCPS, the upregulation of proinflammatory cytokines: interleukin (IL)-6, tumor necrosis factor (TNF)-α, and interferon (IFN-γ) that all are capable of activating the endothelium, have been reported in both hantavirus diseases (Linderholm et al., 1996; Peters et al., 1999; Klingstrom et al., 2002; Abel Borges and Figueiredo, 2008; Sadeghi et al., 2011; Saksida et al., 2011; Korva et al., 2013; Kyriakidis and Papa, "