Abstract
Galectin-3, a chimeric type β-galactoside-binding protein, is known to modulate viral infection; however, its role in enterovirus 71 (EV71) infection has not been investigated. We generated galectin-3 null rhabdomyosarcoma (RD) cells and evaluated whether EV71 infection would be affected. In galectin-3 null cells, the released and intracellular EV71 viral loads were suppressed after 24 h of infection, and cell death rates were significantly lower, while cell proliferation remained unaltered. In addition, RD cells expressing a nonsynonymous genetic variant of galectin-3, rs4644 (LGALS3 +191C/A, P64H), produced lower virus titers than those with wild-type galectin-3 (C allele). To clarify whether the in vitro viral load reduction correlates with clinical severity, we enrolled children with laboratory-confirmed EV71 infection. Since hyperglycemia is an indicator of severe EV71 infection in children, 152 of 401 enrolled children had glucose examinations at admission, and 59 subjects had serum glucose levels ≥ 150 mg/dL. In comparison to the rs4644 AA genotype (2.2 ± 0.06 log10 mg/dL), serum glucose levels during EV71 infection were higher in patients with CC (2.4 ± 0.17 log10 mg/dL, p = 0.03) and CA (2.4 ± 0.15 log10 mg/dL, p = 0.02) genotypes, respectively. These findings suggest that the rs4644 AA genotype of galectin-3 might exert a protective effect. In summary, galectin-3 affects EV71 replication in our cellular model and its variant, rs4644, is associated with hyperglycemia in the clinical setting. The underlying mechanism and its potential therapeutic application warrant further investigation.
Highlights
Encephalitis and cardiopulmonary failure are the most critical complications occurring in young children or in immunocompromised hosts with enterovirus 71 (EV71) infections [1,2]
We have found that galectin-3 modulated EV71 replication via in vitro model
The A allele of rs4644, which mimics the findings in galectin-3 ablated cells, was associated with lower EV71 titers in our cellular model, and clinically the AA genotype was protective against higher levels of hyperglycemia, an indicator for severe EV71 infection
Summary
Encephalitis and cardiopulmonary failure are the most critical complications occurring in young children or in immunocompromised hosts with EV71 infections [1,2]. Approximately 10% of all EV71 patients presented with these severe complications, with a mortality rate of up to 40% in children with cardiopulmonary failure [3,4]. Among the genetic variants of galectin-3, rs4644 is one of the two major single nucleotide polymorphisms (SNPs) with minor allele frequency of > 5%. An European study revealed that the elderly carriers of rs4644 AA genotype had higher levels of C-reactive protein (CRP) [20]. These results suggest that this genetic variant of galectin-3 may be associated with inflammatory status in human diseases. We intended to evaluate whether galectin-3 and its variant, rs4644, affect EV71 infection in both laboratory and clinical settings
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