Dengue virus (DENV) is the most prevalent mosquito-borne flavivirus. Severe disease including dengue shock syndrome has an abrupt onset when fever and viraemia are abating. Serum bacterial lipopolysaccharide levels correlate with disease severity in patients (1,2), and gut-related symptoms are included amongst the warning signs for severe disease. We hypothesised that gut barrier breakdown and influx of inflammatory bacterial products is a key factor promoting severe disease and could account for sudden deteriorations. We examined the time course of appearance of DENV-infected cells in various tissues in mouse models of DENV infection. Following the peak of DENV replication in the spleen of AG129 and IFNAR-/- mice, infected cells appeared in the small intestine and colon, prior to substantial infection in other tissues. Major inflammatory pathology was seen in the gut, accompanied by elevated cytokine and chemokine expression, transient gut barrier breakdown and diarrhoea. However, pathology in other tissues was relatively mild. Gut pathology scores as well as cytokine and DENV RNA levels in the colon and liver were decreased in mice treated with an antibiotic cocktail, suggesting pathogenic roles for gut bacteria. Gut inflammation and leak are frequently associated with dysbiosis, and the faecal microbiome was substantially altered by day 3 of DENV infection. We propose that microbiome change and influx of bacterial products when the gut becomes leaky promotes inflammation and liver infection, and exacerbates dengue disease. Supporting our conclusions, a recent study directly demonstrated the loss of gut epithelial barrier integrity in severe dengue patients (2). Inhibiting innate immune activation by bacterial products, supporting healthy microbiota or maintaining gut barrier integrity may help to limit disease severity.
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