IL-6 trans-signaling mediates cytokine secretion and barrier dysfunction in hantavirus infected cells and correlate to severity in HFRS
Authors: Maleki Kimia T. , Niemetz Linda , Christ Wanda , Wigren Byström Julia , Thunberg Therese , Ahlm Clas , Klingström Jonas 
Published: August 2024

AbstractBackgroundHantavirus causes hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Strong inflammatory responses and vascular leakage are important hallmarks of these often fatal diseases. The mechanism behind pathogenesis is unknown and no specific treatment is available. IL-6 was recently highlighted as a biomarker for HPS/HFRS severity. IL-6 signaling is complex and context dependent: while classical signaling generally provide protective responses, trans-signaling can cause severe pathogenic responses. This study aims to investigate a potential role for IL-6 trans-signaling in hantavirus pathogenesis.MethodsEffects of IL-6 trans-signaling duringin vitrohantavirus infection were assessed using primary human endothelial cells treated with recombinant soluble IL-6 receptor (sIL-6R). Plasma from Puumala orthohantavirus-infected HFRS patients (n=28) were analyzed for IL-6 trans-signaling potential and its associations to severity.FindingsIn vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients that did not.InterpretationIL-6 trans-signaling is linked to hantavirus pathogenesis. Targeting IL-6 trans-signaling might provide a therapeutic strategy for treatment of HPS and severe HFRS.Research in contextEvidence before this studyIL-6 have dual effects, it provides important antiviral responses but can also cause severe pathogenesis. IL-6 mediated effects are activated by two different mechanisms, classical signaling and trans-signaling. IL-6 trans-signaling have recently been shown to be responsible for IL-6 mediated pathogenesis. Endothelial cells lack membrane-bound IL-6 receptor and only respond to IL-6 trans-signaling. Orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS; also called hantavirus cardiopulmonary syndrome (HCPS)), acute severe zoonotic diseases with high fatality rates for which specific treatments and vaccines are lacking. Deregulated vascular permeability and inflammation are hallmarks of HPS and severe HFRS. However, the mechanisms underlying hantavirus disease are unknown, hampering the development of treatments. Orthohantaviruses primarily infect endothelial cells. Previous studies have demonstrated a correlation between elevated IL-6 levels and increased severity of HPS and HFRS. Whether this link is causal, and if so the mechanisms behind it, has not been determined.Added value of this studyThis study demonstrates that hantavirus-infected endothelial cells produce large amounts of IL-6, and are highly sensitive to IL-6 trans-signaling mechanisms. Together this strongly amplifies the IL-6 production and disrupt the endothelial cell barrier causing severe fluid leakage. When analyzing a potential role for IL-6 trans-signaling in patients, we observed increased systemic IL-6 trans-signaling potential, and that this was linked to severity, in Puumala virus-infected HFRS patients.Implications of all the available evidenceThese data suggest the two hallmarks of HPS and HFRS; increased vascular permeability and strong inflammation, is linked via hantavirus-induced endothelial cell IL-6 production and IL-6 trans-signaling effects. Treatment targeting IL-6 trans-signaling might provide a therapeutic strategy for HPS and severe HFRS.