Fatal progression of experimental visceral leishmaniasis is associated with secondary infection by commensal bacteria and severe anaemia.

Tue10  Apr03:15pm(15 mins)
Where:
Stream 1 - Edward Llwyd 0.26 Biology Main
Speaker:

Authors

M D Lewis2; A Paun1; A R Romano1; H Langston2; D L Sacks1
1 Laboratory of Parasitic Diseases, National Institutes of Health, NIAID, United States;  2 London School of Hygiene and Tropical Medicine, UK

Discussion

The canonical target organs for Leishmania donovani are spleen, liver, bone marrow and lymph nodes. Using qPCR and histology we observed that in the hamster, a model of progressive, fatal VL, the GI tract was also a site of intense parasitism. GI infection was not detected in mice, in which VL is much less severe. We therefore reasoned that the host-microbiota homeostasis could be perturbed by L. donovani in hamsters, and that this could contribute to VL outcome.  To address this, we induced intestinal dysbiosis using broad spectrum antibiotic treatment prior to and during L. donovani infection in both hamsters and mice. This treatment had no impact in the mouse model. Treated hamsters had delayed onset and progression of weight loss, and significantly less severe hepatosplenomegaly. Antibiotic-treated hamsters also had a significant survival advantage compared to untreated controls. However, parasite loads in the liver and spleen were not significantly different between groups and they did not correlate with progression. Only marginal differences in immune response profiles were observed. Protection from VL in antibiotic-treated hamsters was associated with reduced susceptibility to secondary bacterial infection, revealed through immunohistochemical detection of lipopolysaccharide in the liver. Further multiparametric analysis of blood biomarkers identified anaemia as the strongest overall correlate of VL progression. Therefore, VL in the hamster model is associated with bacterial sepsis and severe anaemia, potentially linked to parasitism of the GI tract. We conclude that these factors, rather than L. donovani parasite loads, are the main drivers of fatal VL disease progression.

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