Abdominal Symptoms During the Febrile Phase Indicate Profound Innate Immune Responses in Dengue

Area of Science:

• Immunology
• Virology
• Gastroenterology

Background:

• Gastrointestinal (GI) symptoms during the febrile phase of dengue virus (DENV) infection may signal heightened innate immune activity.
• Understanding the mechanisms behind GI symptoms in dengue is crucial for patient management and therapeutic development.

Purpose of the Study:

• To investigate the association between GI symptoms in dengue and specific innate immune responses.
• To explore the role of neutrophil extracellular traps (NETs), fibroblast growth factor 21 (FGF21), and the fecal microbiome in dengue-associated GI symptoms.

Main Methods:

• Analysis of serum and fecal samples from dengue patients with and without GI symptoms (n=20 per group).
• Measurement of neutrophil extracellular traps (NETs), serum FGF21, fecal microbiome, routine parameters, endotoxemia, and serum cytokines.
• In vitro experiments using hepatocytes, macrophages, and neutrophils stimulated with lipopolysaccharide (LPS) and DENV.

Main Results:

• Dengue patients with GI symptoms exhibited higher levels of NETs, serum FGF21, and distinct fecal microbiome profiles compared to non-GI cases.
• In vitro, LPS and DENV upregulated FGF receptor 1 (FGFR1) and cytokines in liver cells and macrophages, and induced NETs in neutrophils.
• Recombinant FGF21 demonstrated anti-inflammatory effects by reducing cytokines and NETs in activated cells.

Conclusions:

• Abdominal symptoms in early dengue correlate with robust innate immune responses, characterized by NETs and FGF21, indicating hepatic stress.
• FGF21 may play a counteracting anti-inflammatory role in dengue pathogenesis.
• These findings highlight potential biomarkers and therapeutic targets for managing dengue with GI manifestations.