Investigation into the Pancreatic Pathogenesis of SFTSV across Multiple Levels

Abstract Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) infection induces hepatitis, myocarditis, and even multi‐organ dysfunction with a high mortality rate, while the impact on the pancreas remains unknown. In a retrospective analysis of clinical parameters in a cohort of 290 patients with severe fever with thrombocytopenia syndrome (SFTS), it is observed that pancreatic injury biomarkers in 19.4% (elevated serum amylase ≥3 × upper limit of normal (ULN)) and 25.8% (elevated serum lipase ≥3 × ULN). Notably, 17.6% of patients met the diagnostic criteria for clinically confirmed pancreatitis. Mechanistic studies using human pancreatic organoids and murine models demonstrated that SFTSV directly infects pancreatic tissue, facilitated by viral receptors C‐C motif chemokine receptor 2 (CCR2) and lipoprotein receptor‐related protein 1 (LRP1), provoking cell death in pancreatic tissue. Transcriptomic profiling revealed that SFTSV infection triggers a robust innate immune response characterized by interferon pathway activation and pro‐inflammatory cytokine upregulation. Pathological analysis of infected murine pancreatic tissues showed acinar cell vacuolization, viral inclusions, and immune cell infiltration. Comparative studies with caerulein‐induced pancreatitis models identified C3‐mediated complement hyperactivation as a key pathological driver. The studies identified that SFTSV exhibits a specific pancreatic tropism, with direct infection leading to cell death and initiating a strong inflammatory immune response, resulting in viral pancreatitis.