Cytokines as mediators for or effectors against rotavirus disease in children

Abstract

Rotavirus is the most common cause of severe gastroenteritis in young children, but the pathogenesis and immunity of this disease are not completely understood. To examine the host response to acute infection, we collected paired serum specimens from 30 children with rotavirus diarrhea and measured the levels of nine cytokines (interleukin-1beta [IL-1beta], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) using a microsphere-based Luminex Flowmetrix system. Patients with acute rotavirus infection had elevated median levels of seven cytokines in serum, and of these, the levels of three (IL-6, IL-10, and IFN-gamma) were significantly (P < 0.05) higher than those in serum from control children without diarrhea. Patients with fever had significantly (P < 0.05) higher levels of IL-6 in serum than control children, and those with fever and more episodes of diarrhea had significantly (P < 0.05) higher levels of TNF-alpha than those without fever and with fewer episodes of diarrhea. We further demonstrated a negative association (P < 0.05) between the levels of IL-2 and the number of stools on the day on which the first blood sample was collected. Finally, patients with vomiting had significantly (P < 0.05) lower levels of IFN-gamma than those without vomiting. Our pilot study provides evidence that the types and magnitudes of cytokine responses to rotavirus infection in children influence or reflect the clinical outcome of disease. These findings suggest that certain cytokines may play an important role in the pathogenesis of and the protection against rotavirus disease in children and, consequently, may provide directions and insights that could prove critical to the prevention or treatment of this important disease.

FIG. 1.

Associations of serum TNF-α levels with severity of fever (A) and diarrhea (B). TNF-α levels and symptom scores for 24 patients were analyzed as described in the text. Spearman's rank correlation coefficient (r_s) is presented (P < 0.05).

FIG. 2.

Comparison of IL-6 levels in sera of patients with fever and control children. The concentrations of IL-6 in 21 serum specimens from patients with fever and 15 specimens from controls are shown. Patients had significantly higher levels of IL-6 than control children. The statistical significance of the differences was determined by the two-tailed t test (P < 0.05).

FIG. 3.

Concentrations of IL-2 in sera of patients with diarrhea (A) and association of serum IL-2 levels with severity of diarrhea (B). Of the 24 serum specimens from patients, 12 were collected 4 days after the onset of illness and had significantly higher levels of IL-2 than those collected in the first 3 days of illness. The statistical significance of the difference was determined by the two-tailed t test (P < 0.01). Elevated levels of IL-2 were significantly associated with fewer stools on the day of blood collection. Spearman's rank correlation coefficient (r_s) is presented (P < 0.05).

FIG. 4.

Concentrations of IFN-γ in sera of patients with rotavirus infection. (A) Concentrations of IFN-γ in 7 serum specimens from patients with vomiting, 17 specimens from patients without vomiting, and 15 specimens from control children. Patients with vomiting had significantly lower levels of IFN-γ than those without vomiting. (B) Sera collected 4 days after the onset of illness had significantly higher levels of IFN-γ than those collected in the first 3 days of illness. The statistical significance of the differences was determined by the two-tailed t test (P < 0.05).

FIG. 5.

Age and disease severity by selected symptoms. Demographic and clinical data for 25 patients were analyzed as described in the text. Spearman's rank correlation coefficient (r_s) is presented. +, P < 0.05; #, P < 0.01.