Background: Dengue virus, a mosquito-borne flavivirus, is endemic in the equatorial area, infecting 390 million people out of .9 billion living in the region annually. There have been many efforts to reverse its spread, and reduce mortality and morbidity, however, the number of new cases is not decreasing. Thus, dengue pathogenesis needs to be studied for development of treatments to reduce the severity of the disease. Published work has shown LPS is elevated in dengue patients, and it is possible that influx of bacterial products contributes to severe dengue disease.
Aim: To investigate the contribution of the microbiota to disease in a mouse model of dengue virus infection, using an antibiotic cocktail (ampicillin, vancomycin, neomycin, metronidazole) and germ-free (GF) mice.
Results: Antibiotic treatment greatly decreased bacterial load. In dengue virus-infected mice, antibiotics led to decreased diarrhoea as well as inflammatory pathology and cytokine/chemokine mRNA in the colon but not ileum, whilst having no clear effect on morbidity or viral titre. When GF mice were infected with dengue virus, they still got substantial gut inflammation. The re-establishment of normal gut flora in the GF mice did not affect viremia, serum NS1 level, morbidity, ileum and colon pathology scores, but GF mice with flora had more severe diarrhoea whilst having less inflammation in the stomach.
Conclusion: Results of antibiotic treatment support the hypothesis that bacteria or bacterial products contribute to colon inflammation and diarrhoea during dengue infection. Surprisingly, GF mice did not have lower colon inflammation, and in fact showed an elevated inflammatory response in the stomach relative to GF mice recolonised with bacteria. The discrepancy between antibiotic and GF results may be a function of abnormal development of the immune system in GF mice, with exacerbated inflammatory responses. The effect of antibiotics most likely indicates a role for bacteria rather than a non-specific anti-inflammatory effect, since inflammation was not reduced in the ileum, which has a much lower bacterial load.