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

Gastrointestinal symptoms (GI) (abdominal pain, vomiting, and diarrhea) during the febrile phase of dengue (less than 5 days from fever onset) might indicate prominent innate immune responses. Serum and feces samples from cases with GI symptoms versus those without GI symptoms (n = 20 per group) were analyzed. From these, only the neutrophil extracellular traps (NETs), serum fibroblast growth factor (FGF) 21, and fecal microbiome analyses, but not the routine parameters, endotoxemia, or serum cytokines, were higher in the GI cases than in the non-GI cases. From the in vitro experiments, both lipopolysaccharide (LPS) and the dengue virus (DENV) upregulated the FGF receptor 1 (FGFR1) and cytokines in hepatocytes (HepG2) and THP-1-differentiated macrophages. Meanwhile, LPS and DENV induced NETs in isolated neutrophils from healthy volunteers. Only the starvation protocol, but not LPS or DENV, enhanced supernatant FGF-21 from hepatocytes. Incubation of recombinant FGF-21 in LPS + DENV-activated cells (hepatocytes, macrophages, and neutrophils) attenuated inflammation, as determined by supernatant cytokines and NETs. Hence, abdominal symptoms in dengue during the febrile phase indicate prominent innate immune responses, as detected by NETs and FGF-21 (an acute-phase protein), implying significant hepatic stress with a possible counteracting anti-inflammation.