Serum Cytokine Profiles Differentiating Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome

Abstract

Hantavirus infection is an acute zoonosis that clinically manifests in two primary forms, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). HFRS is endemic in Europe and Russia, where the mild form of the disease is prevalent in the Tatarstan region. HPS is endemic in Argentina, as well as other countries of North and South American. HFRS and HPS are usually acquired via the upper respiratory tract by inhalation of virus-contaminated aerosol. Although the pathogenesis of HFRS and HPS remains largely unknown, postmortem tissue studies have identified endothelial cells as the primary target of infection. Importantly, cell damage due to virus replication, or subsequent tissue repair, has not been documented. Since no single factor has been identified that explains the complexity of HFRS or HPS pathogenesis, it has been suggested that a cytokine storm may play a crucial role in the manifestation of both diseases. In order to identify potential serological markers that distinguish HFRS and HPS, serum samples collected during early and late phases of the disease were analyzed for 48 analytes using multiplex magnetic bead-based assays. Overall, serum cytokine profiles associated with HPS revealed a more pro-inflammatory milieu as compared to HFRS. Furthermore, HPS was strictly characterized by the upregulation of cytokine levels, in contrast to HFRS where cases were distinguished by a dichotomy in serum cytokine levels. The severe form of hantavirus zoonosis, HPS, was characterized by the upregulation of a higher number of cytokines than HFRS (40 vs 21). In general, our analysis indicates that, although HPS and HFRS share many characteristic features, there are distinct cytokine profiles for these diseases. These profiles suggest a strong activation of an innate immune and inflammatory responses are associated with HPS, relative to HFRS, as well as a robust activation of Th1-type immune responses. Finally, the results of our analysis suggest that serum cytokines profiles of HPS and HFRS cases are consistent with the presence of extracellular matrix degradation, increased mononuclear leukocyte proliferation, and transendothelial migration.

The generation of plasma cells and CD27−IgD−B cells during Hantavirus infection are associated with distinct pathological findings

“…Thrombocytes are a major source of the chemokine CXCL12 (28), which is critically involved in PB migration (29). Since Puumala virus infection can induce thrombocyte activation (30) and elevated levels of CXCL12 were detected during both PUUV-induced HFRS and Andes virus-induced HPS (31), we hypothesized that the infection may have mobilized both active and resting PBs/PCs into circulation. Therefore, we assessed the levels of proliferating PBs (Ki67 + ) and non-proliferating (Ki67 − ) PBs/PCs in circulation (Figure 2E).…”

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

“…Elevated IL‐6 levels in plasma have been associated with more severe HFRS . Elevated levels of IL‐6 and other cytokines such as IL‐8, IL‐10, TNF and IFN‐γ have also been detected in Dobrava virus‐infected and Hantaan virus‐infected HFRS patients and in HPS patients indicating that elevated levels of these cytokines are a general consequence of human hantavirus infection.…”

Preliminary insights into the genetics of bank vole tolerance to Puumala hantavirus in Sweden

“…Interferons produced following TLR binding to viruses activate the JAK-STAT signaling pathway, which is essential in directing the immune response to virus infection. Moreover, hantaviral proteins have been shown to suppress the activation of this pathway (Levine et al, 2010;Schountz & Prescott, 2014), which is fatal in humans (Khaiboullina et al, 2017). Besides, VEGF is a cytokine that enhances endothelial cell permeability and shows elevated levels in hantavirus-infected humans, suggesting that it could be involved in hantavirus pathogenesis (Gavrilovskaya et al, 2008;Gavrilovskaya, Gorbunova, Koster, & Mackow, 2012).…”

“…In reservoirs, hantaviruses persist without exhibiting any sign of immune pathology and they evade immune responses to establish persistence (Easterbrook & Klein, 2008 Interleukin-7 is a cytokine involved in the adaptive immune system and in particular in the development of B cells, T cells, and regulatory T cells. Its contribution to the response to hantavirus infections has only been scarcely shown in humans, with an upregulation observed during non fatal human infections compared to fatal cases (Khaiboullina et al, 2017). Again, its role in rodent/ hantavirus interactions remains to be explored, especially with regard to its potential influence on regulatory T-cell maturation (Easterbrook, Zink, & Klein, 2007), and in turn on rodent tolerance to hantavirus.…”